(1/1571) Daunorubicin-induced apoptosis in rat cardiac myocytes is inhibited by dexrazoxane.

-The clinical efficacy of anthracycline antineoplastic agents is limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. In primary cultures of neonatal and adult rat ventricular myocytes, we found that daunorubicin, at concentrations /=10 micromol/L induced necrotic cell death within 24 hours, with no changes characteristic of apoptosis. To determine whether reactive oxygen species play a role in daunorubicin-mediated apoptosis, we monitored the generation of hydrogen peroxide with dichlorofluorescein (DCF). However, daunorubicin (1 micromol/L) did not increase DCF fluorescence, nor were the antioxidants N-acetylcysteine or the combination of alpha-tocopherol and ascorbic acid able to prevent apoptosis. In contrast, dexrazoxane (10 micromol/L), known clinically to limit anthracycline cardiac toxicity, prevented daunorubicin-induced myocyte apoptosis, but not necrosis induced by higher anthracycline concentrations (>/=10 micromol/L). The antiapoptotic action of dexrazoxane was mimicked by the superoxide-dismutase mimetic porphyrin manganese(II/III)tetrakis(1-methyl-4-peridyl)porphyrin (50 micromol/L). The recognition that anthracycline-induced cardiac myocyte apoptosis, perhaps mediated by superoxide anion generation, occurs at concentrations well below those that result in myocyte necrosis, may aid in the design of new therapeutic strategies to limit the toxicity of these drugs.  (+info)

(2/1571) Pharmacokinetic analysis of the cardioprotective effect of 3-(2,2, 2-trimethylhydrazinium) propionate in mice: inhibition of carnitine transport in kidney.

The site of action of 3-(2,2,2-trimethylhydrazinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. I.p. administration of THP decreased the concentrations of free carnitine and long-chain acylcarnitine in heart tissue. In isolated myocytes, THP inhibited free carnitine transport with a Ki of 1340 microM, which is considerably higher than the observed serum concentration of THP. The major cause of the decreased free carnitine concentration in heart was found to be the decreased serum concentration of free carnitine that resulted from the increased renal clearance of carnitine by THP. The estimated Ki of THP for inhibiting the reabsorption of free carnitine in kidneys was 52.2 microM, which is consistent with the serum THP concentration range. No inhibition of THP on the carnitine palmitoyltransferase activity in isolated mitochondrial fractions was observed. These results indicate that the principal site of action of THP as a cardioprotective agent is the carnitine transport carrier in the kidney, but not the carrier in the heart.  (+info)

(3/1571) Treatment patterns for heart failure in a primary care environment.

Little published information regarding current pharmacotherapeutic treatment patterns for congestive heart failure (CHF) in nonacademic, ambulatory care settings is available. We sought to assess, in a nonacademic primary care environment, pharmacotherapeutic treatment patterns for CHF with respect to consistency with clinical trial evidence and published treatment guideline recommendations. Over an 18-month period, we examined CHF pharmacotherapy using a computerized, integrated clinical diagnoses and prescription database from an outpatient community healthcare center without academic affiliations. We identified adult patients meeting contact criteria and with diagnosis of CHF by International Classification of Diseases (ICD-9-CM) coding and assessed prescribed therapy as well as select comorbid conditions. Drugs of interest included those with known or suspected benefit or detriment and those with unproven benefit. An eligible group of 14,983 patients was identified, from which a cohort of 148 patients with CHF was selected. Forty-one percent of these 148 patients were prescribed an angiotensin converting enzyme (ACE) inhibitor, 34% digoxin, 12% diuretic, 12% hydralazine + nitrate, 20% inhaled beta-agonists, and 66% warfarin. Only 5% of patients were prescribed the combination of an ACE inhibitor, digoxin, and diuretic. Thirty-one percent had a comorbid diagnosis of atrial fibrillation, of whom 44% were prescribed digoxin, 22% diltiazem, 15% beta-blockers, 15% digoxin and diltiazem, 7% digoxin and a beta-blocker, and 33% warfarin. In general, recommended therapies for CHF appeared underutilized in this cohort, whereas those of unclear benefit and potential detriment appeared overutilized. Although these results may not be readily generalized to the entire healthcare system, they do suggest a need for additional analysis and potential intervention.  (+info)

(4/1571) Antagonism by acetyl-RYYRIK-NH2 of G protein activation in rat brain preparations and of chronotropic effect on rat cardiomyocytes evoked by nociceptin/orphanin FQ.

For the further elucidation of the central functions of nociceptin/orphanin FQ (noc/OFQ), the endogenous ligand of the G protein-coupled opioid receptor-like receptor ORL1, centrally acting specific antagonists will be most helpful. In this study it was found that the hexapeptide acetyl-RYYRIK-NH2 (Ac-RYYRIK-NH2), described in literature as partial agonist on ORL1 transfected in CHO cells, antagonizes the stimulation of [35S]-GTPgammaS binding to G proteins by noc/OFQ in membranes and sections of rat brain. The antagonism of the peptide was competitive, of high affinity (Schild constant 6.58 nM), and specific for noc/OFQ in that the stimulation of GTP binding by agonists for the mu-, delta-, and kappa-opioid receptor was not inhibited. The hexapeptide also fully inhibited the chronotropic effect of noc/OFQ on neonatal rat cardiomyocytes. It is suggested that Ac-RYYRIK-NH2 may provide a promising starting point for in vivo tests for antagonism of the action of noc/OFQ and for the further development of highly active and specific antagonists.  (+info)

(5/1571) Acute anti-ischemic effect of testosterone in men with coronary artery disease.

BACKGROUND: The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men. METHODS AND RESULTS: After withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05). CONCLUSIONS: Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.  (+info)

(6/1571) Drug-induced heart failure.

Heart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure.  (+info)

(7/1571) Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice.

1. We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) alpha2-adrenoceptors and at endogenous (dog) alpha2A-adrenoceptors. 2. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 microg kg(-1), i.v.) and clonidine (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3. In D79N alpha2A-adrenoceptor mice, responses to rilmenidine and moxonidine did not differ from vehicle control. Clonidine-induced hypotension was absent, but dose-dependent hypertension and bradycardia were observed. 4. In wild-type mice, responses to moxonidine (1 mg kg(-1), i.v.) were antagonized by the non-selective, non-imidazoline alpha2-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5. Affinity estimates (pKi) at human alpha2A-, alpha2B- and alpha2C-adrenoceptors, respectively, were: rilmenidine (5.80, 5.76 and 5.33), moxonidine (5.37, <5 and <5) and clonidine (7.21, 7.16 and 6.87). In a [35S]-GTPgammaS incorporation assay, moxonidine and clonidine were alpha2A-adrenoceptor agonists (pEC50/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). 6. In dog saphenous vein, concentration-dependent contractions were observed (pEC50/intrinsic activity relative to noradrenaline): rilmenidine (5.83/0.70), moxonidine (6.48/0.98) and clonidine (7.22/0.83). Agonist-independent affinities were obtained with RS-79948-197. 7. Thus, expression of alpha2A-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice. There was no evidence of I1-imidazoline receptor-mediated effects. The ability of these compounds to act as alpha2A-adrenoceptor agonists in vitro supports this conclusion.  (+info)

(8/1571) Effects of a novel cardioprotective drug, JTV-519, on membrane currents of guinea pig ventricular myocytes.

We investigated effects of a novel cardioprotective drug, JTV-519 (4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahy dro-1,4-benzothiazepine monohydrochloride) on membrane currents of guinea pig ventricular myocytes by whole-cell voltage and current clamp methods. The fast Na+ current (iNa) was activated by ramp pulses from various holding potentials of -90, -80 or -60 mV to 10 mV with various intervals. At 0.2 Hz, JTV-519 inhibited iNa in a concentration-dependent manner with an IC50 of approximately 1.2 and 2 microM at the holding potential of -60 and -90 mM, respectively, implicating a voltage-dependent block. Increasing the pulse frequency from 1 to 2 or 3.3 Hz in the presence of 1 microM JTV-519 shortened the time-course and increased the level of iNa block, indicating a frequency-dependent block. The time-course of iNa blocking by JTV-519 was slower than that of lidocaine and similar to that of quinidine. Ca2+ current (iCa) and the inwardly rectifying K+ current (iK1) were also inhibited by JTV-519. JTV-519 decreased the duration and the height of the plateau of the action potential. We conclude that JTV-519 has frequency- and voltage-dependent blocking effects on iNa as well as inhibition of iCa and iK1.  (+info)