Angiotensin-Converting Enzyme Inhibitors: A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility.Enalapril: An angiotensin-converting enzyme inhibitor that is used to treat HYPERTENSION and HEART FAILURE.Captopril: A potent and specific inhibitor of PEPTIDYL-DIPEPTIDASE A. It blocks the conversion of ANGIOTENSIN I to ANGIOTENSIN II, a vasoconstrictor and important regulator of arterial blood pressure. Captopril acts to suppress the RENIN-ANGIOTENSIN SYSTEM and inhibits pressure responses to exogenous angiotensin.Lisinopril: One of the ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACE inhibitors), orally active, that has been used in the treatment of hypertension and congestive heart failure.Angiotensin Receptor Antagonists: Agents that antagonize ANGIOTENSIN RECEPTORS. Many drugs in this class specifically target the ANGIOTENSIN TYPE 1 RECEPTOR.Perindopril: An angiotensin-converting enzyme inhibitor. It is used in patients with hypertension and heart failure.Enalaprilat: The active metabolite of ENALAPRIL and a potent intravenously administered angiotensin-converting enzyme inhibitor. It is an effective agent for the treatment of essential hypertension and has beneficial hemodynamic effects in heart failure. The drug produces renal vasodilation with an increase in sodium excretion.Antihypertensive Agents: Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat.Angiotensin II Type 1 Receptor Blockers: Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS.Cilazapril: One of the ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACE inhibitors) used for hypertension. It is a prodrug that is hydrolyzed after absorption to its main metabolite cilazaprilat.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Teprotide: A synthetic nonapeptide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) which is identical to the peptide from the venom of the snake, Bothrops jararaca. It inhibits kininase II and ANGIOTENSIN I and has been proposed as an antihypertensive agent.Renin-Angiotensin System: A BLOOD PRESSURE regulating system of interacting components that include RENIN; ANGIOTENSINOGEN; ANGIOTENSIN CONVERTING ENZYME; ANGIOTENSIN I; ANGIOTENSIN II; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming ANGIOTENSIN I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to ANGIOTENSIN II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal VASCULAR SMOOTH MUSCLE, leading to retention of salt and water in the KIDNEY and increased arterial blood pressure. In addition, angiotensin II stimulates the release of ALDOSTERONE from the ADRENAL CORTEX, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down BRADYKININ, a powerful vasodilator and component of the KALLIKREIN-KININ SYSTEM.Hypertension: Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.ThiazepinesBlood Pressure: PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS.TetrazolesRenin: A highly specific (Leu-Leu) endopeptidase that generates ANGIOTENSIN I from its precursor ANGIOTENSINOGEN, leading to a cascade of reactions which elevate BLOOD PRESSURE and increase sodium retention by the kidney in the RENIN-ANGIOTENSIN SYSTEM. The enzyme was formerly listed as EC Agents that promote the excretion of urine through their effects on kidney function.Adrenergic beta-Antagonists: Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Imidazolidines: Compounds based on reduced IMIDAZOLINES which contain no double bonds in the ring.Angioedema: Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.Tetrahydroisoquinolines: A group of ISOQUINOLINES in which the nitrogen containing ring is protonated. They derive from the non-enzymatic Pictet-Spengler condensation of CATECHOLAMINES with ALDEHYDES.Losartan: An antagonist of ANGIOTENSIN TYPE 1 RECEPTOR with antihypertensive activity due to the reduced pressor effect of ANGIOTENSIN II.3-Mercaptopropionic Acid: An inhibitor of glutamate decarboxylase. It decreases the GAMMA-AMINOBUTYRIC ACID concentration in the brain, thereby causing convulsions.Angiotensin II: An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the C-terminal by ANGIOTENSIN CONVERTING ENZYME. The amino acid in position 5 varies in different species. To block VASOCONSTRICTION and HYPERTENSION effect of angiotensin II, patients are often treated with ACE INHIBITORS or with ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS.Bradykinin: A nonapeptide messenger that is enzymatically produced from KALLIDIN in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from MAST CELLS during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter.Heart Failure: A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (VENTRICULAR DYSFUNCTION), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as MYOCARDIAL INFARCTION.Peptidyl-Dipeptidase A: A peptidyl-dipeptidase that catalyzes the release of a C-terminal dipeptide, -Xaa-*-Xbb-Xcc, when neither Xaa nor Xbb is Pro. It is a Cl(-)-dependent, zinc glycoprotein that is generally membrane-bound and active at neutral pH. It may also have endopeptidase activity on some substrates. (From Enzyme Nomenclature, 1992) EC Therapy, Combination: Therapy with two or more separate preparations given for a combined effect.Kinins: A generic term used to describe a group of polypeptides with related chemical structures and pharmacological properties that are widely distributed in nature. These peptides are AUTACOIDS that act locally to produce pain, vasodilatation, increased vascular permeability, and the synthesis of prostaglandins. Thus, they comprise a subset of the large number of mediators that contribute to the inflammatory response. (From Goodman and Gilman's The Pharmacologic Basis of Therapeutics, 8th ed, p588)Proteinuria: The presence of proteins in the urine, an indicator of KIDNEY DISEASES.Angiotensin I: A decapeptide that is cleaved from precursor angiotensinogen by RENIN. Angiotensin I has limited biological activity. It is converted to angiotensin II, a potent vasoconstrictor, after the removal of two amino acids at the C-terminal by ANGIOTENSIN CONVERTING ENZYME.Biphenyl CompoundsFosinopril: A phosphinic acid-containing angiotensin-converting enzyme inhibitor that is effective in the treatment of hypertension. It is a prodrug that is converted to its active metabolite fosinoprilat.Rats, Inbred SHR: A strain of Rattus norvegicus with elevated blood pressure used as a model for studying hypertension and stroke.Saralasin: An octapeptide analog of angiotensin II (bovine) with amino acids 1 and 8 replaced with sarcosine and alanine, respectively. It is a highly specific competitive inhibitor of angiotensin II that is used in the diagnosis of HYPERTENSION.Receptors, Bradykinin: Cell surface receptors that bind BRADYKININ and related KININS with high affinity and trigger intracellular changes which influence the behavior of cells. The identified receptor types (B-1 and B-2, or BK-1 and BK-2) recognize endogenous KALLIDIN; t-kinins; and certain bradykinin fragments as well as bradykinin itself.Hyperkalemia: Abnormally high potassium concentration in the blood, most often due to defective renal excretion. It is characterized clinically by electrocardiographic abnormalities (elevated T waves and depressed P waves, and eventually by atrial asystole). In severe cases, weakness and flaccid paralysis may occur. (Dorland, 27th ed)Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Kidney: Body organ that filters blood for the secretion of URINE and that regulates ion concentrations.Angiotensins: Oligopeptides which are important in the regulation of blood pressure (VASOCONSTRICTION) and fluid homeostasis via the RENIN-ANGIOTENSIN SYSTEM. These include angiotensins derived naturally from precursor ANGIOTENSINOGEN, and those synthesized.Imidazoles: Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).Benzimidazoles: Compounds with a BENZENE fused to IMIDAZOLES.Sodium Chloride Symporter Inhibitors: Agents that inhibit SODIUM CHLORIDE SYMPORTERS. They act as DIURETICS. Excess use is associated with HYPOKALEMIA.Aldosterone: A hormone secreted by the ADRENAL CORTEX that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium.Hydrochlorothiazide: A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It is used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism.Cardiovascular Agents: Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Hydralazine: A direct-acting vasodilator that is used as an antihypertensive agent.Hypertension, Renal: Persistent high BLOOD PRESSURE due to KIDNEY DISEASES, such as those involving the renal parenchyma, the renal vasculature, or tumors that secrete RENIN.Receptor, Angiotensin, Type 1: An angiotensin receptor subtype that is expressed at high levels in a variety of adult tissues including the CARDIOVASCULAR SYSTEM, the KIDNEY, the ENDOCRINE SYSTEM and the NERVOUS SYSTEM. Activation of the type 1 angiotensin receptor causes VASOCONSTRICTION and sodium retention.Indoles: Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.Benzazepines: Compounds with BENZENE fused to AZEPINES.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Receptors, Angiotensin: Cell surface proteins that bind ANGIOTENSINS and trigger intracellular changes influencing the behavior of cells.Double-Blind Method: A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Hemodynamics: The movement and the forces involved in the movement of the blood through the CARDIOVASCULAR SYSTEM.Diabetic Nephropathies: KIDNEY injuries associated with diabetes mellitus and affecting KIDNEY GLOMERULUS; ARTERIOLES; KIDNEY TUBULES; and the interstitium. Clinical signs include persistent PROTEINURIA, from microalbuminuria progressing to ALBUMINURIA of greater than 300 mg/24 h, leading to reduced GLOMERULAR FILTRATION RATE and END-STAGE RENAL DISEASE.Mineralocorticoid Receptor Antagonists: Drugs that bind to and block the activation of MINERALOCORTICOID RECEPTORS by MINERALOCORTICOIDS such as ALDOSTERONE.Rats, Inbred WKY: A strain of Rattus norvegicus used as a normotensive control for the spontaneous hypertensive rats (SHR).Kidney Diseases: Pathological processes of the KIDNEY or its component tissues.Amlodipine: A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of ANGINA PECTORIS and HYPERTENSION.Proline: A non-essential amino acid that is synthesized from GLUTAMIC ACID. It is an essential component of COLLAGEN and is important for proper functioning of joints and tendons.Kidney Failure, Chronic: The end-stage of CHRONIC RENAL INSUFFICIENCY. It is characterized by the severe irreversible kidney damage (as measured by the level of PROTEINURIA) and the reduction in GLOMERULAR FILTRATION RATE to less than 15 ml per min (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002). These patients generally require HEMODIALYSIS or KIDNEY TRANSPLANTATION.Spironolactone: A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827)Hypertension, Renovascular: Hypertension due to RENAL ARTERY OBSTRUCTION or compression.Mopidamol: A phosphodiesterase inhibitor which inhibits platelet aggregation. Formerly used as an antineoplastic.Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to INULIN clearance.Dipeptides: Peptides composed of two amino acid units.Receptor, Bradykinin B2: A constitutively expressed subtype of bradykinin receptor that may play a role in the acute phase of the inflammatory and pain response. It has high specificity for intact forms of BRADYKININ and KALLIDIN. The receptor is coupled to G-PROTEIN, GQ-G11 ALPHA FAMILY and G-PROTEIN, GI-GO ALPHA FAMILY signaling proteins.Albuminuria: The presence of albumin in the urine, an indicator of KIDNEY DISEASES.Hydroxymethylglutaryl-CoA Reductase Inhibitors: Compounds that inhibit HMG-CoA reductases. They have been shown to directly lower cholesterol synthesis.CreatinineMyocardial Infarction: NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION).Oligohydramnios: A condition of abnormally low AMNIOTIC FLUID volume. Principal causes include malformations of fetal URINARY TRACT; FETAL GROWTH RETARDATION; GESTATIONAL HYPERTENSION; nicotine poisoning; and PROLONGED PREGNANCY.Cardiac Output, Low: A state of subnormal or depressed cardiac output at rest or during stress. It is a characteristic of CARDIOVASCULAR DISEASES, including congenital, valvular, rheumatic, hypertensive, coronary, and cardiomyopathic. The serious form of low cardiac output is characterized by marked reduction in STROKE VOLUME, and systemic vasoconstriction resulting in cold, pale, and sometimes cyanotic extremities.Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway.Cough: A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation. It is a protective response that serves to clear the trachea, bronchi, and/or lungs of irritants and secretions, or to prevent aspiration of foreign materials into the lungs.Fumarates: Compounds based on fumaric acid.Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).Heart Rate: The number of times the HEART VENTRICLES contract per unit of time, usually per minute.Oligopeptides: Peptides composed of between two and twelve amino acids.Ventricular Dysfunction, Left: A condition in which the LEFT VENTRICLE of the heart was functionally impaired. This condition usually leads to HEART FAILURE; MYOCARDIAL INFARCTION; and other cardiovascular complications. Diagnosis is made by measuring the diminished ejection fraction and a depressed level of motility of the left ventricular wall.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Renal Circulation: The circulation of the BLOOD through the vessels of the KIDNEY.Phenylmethylsulfonyl Fluoride: An enzyme inhibitor that inactivates IRC-50 arvin, subtilisin, and the fatty acid synthetase complex.Retrospective Studies: Studies used to test etiologic hypotheses in which inferences about an exposure to putative causal factors are derived from data relating to characteristics of persons under study or to events or experiences in their past. The essential feature is that some of the persons under study have the disease or outcome of interest and their characteristics are compared with those of unaffected persons.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Angiotensinogen: An alpha-globulin of about 453 amino acids, depending on the species. It is produced by the liver and secreted into blood circulation. Angiotensinogen is the inactive precursor of natural angiotensins. Upon successive enzyme cleavages, angiotensinogen yields angiotensin I, II, and III with amino acids numbered at 10, 8, and 7, respectively.Receptor, Angiotensin, Type 2: An angiotensin receptor subtype that is expressed at high levels in fetal tissues. Many effects of the angiotensin type 2 receptor such as VASODILATION and sodium loss are the opposite of that of the ANGIOTENSIN TYPE 1 RECEPTOR.Nephrectomy: Excision of kidney.Drug Utilization Review: Formal programs for assessing drug prescription against some standard. Drug utilization review may consider clinical appropriateness, cost effectiveness, and, in some cases, outcomes. Review is usually retrospective, but some analysis may be done before drugs are dispensed (as in computer systems which advise physicians when prescriptions are entered). Drug utilization review is mandated for Medicaid programs beginning in 1993.Hypertrophy, Left Ventricular: Enlargement of the LEFT VENTRICLE of the heart. This increase in ventricular mass is attributed to sustained abnormal pressure or volume loads and is a contributor to cardiovascular morbidity and mortality.Risk Factors: An aspect of personal behavior or lifestyle, environmental exposure, or inborn or inherited characteristic, which, on the basis of epidemiologic evidence, is known to be associated with a health-related condition considered important to prevent.Secondary Prevention: The prevention of recurrences or exacerbations of a disease or complications of its therapy.Randomized Controlled Trials as Topic: Works about clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table.Chronic Disease: Diseases which have one or more of the following characteristics: they are permanent, leave residual disability, are caused by nonreversible pathological alteration, require special training of the patient for rehabilitation, or may be expected to require a long period of supervision, observation, or care. (Dictionary of Health Services Management, 2d ed)Follow-Up Studies: Studies in which individuals or populations are followed to assess the outcome of exposures, procedures, or effects of a characteristic, e.g., occurrence of disease.Receptor, Bradykinin B1: A subtype of BRADYKININ RECEPTOR that is induced in response to INFLAMMATION. It may play a role in chronic inflammation and has a high specificity for KININS lacking the C-terminal ARGININE such as des-Arg(10)-kallidin and des-Arg(9)-bradykinin. The receptor is coupled to G-PROTEIN, GQ-G11 ALPHA FAMILY and G-PROTEIN, GI-GO ALPHA FAMILY signaling proteins.Digitalis: A genus of toxic herbaceous Eurasian plants of the Plantaginaceae which yield cardiotonic DIGITALIS GLYCOSIDES. The most useful species are Digitalis lanata and D. purpurea.Cyclohexanones: Cyclohexane ring substituted by one or more ketones in any position.Dogs: The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)Ventricular Function, Left: The hemodynamic and electrophysiological action of the left HEART VENTRICLE. Its measurement is an important aspect of the clinical evaluation of patients with heart disease to determine the effects of the disease on cardiac performance.Practice Guidelines as Topic: Directions or principles presenting current or future rules of policy for assisting health care practitioners in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery.Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group.Doxazosin: A prazosin-related compound that is a selective alpha-1-adrenergic blocker.Digoxin: A cardiotonic glycoside obtained mainly from Digitalis lanata; it consists of three sugars and the aglycone DIGOXIGENIN. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in ATRIAL FIBRILLATION and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. (From Martindale, The Extra Pharmacopoeia, 30th ed, p666)Organ Size: The measurement of an organ in volume, mass, or heaviness.Angiotensin II Type 2 Receptor Blockers: Agents that antagonize the ANGIOTENSIN II TYPE 2 RECEPTOR.Kidney Glomerulus: A cluster of convoluted capillaries beginning at each nephric tubule in the kidney and held together by connective tissue.Atenolol: A cardioselective beta-1 adrenergic blocker possessing properties and potency similar to PROPRANOLOL, but without a negative inotropic effect.Aspirin: The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia, 30th ed, p5)Diet, Sodium-Restricted: A diet which contains very little sodium chloride. It is prescribed by some for hypertension and for edematous states. (Dorland, 27th ed)Drug Utilization: The utilization of drugs as reported in individual hospital studies, FDA studies, marketing, or consumption, etc. This includes drug stockpiling, and patient drug profiles.Guideline Adherence: Conformity in fulfilling or following official, recognized, or institutional requirements, guidelines, recommendations, protocols, pathways, or other standards.Neprilysin: Enzyme that is a major constituent of kidney brush-border membranes and is also present to a lesser degree in the brain and other tissues. It preferentially catalyzes cleavage at the amino group of hydrophobic residues of the B-chain of insulin as well as opioid peptides and other biologically active peptides. The enzyme is inhibited primarily by EDTA, phosphoramidon, and thiorphan and is reactivated by zinc. Neprilysin is identical to common acute lymphoblastic leukemia antigen (CALLA Antigen), an important marker in the diagnosis of human acute lymphocytic leukemia. There is no relationship with CALLA PLANT.Hypotension: Abnormally low BLOOD PRESSURE that can result in inadequate blood flow to the brain and other vital organs. Common symptom is DIZZINESS but greater negative impacts on the body occur when there is prolonged depravation of oxygen and nutrients.Kidney Function Tests: Laboratory tests used to evaluate how well the kidneys are working through examination of blood and urine.Cardiovascular Diseases: Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Cardiotonic Agents: Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE).Aminopeptidases: A subclass of EXOPEPTIDASES that act on the free N terminus end of a polypeptide liberating a single amino acid residue. EC 3.4.11.Myocardium: The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.Systole: Period of contraction of the HEART, especially of the HEART VENTRICLES.Bicyclo CompoundsEndothelins: 21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, ENDOTHELIN-1; ENDOTHELIN-2; and ENDOTHELIN-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides.Furosemide: A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for EDEMA and chronic RENAL INSUFFICIENCY.Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.Indapamide: A benzamide-sulfonamide-indole derived DIURETIC that functions by inhibiting SODIUM CHLORIDE SYMPORTERS.Benzoates: Derivatives of BENZOIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxybenzene structure.Disease Progression: The worsening of a disease over time. This concept is most often used for chronic and incurable diseases where the stage of the disease is an important determinant of therapy and prognosis.Vascular Resistance: The force that opposes the flow of BLOOD through a vascular bed. It is equal to the difference in BLOOD PRESSURE across the vascular bed divided by the CARDIAC OUTPUT.Rats, Inbred Strains: Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding.Cross-Over Studies: Studies comparing two or more treatments or interventions in which the subjects or patients, upon completion of the course of one treatment, are switched to another. In the case of two treatments, A and B, half the subjects are randomly allocated to receive these in the order A, B and half to receive them in the order B, A. A criticism of this design is that effects of the first treatment may carry over into the period when the second is given. (Last, A Dictionary of Epidemiology, 2d ed)PyridazinesEndothelin-1: A 21-amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. (N Eng J Med 1995;333(6):356-63)Sulfinpyrazone: A uricosuric drug that is used to reduce the serum urate levels in gout therapy. It lacks anti-inflammatory, analgesic, and diuretic properties.Stroke Volume: The amount of BLOOD pumped out of the HEART per beat, not to be confused with cardiac output (volume/time). It is calculated as the difference between the end-diastolic volume and the end-systolic volume.Cyclooxygenase Inhibitors: Compounds or agents that combine with cyclooxygenase (PROSTAGLANDIN-ENDOPEROXIDE SYNTHASES) and thereby prevent its substrate-enzyme combination with arachidonic acid and the formation of eicosanoids, prostaglandins, and thromboxanes.Cardiology: The study of the heart, its physiology, and its functions.Heart: The hollow, muscular organ that maintains the circulation of the blood.Nephrotic Syndrome: A condition characterized by severe PROTEINURIA, greater than 3.5 g/day in an average adult. The substantial loss of protein in the urine results in complications such as HYPOPROTEINEMIA; generalized EDEMA; HYPERTENSION; and HYPERLIPIDEMIAS. Diseases associated with nephrotic syndrome generally cause chronic kidney dysfunction.Benzothiadiazines: Heterocyclic compounds of a ring with SULFUR and two NITROGEN atoms fused to a BENZENE ring. Members inhibit SODIUM-POTASSIUM-CHLORIDE SYMPORTERS and are used as DIURETICS.Renal Insufficiency: Conditions in which the KIDNEYS perform below the normal level in the ability to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of PROTEINURIA) and reduction in GLOMERULAR FILTRATION RATE.Kallikreins: Proteolytic enzymes from the serine endopeptidase family found in normal blood and urine. Specifically, Kallikreins are potent vasodilators and hypotensives and increase vascular permeability and affect smooth muscle. They act as infertility agents in men. Three forms are recognized, PLASMA KALLIKREIN (EC, TISSUE KALLIKREIN (EC, and PROSTATE-SPECIFIC ANTIGEN (EC Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Thiorphan: A potent inhibitor of membrane metalloendopeptidase (ENKEPHALINASE). Thiorphan potentiates morphine-induced ANALGESIA and attenuates naloxone-precipitated withdrawal symptoms.Amides: Organic compounds containing the -CO-NH2 radical. Amides are derived from acids by replacement of -OH by -NH2 or from ammonia by the replacement of H by an acyl group. (From Grant & Hackh's Chemical Dictionary, 5th ed)Vasodilation: The physiological widening of BLOOD VESSELS by relaxing the underlying VASCULAR SMOOTH MUSCLE.Acute Kidney Injury: Abrupt reduction in kidney function. Acute kidney injury encompasses the entire spectrum of the syndrome including acute kidney failure; ACUTE KIDNEY TUBULAR NECROSIS; and other less severe conditions.IndolizinesHypertension, Malignant: A condition of markedly elevated BLOOD PRESSURE with DIASTOLIC PRESSURE usually greater than 120 mm Hg. Malignant hypertension is characterized by widespread vascular damage, PAPILLEDEMA, retinopathy, HYPERTENSIVE ENCEPHALOPATHY, and renal dysfunction.Diabetes Mellitus, Type 2: A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY.Receptors, Endothelin: Cell surface proteins that bind ENDOTHELINS with high affinity and trigger intracellular changes which influence the behavior of cells.Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic.Sodium, Dietary: Sodium or sodium compounds used in foods or as a food. The most frequently used compounds are sodium chloride or sodium glutamate.Felodipine: A dihydropyridine calcium antagonist with positive inotropic effects. It lowers blood pressure by reducing peripheral vascular resistance through a highly selective action on smooth muscle in arteriolar resistance vessels.Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Fees, Pharmaceutical: Amounts charged to the patient or third-party payer for medication. It includes the pharmacist's professional fee and cost of ingredients, containers, etc.Vasodilator Agents: Drugs used to cause dilation of the blood vessels.Cardiomyopathy, Dilated: A form of CARDIAC MUSCLE disease that is characterized by ventricular dilation, VENTRICULAR DYSFUNCTION, and HEART FAILURE. Risk factors include SMOKING; ALCOHOL DRINKING; HYPERTENSION; INFECTION; PREGNANCY; and mutations in the LMNA gene encoding LAMIN TYPE A, a NUCLEAR LAMINA protein.Physician's Practice Patterns: Patterns of practice related to diagnosis and treatment as especially influenced by cost of the service requested and provided.Severity of Illness Index: Levels within a diagnostic group which are established by various measurement criteria applied to the seriousness of a patient's disorder.Metalloendopeptidases: ENDOPEPTIDASES which use a metal such as ZINC in the catalytic mechanism.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Body Weight: The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms.Bronchial Spasm: Spasmodic contraction of the smooth muscle of the bronchi.Glomerulonephritis, IGA: A chronic form of glomerulonephritis characterized by deposits of predominantly IMMUNOGLOBULIN A in the mesangial area (GLOMERULAR MESANGIUM). Deposits of COMPLEMENT C3 and IMMUNOGLOBULIN G are also often found. Clinical features may progress from asymptomatic HEMATURIA to END-STAGE KIDNEY DISEASE.Cohort Studies: Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics.Sodium: A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23.Ventricular Remodeling: The geometric and structural changes that the HEART VENTRICLES undergo, usually following MYOCARDIAL INFARCTION. It comprises expansion of the infarct and dilatation of the healthy ventricle segments. While most prevalent in the left ventricle, it can also occur in the right ventricle.Atrial Natriuretic Factor: A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight PEPTIDES derived from a common precursor and secreted mainly by the HEART ATRIUM. All these peptides share a sequence of about 20 AMINO ACIDS.Dihydralazine: 1,4-Dihydrazinophthalazine. An antihypertensive agent with actions and uses similar to those of HYDRALAZINE. (From Martindale, The Extra Pharmacopoeia, 30th ed, p354)Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable.Metoprolol: A selective adrenergic beta-1 blocking agent that is commonly used to treat ANGINA PECTORIS; HYPERTENSION; and CARDIAC ARRHYTHMIAS.United StatesCardiomegaly: Enlargement of the HEART, usually indicated by a cardiothoracic ratio above 0.50. Heart enlargement may involve the right, the left, or both HEART VENTRICLES or HEART ATRIA. Cardiomegaly is a nonspecific symptom seen in patients with chronic systolic heart failure (HEART FAILURE) or several forms of CARDIOMYOPATHIES.Drug Synergism: The action of a drug in promoting or enhancing the effectiveness of another drug.Aspartic Acid Endopeptidases: A sub-subclass of endopeptidases that depend on an ASPARTIC ACID residue for their activity.Thiazolidines: Reduced (protonated) form of THIAZOLES. They can be oxidized to THIAZOLIDINEDIONES.NG-Nitroarginine Methyl Ester: A non-selective inhibitor of nitric oxide synthase. It has been used experimentally to induce hypertension.Evidence-Based Medicine: An approach of practicing medicine with the goal to improve and evaluate patient care. It requires the judicious integration of best research evidence with the patient's values to make decisions about medical care. This method is to help physicians make proper diagnosis, devise best testing plan, choose best treatment and methods of disease prevention, as well as develop guidelines for large groups of patients with the same disease. (from JAMA 296 (9), 2006)Glycopeptides: Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight.Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system.Drug Prescriptions: Directions written for the obtaining and use of DRUGS.Coronary Artery Disease: Pathological processes of CORONARY ARTERIES that may derive from a congenital abnormality, atherosclerotic, or non-atherosclerotic cause.Glomerulosclerosis, Focal Segmental: A clinicopathological syndrome or diagnostic term for a type of glomerular injury that has multiple causes, primary or secondary. Clinical features include PROTEINURIA, reduced GLOMERULAR FILTRATION RATE, and EDEMA. Kidney biopsy initially indicates focal segmental glomerular consolidation (hyalinosis) or scarring which can progress to globally sclerotic glomeruli leading to eventual KIDNEY FAILURE.Diabetes Mellitus: A heterogeneous group of disorders characterized by HYPERGLYCEMIA and GLUCOSE INTOLERANCE.Renal Artery Obstruction: Narrowing or occlusion of the RENAL ARTERY or arteries. It is due usually to ATHEROSCLEROSIS; FIBROMUSCULAR DYSPLASIA; THROMBOSIS; EMBOLISM, or external pressure. The reduced renal perfusion can lead to renovascular hypertension (HYPERTENSION, RENOVASCULAR).Risk Assessment: The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. (Last, Dictionary of Epidemiology, 1988)Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (CORONARY ARTERY DISEASE), to obstruction by a thrombus (CORONARY THROMBOSIS), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (MYOCARDIAL INFARCTION).Random Allocation: A process involving chance used in therapeutic trials or other research endeavor for allocating experimental subjects, human or animal, between treatment and control groups, or among treatment groups. It may also apply to experiments on inanimate objects.Diabetes Complications: Conditions or pathological processes associated with the disease of diabetes mellitus. Due to the impaired control of BLOOD GLUCOSE level in diabetic patients, pathological processes develop in numerous tissues and organs including the EYE, the KIDNEY, the BLOOD VESSELS, and the NERVE TISSUE.Drinking: The consumption of liquids.Aorta: The main trunk of the systemic arteries.Indomethacin: A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes.

The interaction of rhodium(II) carboxylates with enzymes. (1/39504)

The effect of rhodium(II) acetate, propionate, and methoxyacetate on the activity of 17 enzymes was evaluated. The enzymes were preincubated with the rhodium(II) complexes in order to detect irreversible inhibition. All enzymes that have essential sulfhydryl groups in or near their active site were found to be irreversibly inhibited. Those enzymes without essential sulfhydryl groups were not affected. In each case, the rate of inactivation closely paralleled the observed toxicity and antitumor activity of rhodium(II) carboxylates; that is, rhodium(II) propionate greater than rhodium(II) acetate greater than rhodium(II) methoxyacetate. In addition, those enzymes that have been demonstrated to be most sensitive to established sulfhydryl inhibitors, such as glyceraldehyde-3-phosphate dehydrogenase, were also most sensitive to rhodium(II) carboxylate inactivation. Proton nuclear magnetic resonance measurements made during the titration of rhodium(II) acetate with cysteine showed that breakdown of the carboxylate cage occurred as a result of reaction with this sulfhydryl-containing amino acid.  (+info)

Does gill boundary layer carbonic anhydrase contribute to carbon dioxide excretion: a comparison between dogfish (Squalus acanthias) and rainbow trout (Oncorhynchus mykiss). (2/39504)

In vivo experiments were conducted on spiny dogfish (Squalus acanthias) and rainbow trout (Oncorhynchus mykiss) in sea water to determine the potential role of externally oriented or gill boundary layer carbonic anhydrase in carbon dioxide excretion. This was accomplished by assessing pH changes in expired water using a stopped-flow apparatus. In dogfish, expired water was in acid-base disequilibrium as indicated by a pronounced acidification (delta pH=-0.11+/-0.01; N=22; mean +/- s.e.m.) during the period of stopped flow; inspired water, however, was in acid-base equilibrium (delta pH=-0.002+/-0.01; N=22). The acid-base disequilibrium in expired water was abolished (delta pH=-0.005+/-0.01; N=6) by the addition of bovine carbonic anhydrase (5 mg l-1) to the external medium. Addition of the carbonic anhydrase inhibitor acetazolamide (1 mmol l-1) to the water significantly reduced the magnitude of the pH disequilibrium (from -0.133+/-0.03 to -0.063+/-0.02; N=4). However, after correcting for the increased buffering capacity of the water caused by acetazolamide, the acid-base disequilibrium during stopped flow was unaffected by this treatment (control delta [H+]=99.8+/-22.8 micromol l-1; acetazolamide delta [H+]=81.3+/-21.5 micromol l-1). In rainbow trout, expired water displayed an acid-base disequilibrium (delta pH=0.09+/-0.01; N=6) that also was abolished by the application of external carbonic anhydrase (delta pH=0.02+/-0.01). The origin of the expired water acid-base disequilibrium was investigated further in dogfish. Intravascular injection of acetazolamide (40 mg kg-1) to inhibit internal carbonic anhydrase activity non-specifically and thus CO2 excretion significantly diminished the extent of the expired water disequilibrium pH after 30 min (from -0.123+/-0.01 to -0.065+/-0.01; N=6). Selective inhibition of extracellular carbonic anhydrase activity using a low intravascular dose (1.3 mg kg-1) of the inhibitor benzolamide caused a significant reduction in the acid-base disequilibrium after 5 min (from -0.11+/-0.01 to -0.07+/-0. 01; N=14). These results demonstrate that the expired water acid-base disequilibrium originates, at least in part, from excretory CO2 and that extracellular carbonic anhydrase in dogfish may have a significant role in carbon dioxide excretion. However, externally oriented carbonic anhydrase (if present in dogfish) plays no role in catalysing the hydration of the excretory CO2 in water flowing over the gills and thus is unlikely to facilitate CO2 excretion.  (+info)

A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. (3/39504)

Mouse cytomegalovirus (MCMV) early gene expression interferes with the major histocompatibility complex class I (MHC class I) pathway of antigen presentation. Here we identify a 48 kDa type I transmembrane glycoprotein encoded by the MCMV early gene m06, which tightly binds to properly folded beta2-microglobulin (beta2m)-associated MHC class I molecules in the endoplasmic reticulum (ER). This association is mediated by the lumenal/transmembrane part of the protein. gp48-MHC class I complexes are transported out of the ER, pass the Golgi, but instead of being expressed on the cell surface, they are redirected to the endocytic route and rapidly degraded in a Lamp-1(+) compartment. As a result, m06-expressing cells are impaired in presenting antigenic peptides to CD8(+) T cells. The cytoplasmic tail of gp48 contains two di-leucine motifs. Mutation of the membrane-proximal di-leucine motif of gp48 restored surface expression of MHC class I, while mutation of the distal one had no effect. The results establish a novel viral mechanism for downregulation of MHC class I molecules by directly binding surface-destined MHC complexes and exploiting the cellular di-leucine sorting machinery for lysosomal degradation.  (+info)

p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. (4/39504)

Genetic screens in Drosophila have identified p50(cdc37) to be an essential component of the sevenless receptor/mitogen-activated kinase protein (MAPK) signaling pathway, but neither the function nor the target of p50(cdc37) in this pathway has been defined. In this study, we examined the role of p50(cdc37) and its Hsp90 chaperone partner in Raf/Mek/MAPK signaling biochemically. We found that coexpression of wild-type p50(cdc37) with Raf-1 resulted in robust and dose-dependent activation of Raf-1 in Sf9 cells. In addition, p50(cdc37) greatly potentiated v-Src-mediated Raf-1 activation. Moreover, we found that p50(cdc37) is the primary determinant of Hsp90 recruitment to Raf-1. Overexpression of a p50(cdc37) mutant which is unable to recruit Hsp90 into the Raf-1 complex inhibited Raf-1 and MAPK activation by growth factors. Similarly, pretreatment with geldanamycin (GA), an Hsp90-specific inhibitor, prevented both the association of Raf-1 with the p50(cdc37)-Hsp90 heterodimer and Raf-1 kinase activation by serum. Activation of Raf-1 via baculovirus coexpression with oncogenic Src or Ras in Sf9 cells was also strongly inhibited by dominant negative p50(cdc37) or by GA. Thus, formation of a ternary Raf-1-p50(cdc37)-Hsp90 complex is crucial for Raf-1 activity and MAPK pathway signaling. These results provide the first biochemical evidence for the requirement of the p50(cdc37)-Hsp90 complex in protein kinase regulation and for Raf-1 function in particular.  (+info)

Cyclin D-CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. (5/39504)

The D-type cyclins and their major kinase partners CDK4 and CDK6 regulate G0-G1-S progression by contributing to the phosphorylation and inactivation of the retinoblastoma gene product, pRB. Assembly of active cyclin D-CDK complexes in response to mitogenic signals is negatively regulated by INK4 family members. Here we show that although all four INK4 proteins associate with CDK4 and CDK6 in vitro, only p16(INK4a) can form stable, binary complexes with both CDK4 and CDK6 in proliferating cells. The other INK4 family members form stable complexes with CDK6 but associate only transiently with CDK4. Conversely, CDK4 stably associates with both p21(CIP1) and p27(KIP1) in cyclin-containing complexes, suggesting that CDK4 is in equilibrium between INK4 and p21(CIP1)- or p27(KIP1)-bound states. In agreement with this hypothesis, overexpression of p21(CIP1) in 293 cells, where CDK4 is bound to p16(INK4a), stimulates the formation of ternary cyclin D-CDK4-p21(CIP1) complexes. These data suggest that members of the p21 family of proteins promote the association of D-type cyclins with CDKs by counteracting the effects of INK4 molecules.  (+info)

Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. (6/39504)

Recent results have shown that the ability of farnesyltransferase inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously that farnesylated Rho proteins are important targets for alternation by FTIs, based on studies of RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with loss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in Ras-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects were similar to FTI treatment insofar as they were all induced in transformed cells but not in normal cells. RhoB-GG did not promote anoikis of Ras-transformed cells, implying that this response to FTIs involves loss-of-function effects. Our findings corroborate the FTI-Rho hypothesis and demonstrate that gain-of-function effects on Rho are part of the drug mechanism. Gain of RhoB-GG may explain how FTIs inhibit the growth of human tumor cells that lack Ras mutations.  (+info)

Neu differentiation factor stimulates phosphorylation and activation of the Sp1 transcription factor. (7/39504)

Neu differentiation factors (NDFs), or neuregulins, are epidermal growth factor-like growth factors which bind to two tyrosine kinase receptors, ErbB-3 and ErbB-4. The transcription of several genes is regulated by neuregulins, including genes encoding specific subunits of the acetylcholine receptor at the neuromuscular junction. Here, we have examined the promoter of the acetylcholine receptor epsilon subunit and delineated a minimal CA-rich sequence which mediates transcriptional activation by NDF (NDF-response element [NRE]). Using gel mobility shift analysis with an NRE oligonucleotide, we detected two complexes that are induced by treatment with neuregulin and other growth factors and identified Sp1, a constitutively expressed zinc finger phosphoprotein, as a component of one of these complexes. Phosphatase treatment, two-dimensional gel electrophoresis, and an in-gel kinase assay indicated that Sp1 is phosphorylated by a 60-kDa kinase in response to NDF-induced signals. Moreover, Sp1 seems to act downstream of all members of the ErbB family and thus may funnel the signaling of the ErbB network into the nucleus.  (+info)

Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. (8/39504)

To investigate the mode of action of the p16(INK4a) tumor suppressor protein, we have established U2-OS cells in which the expression of p16(INK4a) can be regulated by addition or removal of isopropyl-beta-D-thiogalactopyranoside. As expected, induction of p16(INK4a) results in a G1 cell cycle arrest by inhibiting phosphorylation of the retinoblastoma protein (pRb) by the cyclin-dependent kinases CDK4 and CDK6. However, induction of p16(INK4a) also causes marked inhibition of CDK2 activity. In the case of cyclin E-CDK2, this is brought about by reassortment of cyclin, CDK, and CDK-inhibitor complexes, particularly those involving p27(KIP1). Size fractionation of the cellular lysates reveals that a substantial proportion of CDK4 participates in active kinase complexes of around 200 kDa. Upon induction of p16(INK4a), this complex is partly dissociated, and the majority of CDK4 is found in lower-molecular-weight fractions consistent with the formation of a binary complex with p16(INK4a). Sequestration of CDK4 by p16(INK4a) allows cyclin D1 to associate increasingly with CDK2, without affecting its interactions with the CIP/KIP inhibitors. Thus, upon the induction of p16(INK4a), p27(KIP1) appears to switch its allegiance from CDK4 to CDK2, and the accompanying reassortment of components leads to the inhibition of cyclin E-CDK2 by p27(KIP1) and p21(CIP1). Significantly, p16(INK4a) itself does not appear to form higher-order complexes, and the overwhelming majority remains either free or forms binary associations with CDK4 and CDK6.  (+info)

  • A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant , which indicates the concentration needed to inhibit the enzyme). (
  • Thus, CA9 is a possible therapeutic target, and the inhibitor SLC-0111 shows more than 100-fold specificity against CA9, versus two other forms of human carbonic anhydrases, CA1 or CA2. (
  • The potent inhibitor MLN-4760 ((S,S)-2-[1-carboxy-2-[3-(3,5-dichlorobenzyl)-3H-imidazol4-yl]-ethylamino]-4-methylpentanoic acid) makes key binding interactions within the active site and offers insights regarding the action of residues involved in catalysis and substrate specificity. (
  • 3. The advantages offered by the novel inhibitor binding assay include simplicity, specificity, absence of interference by other enzymes or immunological cross-reactions, and great sensitivity enabling measurement of ACE in concentrations less than 0.1 units/ml. (
  • 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride Specificity: Specific irreversible inhibitor of serine proteases, including chymotrypsin, kallikrein, plasmin, thrombin and trypsin. (
  • Researchmoz added Most up-to-date research on "Global Dissociation Enzyme-Inhibitor Complex Industry 2018, Trends and Forecast Report" to its huge collection of research reports. (
  • The UWA researchers-in collaboration with colleagues at the Fiona Wood Foundation, Royal Perth Hospital Burns Unit, and Pharmaxis, all in Australia-are studying compounds that inhibit the enzyme lysyl oxidase. (
  • When studying the action of enzymes on biological processes it if often useful to inhibit the enzyme of interest. (
  • Other cellular enzyme inhibitors are proteins that specifically bind to and inhibit an enzyme target. (
  • Normally, the NMT enzymes add a fatty acid to the end of certain proteins in a reaction called myristoylation, explained Marc B. Hershenson, MD, Huetwell Professor of Pediatrics and Communicable Diseases and professor of molecular and integrative physiology at the University of Michigan Medical School, Ann Arbor. (
  • These enzymes wreak havoc inside the bodies of venomous snake-bite victims by causing widespread breakdown of important proteins (proteolyisis) in the tissue surroundings blood vessels and within cells themselves. (
  • Because most types of cancer cells have normal BRCA proteins, PARP inhibitors are less effective on them. (
  • Features and Benefits Use cOmplete Protease Inhibitor Tablets to protect your proteins from a wide range of proteases. (
  • This system provides information on trypanosomal proteins with useful annotations, including the protein structure from the Protein Data Bank (PDB) and the protein inhibitors from ChEMBL. (
  • However, while studies have shown a preventive benefit for ACE inhibitors, there are no such studies for ARBs. (
  • We found no reliable difference between ACE inhibitors and ARBs for total deaths, deaths due to heart disease, or total heart disease and stroke. (
  • However, our conclusions alone cannot be taken to mean that ARBs would show similar benefit like ACE inhibitors if compared with placebo (a dummy treatment). (
  • ARBs do have a 1.8% lower chance of being stopped due to side effects over 4.1 years, meaning that for every 55 people treated with an ARB instead of an ACE inhibitor for 4.1 years, one person would be spared from a side effect leading to stopping the drug. (
  • Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors, while ARBs caused slightly fewer WDAEs than ACE inhibitors. (
  • Thus, the substitution of an ARB for an ACE inhibitor, while supported by evidence on grounds of tolerability, must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors. (
  • However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo -controlled trials, ARBs have not. (
  • In order to carry out its function, the UDG enzyme first identifies the damaged DNA by locating uracil residues and then attaches itself to the DNA to repair it. (
  • Comparison of these structures revealed a large inhibitor-dependent hinge-bending movement of one catalytic subdomain relative to the other ( approximately 16 degrees ) that brings important residues into position for catalysis. (
  • Bisdemethoxycurcumin from Curcuma longa rhizome is a potent small molecule inhibitor of human pancreatic α-amylase, a target for type-2 diabetes. (
  • Knowing from previous work that the viruses use a human enzyme, N-myristoyltransferases 1 and 2 (NMT), to make their protein coat, the investigators developed a small molecule inhibitor of NMT. (
  • The researchers are now studying the efficacy of inhibitors in animal models and hope to start human trials of topical nanoformulations in a few years. (
  • Indeed there are no large clinical trials comparing the efficacy of one ACE inhibitor with another to determine which one best improves survival. (
  • Philadelphia, PA, September 9, 2016 - Many acute and chronic liver diseases, including alcoholic hepatitis, result from apoptotic (programmed) cell death mediated by the enzyme caspase. (
  • Objectives: In this study, we attempt to design potent inhibitor specifically targeting the enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis. (
  • A well-characterised example of this is the ribonuclease inhibitor , which binds to ribonucleases in one of the tightest known protein-protein interactions . (
  • 2007), recounting how the viral protein p56 manages to inhibit the activity of the UDG enzyme. (
  • Their experiments show that the protein p56 conceals the part of the UDG enzyme that interacts with the damaged DNA so that there is no possibility of attachment. (
  • The protein p56 might accomplish this by imitating the structural characteristics of DNA in order to mislead the UDG enzyme. (
  • Rather than directly entering the binding pocket the inhibitor appears to roll on the surface of the protein in its transition between S3 and the final binding pocket, whereas the transition between S2 and the bound pose requires rediffusion to S3. (
  • And the fact that the inhibitor targets a human protein and not the virus itself minimizes the likelihood of the emergence of resistant viral strains . (
  • The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is a type I integral membrane protein of 805 amino acids that contains one HEXXH + E zinc-binding consensus sequence. (
  • Background: The enoyl-acyl carrier protein (ACP) reductase enzyme (FabI) is the target for a series of antimicrobial agents including novel compounds in clinical trial and the biocide triclosan. (
  • The present invention is a cosmetic composition comprising a water-soluble protein-based film-forming agent, the film-forming agent having a tertiary structure capable of undergoing a helix-coil transformation, a protease inhibitor in an amount sufficient to protect the protein on the stratum corneum. (
  • All ACE inhibitors bind to tissue and plasma protein. (
  • The protein interacts with its cognate ubiquitin-conjugating enzyme (E2), Ube2g2, via its RING domain and a unique region called G2BR that strongly binds to E2. (
  • Scientists at Tokyo Tech, Nagasaki University have identified four potential protein inhibitors and unlocked drug discovery strategies for the treatment of Chagas disease by using advanced three-dimensional computer simulation by supercomputer TSUBAME in combination with in vitro experiments and X-ray crystallography. (
  • An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity . (
  • Penicillin covalently binds to the enzyme transpeptidase that links the peptidoglycan molecules in bacteria, it inhibits the molecule so that it cannot react any further and cell wall cannot be further synthesized. (
  • To ensure consistent performance, Thermo Scientific restriction enzyme reaction buffers contain premixed BSA, which enhances the stability of many enzymes and binds contaminants that may be present in DNA preparations. (
  • By analyzing the structures of their initial DAGL inhibitors, the team was also able to devise a new DAGL-tailored activity-based probe that binds to the active site of DAGLs and fluorescently labels these low-abundance and difficult-to-detect enzymes in cell or tissue samples. (
  • The compounds have dehydropeptidase (DHP) enzyme inhibitor activity. (
  • The sera of Virginia opossum avoid toxic reactions to snake venom by containing compounds that block the key enzymes in the venom. (
  • Entomogenous fungi have been probed for putative small molecule drug compounds among their secondary metabolites, but until now no tyrosinase inhibitors have been found. (
  • The invention relates to the use of compounds derived from piperadinyl-methyl-tetrazole-quinolinone and derived from diphenyl-triazolo- pyrimidine as inhibitors of the reparative action of the DNA produced by enzyme O6-alkylguanine-DNA-methyltransferase, and to pharmaceutical compositions containing same, for the preparation of coadjuvant drugs for use in antitumour therapy using alkylating agents. (
  • Cravatt's laboratory had previously developed a set of compounds that act as potent inhibitors of serine hydrolases-the broad enzyme family to which DAGL enzymes belong. (
  • In the new study, Cravatt's team, including first author Ken Hsu, a Hewitt Foundation postdoctoral researcher in the Cravatt laboratory, screened a library of these compounds for specific activity as DAGL inhibitors. (
  • Following selection, potential drug candidate inhibitors were identified through a screening search known as docking simulation-a structure-based drug design approach using 3D simulations to computationally match drug compounds to SpdSyn. (
  • The regression seen in this combination therapy of temozolomide and the inhibitor SLC-0111 - which targets the enzyme carbonic anhydrase 9, or CA9 - was greater than that seen with either SLC-0111 or temozolomide alone, says research leader Anita Hjelmeland, Ph.D., assistant professor in the Department of Cell, Developmental and Integrative Biology at the University of Alabama at Birmingham . (
  • These agents increase the vasodilatory effects of nitric oxide by inhibiting the enzyme phosphodiesterase type 5, which in turn increases sensitivity for erections. (
  • Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. (
  • Alpha-linolenic acid inhibits angiotensin-converting enzyme activity in hypertensive rats. (
  • In the present study, we investigated the inhibitory effects of four tea catechins, including (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECg) and (−)-epigallocatechin gallate (EGCg), on angiotensin converting enzyme (ACE) activity in vitro . (
  • The Virginia opossum is able to block the activity of metalloproteinase enzymes thereby neutralizing their toxic effects. (
  • Among the anthocyanins, cyanidin 3-arabinoside possessed the strongest and cyanidin 3-xyloside the weakest radical scavenging and enzyme inhibitory activity. (
  • This activity implies that tyrosinase inhibitors are likely to exist among the many secondary metabolites of entomopathogenic fungi and might be a useful source of natural insecticides. (
  • According to the experimental results, using DFP (diisopropyl fluorophosphate) and PMSF (phenylmethanesulfonyl fluoride) as inhibitors almost 50% of the enzyme activity could be inhibited when their concentrations were 0.525 and 0.541 mM, respectively. (
  • Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. (
  • All of the enzymes exhibit 100% activity in the recommended buffer and reaction conditions. (
  • In neuron-like mouse cells, human prostate cancer cells, and mouse liver cells and macrophages (a type of immune cell that is frequently involved in inflammatory conditions), the DAGL inhibitors were able to inactivate DAGLβ activity. (
  • Here, we have been able to quantitatively reconstruct the complete binding process of the enzyme-inhibitor complex trypsin-benzamidine by performing 495 molecular dynamics simulations of free ligand binding of 100 ns each, 187 of which produced binding events with an rmsd less than 2 Å compared to the crystal structure. (
  • The global market for enzyme inhibitors should reach $179.9 billion by 2022 from $168 billion in 2017 at a compound annual growth rate (CAGR) of 1.4%, from 2017 to 2022. (
  • Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology . (
  • University of Texas at Arlington) Biologists at the University of Texas at Arlington have demonstrated that removing water molecules can deactivate caspase-3 enzymes, which opens new doors for treatment of autoimmune diseases like arthritis, which have been linked to overactive enzymes. (
  • A family of molecules known as NTS enzyme inhibitors are promising candidates for new herpes virus treatments, a new study shows. (
  • ST. LOUIS - Saint Louis University research findings published in the December issue of Antimicrobial Agents and Chemotherapy report a family of molecules known as nucleotidyltransferase superfamily (NTS) enzyme inhibitors are promi. (
  • Biologists at The University of Texas at Arlington have demonstrated that removing water molecules can deactivate caspase-3 enzymes, which opens new doors for treatment of autoimmune diseases like arthritis, which have been linked t. (
  • That's why doctors in the field are so excited about a new category of drugs called PARP inhibitors. (
  • PARP - short for poly (ADP-ribose) polymerase - enzymes regulate the process by which our bodies repair damaged DNA. (
  • Ovarian cancer is one of these types of cancer, and PARP inhibitors are a hot new field of study for the disease. (
  • At the annual meeting of the American Society of Clinical Oncology in June, the excitement over PARP combating ovarian cancer was palpable, driven by a new phase II study of a PARP inhibitor called olaparib. (
  • Like many "targeted therapies," PARP inhibitors don't necessarily have the same effectiveness against everyone with a certain type of cancer (like ovarian or breast cancer). (
  • The drug was effective in those women too, which significantly expands the pool of ovarian cancer patients that olaparib or another PARP inhibitor might benefit. (
  • When the scientists blocked CDK1 in cancer cell lines, BRCA1 function was disrupted, making the cells susceptible to being killed by a PARP inhibitor. (
  • The new findings, Shapiro said in a press release, "suggest that by blocking CDK1, we can disable BRCA1 in many types of cancers and make them sensitive to a PARP inhibitor. (
  • This volume reviews important progress on the chemical biology of enzymes in the post-genomic era. (
  • The new inhibitors, and chemical probes based on them, now can be used to study the functions of enzymes known as diacylglycerol lipases (DAGL), their products, and the pathways they regulate. (
  • We've developed the first set of chemical probes that effectively allows one to study these DAGL enzymes in living cell and animal models," said Benjamin F. Cravatt, chairman of the Department of Chemical Physiology, professor in the Dorris Neuroscience Center and member of the Skaggs Institute for Chemical Biology at TSRI. (