Reaction of organic nitrate esters and S-nitrosothiols with reduced flavins: a possible mechanism of bioactivation.
(17/1442)
Organic nitrate esters, such as glyceryl trinitrate and isosorbide dinitrate, are a class of compounds used to treat a variety of vascular ailments. Their effectiveness relies on their ability to be bioactivated to nitric oxide (NO) which, in turn, relaxes vascular smooth muscle. Although there have been many biological studies that indicate that NO can be formed from organic nitrate esters in a biological environment, the chemical mechanism by which this occurs has yet to be established. Previous studies have implicated both flavins and thiols in organic nitrate ester bioactivation. Thus, we examined the chemical interactions of flavins and thiols with organic nitrate esters as a means of determining the role these species may play in NO production. Based on these studies we concluded that a reasonable chemical mechanism for organic nitrate ester bioactivation involves reduction to the organic nitrite ester followed by conversion to a nitrosothiol. The release of NO from nitrosothiols can occur via a variety of processes including reaction with dihydroflavins and NADH. (+info)
Coronary and myocardial metabolic effects of combined glyceryl trinitrate and propranolol administration. Observations in patients with and without coronary disease.
(18/1442)
Coronary haemodynamic and metabolic effects of propranolol and glyceryl trinitrate were studied in 12 patients with coronary artery disease and 5 without coronary heart disease, at rest and during tachycardia stress. Propranolol-associated reductions in indices of myocardial oxygen demand, left ventricle work, tension time, and left ventricle oxygen utilisation (LVVO2) were reversed when heart rate was controlled by atrial pacing. Adding glyceryl trinitrate at rest also restored heart rate but decreased the left ventricular work index and tension time index as coronary resistance declined paradoxically. Tachycardia-related increases in tension time index and LVVO2 were unchanged after propranolol, and ischaemia (angina, ST depression, and reduced lactate extraction) was not altered in most of the patients. During tachycardia, the addition of glyceryl trinitrate decreased the tension time index and LVVO2; angina recurred in only 4 patients, and ST depression and lactate extraction improved. Similar haemodynamic changes occurred in the patients with normal coronary arteries. In contrast with propranolol administered alone, propranolol plus glyceryl trinitrate enhances tachycardia tolerance and prevents tachycardia-induced manifestations of ischaemia. This action is attributed to glyceryl trinitrate-associated improvement in the adequacy of myocardial perfusion. (+info)
Impaired beta-adrenoceptor mediated venodilation in patients with diabetes mellitus.
(19/1442)
AIMS: We investigated whether venoconstriction by alpha-adrenoceptor stimulation, and venodilation by beta-adrenoceptor stimulation and nitroglycerin are altered in patients with diabetes mellitus (DM). METHODS: Eight male patients with non insulin-dependent DM and eight age-matched control subjects were included. The patients had neither hypertension nor hyperlipidaemia. Noradrenaline (1 to 512 ng min-1 ), isoprenaline (1 to 256 ng min-1 ) and nitroglycerin (0.5 to 128 ng min-1 ) were infused into a dorsal hand vein and its diameter was measured using a linear variable differential transformer. RESULTS: The venoconstricting response to noradrenaline and the venodilating response to nitroglycerin in DM patients were similar to those in control subjects, while the venodilation by isoprenaline was significantly (P<0.05) smaller in DM patients than in control subjects at the dose of 32 ng min-1 or more [32 ng min-1: 11.5% vs 29.8% (DM vs control subjects), 64 ng min-1: 19.0% vs 40.1%, 128 ng min-1: 25.2% vs 49.0%, 256 ng min-1: 34.3% vs 56.7%]. CONCLUSIONS: These data suggested that venoconstriction by alpha-adrenoceptor stimulation and venodilation by nitroglycerin are not altered, whereas venodilation by beta-adrenoceptor stimulation might be impaired in patients with DM. (+info)
Effect of NO donors on LV diastolic function in patients with severe pressure-overload hypertrophy.
(20/1442)
BACKGROUND: Previous experimental studies have shown that nitric oxide (NO) modulates cardiac function by an abbreviation of systolic contraction and an enhancement of diastolic relaxation. However, the response to NO donors of patients with severe pressure-overload hypertrophy and diastolic dysfunction is unknown. METHODS AND RESULTS: Intracoronary NO donors were given to 17 patients with severe aortic stenosis. A dose-response curve was obtained with nitroglycerin (30, 90, and 150 microg) in 11 patients and sodium nitroprusside (1, 2, and 4 microg/min) in 6. Left ventricular (LV) high-fidelity pressure measurements with simultaneous LV angiograms were performed at baseline and after the maximal dose of NO. The dose-response curve for intracoronary NO donors showed a marked fall in LV end-diastolic pressure, from 23 to 14 mm Hg (-39%; P<0.0001), whereas LV peak systolic pressure fell only slightly, from 206 to 196 mm Hg (-4%; P<0.01). End-diastolic chamber stiffness decreased from 0.12 to 0.07 mm Hg/mL (P<0.0001) and end-systolic stiffness from 1.6 to 1.3 mm Hg/mL (P<0.01). Heart rate, right atrial pressure, LV ejection fraction, the time constant of isovolumic pressure decay (tau), and LV filling rates remained unchanged. CONCLUSIONS: In patients with severe pressure-overload hypertrophy, intracoronary NO donors exert a marked decrease in LV end-diastolic pressure without affecting LV systolic pump function. Thus, the hypertrophied myocardium appears to be particularly susceptible to NO donors, with a marked improvement in diastolic function. (+info)
Nitric oxide and hemoglobin interactions in the vasculature.
(21/1442)
As an endothelium-derived relaxing factor, nitric oxide (NO) maintains blood flow and O2 transport to tissues. Under normal conditions a delicate balance exists in the vascular system between endothelium-derived NO, an antioxidant, and the pro-oxidant elements of the vascular system, O-2, and peroxynitrite (a by-product of the reaction of NO and superoxide); in addition there is a balance between neurogenic tonic contraction and NO-mediated relaxation. The former balance can be disrupted in favor of peroxynitrite and hydrogen peroxide under the conditions of ischemia/reperfusion. This review suggests that NO may be beneficial, not only in terms of its new potential in improving O2 transport without accompanying significant increase in tissue blood flow, but also in its ability to suppress the prooxidative reagents of the vascular systems. These include NO-mediated inhibition of transendothelial migration by leukocyte and the antioxidative effects of NO with regard to ischemia/reperfusion; the relevance of these hypotheses to systemic administration of NO donors is discussed. (+info)
Effect of 17beta-estradiol in hypercholesterolemic rabbits with severe endothelial dysfunction.
(22/1442)
17beta-Estradiol prevents early vascular lesion development and may also affect advanced atherosclerosis. To test the antiatherosclerotic effect of estrogen under conditions that resemble more advanced human atherosclerosis with severe endothelial dysfunction, we have investigated the effect of 17beta-estradiol in hypercholesterolemic rabbits treated with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Chronic L-NAME administration attenuated endothelial nitric oxide (EDNO)-mediated vascular responses leading to significantly accelerated atherosclerotic plaque development. 17beta-Estradiol treatment alone inhibited aortic lesion formation with concurrent increase in EDNO-mediated responses. The beneficial effect of estrogen persisted in the L-NAME-treated rabbits, suggesting that the antiatherogenic action of 17beta-estradiol involves NO-independent mechanisms as well. Serum cholesterol levels were not altered by any of the treatments. 17beta-Estradiol treatment significantly increased EDNO production under these conditions as well. The reduction in plaque size by 17beta-estradiol was always accompanied by increased EDNO production, suggesting a strong association between these two events. The results demonstrate that estrogen treatment may exert protection against atherosclerosis even in patients with severe endothelial dysfunction. (+info)
Alpha-adrenoceptor blockade prevents exercise-induced vasoconstriction of stenotic coronary arteries.
(23/1442)
OBJECTIVES: The study aimed to evaluate the role of alpha-adrenergic mechanisms during dynamic exercise in both normal and stenotic coronary arteries. BACKGROUND: Paradoxical vasoconstriction of stenotic coronary arteries has been reported during dynamic exercise and may be due to several factors such as alpha-adrenergic drive, a decreased release of nitric oxide, platelet aggregation with release of serotonin, or a passive collapse of the vessel wall. METHODS: Twenty-six patients were studied at rest, during two levels of supine bicycle exercise and after 1.6 mg sublingual nitroglycerin. The alpha-blocker phentolamine was given to 16 patients before exercise, five of whom had also taken a beta-adrenergic-blocker the same morning. Ten patients served as controls. The cross-sectional areas of a normal and a stenotic coronary vessel were determined by biplane quantitative coronary arteriography. RESULTS: In the normal vessel segments, coronary cross-sectional area did not change after phentolamine injection, but increased in all patient groups similarly during exercise. Although coronary vasoconstriction existed in stenotic vessel segments in control patients, phentolamine-treated patients showed exercise-induced vasodilation without difference in patients with and without chronic beta-blockade. CONCLUSIONS: Exercise-induced vasoconstriction of stenotic coronary arteries is prevented by intracoronary administration of phentolamine. There was no difference in coronary vasomotion between patients receiving phentolamine alone and patients receiving phentolamine in addition to a beta-blocker. This finding suggests that exercise-induced vasoconstriction is mediated not only by endothelial dysfunction but also by alpha-adrenergic mechanisms. (+info)
Determinants of the response of human blood vessels to nitric oxide donors in vivo.
(24/1442)
The potency of the nitric oxide (NO) donors glyceryltrinitrate (GTN) and 3-morpholinosydnonimine was compared in human dorsal hand veins, the radial artery, and the forearm resistance vessels. NO donors were more potent in veins and the radial artery (vessels with minimal basal NO-mediated dilatation) than in the resistance vascular bed (where basal NO is a major determinant of vascular tone). In contrast, 8-bromoguanosine 3',5'-cyclic monophosphate (a cGMP mimetic) was approximately equipotent in resistance arteries and veins and was less potent in the radial artery. Inhibition of phosphodiesterase V with dipyridamole did not alter the arteriovenous profile of GTN. Increasing the local concentration of NO in veins (by infusing sodium nitroprusside) reduced their sensitivity to GTN but not to 8-bromoguanosine 3',5'-cyclic monophosphate. Conversely, reducing endogenous NO production in the resistance vasculature led to time-dependent increases in the response to GTN. These data suggest that soluble guanylate cyclase rather than cGMP-dependent protein kinase or phosphodiesterase V is the site in the second messenger pathway that determines the arteriovenous profile of NO donors. Moreover, the sensitivity of soluble guanylate cyclase to NO donors might be regulated by the ambient concentration of NO, with increased local NO down-regulating the dilator response to NO donors. (+info)