Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate whether hemodynamic tolerance develops to nicorandil, a nitrate and potassium channel opener, 14 patients with chronic heart failure (CHF) were treated with nicorandil and 11 were treated with nitroglycerin (GTN). Doses of GTN or nicorandil were titrated to achieve a > or = 20% reduction in pulmonary capillary wedge pressure (PCWP) within 1 hour, and the infusion was maintained at a constant rate for 24 hours. Both groups of patients had comparable hemodynamic parameters before drug infusions were started. The fall in PCWP was identical after 1 hour infusion of either GTN or nicorandil. In the GTN group, PCWP was not significantly different from the baseline value at 12 hours; however, in the nicorandil group, PCWP remained significantly lower than the preinfusion value for 24 hours. During the study period changes in plasma atrial natriuretic peptide (ANP) concentrations paralleled and correlated with changes in PCWP (r = 0.84, p < 0.001). These findings indicate that CHF patients develop hemodynamic tolerance to GTN within 12 hours of continuous infusion, but not to nicorandil, which remained hemodynamically effective during the 24-hour period of infusion. Furthermore, plasma ANP concentration may be a useful noninvasive index of hemodynamic tolerance during GTN or nicorandil therapy in patients with CHF.
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PMID:Absence of hemodynamic tolerance to nicorandil in patients with severe congestive heart failure. 815 25

Despite the increasing insight in the clinical importance of nitric oxide (NO), formerly known as endothelium-derived relaxing factor (EDRF), there is limited information about the metabolism and elimination of this mediator in humans. We studied the degradation of NO in healthy subjects inhaling 25 ppm for 60 minutes and in patients with severe heart failure inhaling 20, 40, and 80 ppm in consecutive 10-minute periods. In other healthy subjects, the renal clearance of NO metabolite was measured. The metabolism ex vivo was evaluated by direct incubation of nitrite, the NO oxidation product, in blood from healthy humans. During inhalation of NO, the plasma levels of nitrate increased progressively, both in the healthy subjects (from 26 to 38 mumol/L, P < .001) and in the patients (from 72 to 90 mumol/L, P < .001). Methemoglobin (MetHb) also increased in the healthy subjects (from 7 to 13 mumol/L, P < .001) as well as in the patients (from 19 to 42 mumol/L, P < .01). No change in nitrosohemoglobin (HbNO) was detected, either in the healthy subjects or in the patients. In arterialized blood (O2 saturation, 94% to 99%), incubated nitrite was semiquantitatively converted to nitrate and MetHb. In venous blood (O2 saturation, 36% to 85%) moderate amounts of HbNO were also formed. Plasma and urinary clearance of nitrate in healthy subjects averaged 20 mL/min. We conclude that uptake into the red blood cells with subsequent conversion to nitrate and MetHb is a major metabolic pathway for endogenously formed NO. Nitrate may then enter the plasma to be eliminated via the kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism and excretion of nitric oxide in humans. An experimental and clinical study. 822 83

Vasodilator therapy has been utilized for the treatment of congestive heart failure in the last 20 years. These drugs contribute to increase cardiac output, decrease peripheral vascular resistance and favour venous dilatation. Recent multicenter trials have addressed the issue of the impact of vasodilator therapy upon survival. Thus, the VHEFT-I and Consensus studies have shown that both the combination of nitrates and hydralazine and ACF inhibitors improve life expectancy in patients with moderate and severe heart failure. Moreover, the SOLVD study showed that ACE inhibitors improve survival and reduce cardiac events in patients with mild heart failure and depressed myocardial function at the end of 2 years of follow-up. The VHEFT II trial compared the effects of the nitrate-hydralazine combination versus ACE inhibitors upon the clinical course of patients with moderate heart failure. This last trial showed that although nitrates and hydralazine exerted a slightly better benefit upon exercise tolerance and left ventricular ejection fraction, patients that were treated with ACE inhibitors had a significantly reduced mortality. Differences in mortality when both groups of vasodilators drugs were compared were due to reduction of arrhythmias and sudden death. It is likely that this greater benefit obtained with ACE inhibitors when compared to nitrates and hydralazine in heart failure might be due to their favourable effects upon the abnormal neurohormonal activation observed in this syndrome. Thus ACE inhibitors have turned out to be one of the cornerstones in the treatment of congestive heart failure.
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PMID:[Vasodilator agents in chronic heart failure: which is the best option?]. 823 72

In this revision article, after referring the mechanisms of action of nitrates in the relief of heart failure symptoms, the author presents the results of the controlled studies which show the beneficial effect of the nitrates on heart failure symptoms and mortality. The results of the therapy with nitrates are compared to other heart failure therapies, such as the administration of the angiotensin conversion enzyme (ACE) inhibitors. In spite of the highly favourable results regarding mortality shown by the latest studies with ACE inhibitors, the nitrates still occupy an essential place in the therapy of patients with heart failure, since they have the advantage of a much faster onset of action and are more effective in relieving symptoms than ACE inhibitors. Ancient problems of controversial clinical significance are focused such as resistance and tolerance to nitrates, its clinical implications, and possible methods for prevention of nitrate tolerance and resistance are reviewed. Finally, the author suggests some dosage and administration routes of the nitrates in heart failure, giving attention to particular clinical groups, namely the elderly and other special cases, and their adverse events.
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PMID:[Nitrates in the treatment of congestive heart failure]. 828 41

Objective of the present study was to investigate the hemodynamic response to molsidomine in nitrate tolerance state. In 13 out of 16 patients (5 women, 11 men, 62 [53/71] years [median, 25%/75%-percentiles]) with chronic heart failure (NYHA stage II-III; median angiographic ejection fraction (EF) 55%) and coronary artery disease (stenosis of at least 75%) the development of tolerance under the continuous infusion of high doses of nitroglycerin (10 mg/h) was observed. Tolerance was defined as a benefit loss of at least 50% of the initial nitroglycerin effect with respect to the pulmonary capillary wedge pressure. Compared to the state of tolerance to nitroglycerin the infusion of 10 mg molsidomine over 15 minutes resulted in significant changes of the median values (25%/75%-percentiles) of mean right atrial pressure from 16 (12/21) to 9 (5/12) mmHg (p < 0.01), mean pulmonary artery pressure from 37 (30/40) to 24 (20/30) mmHg (p < 0.001), mean pulmonary capillary wedge pressure from 22 (18/25) to 15 (10/22) mmHg (p < 0.01) and cardiac output from 4.1 (3.5/4.7) to 5.2 (4.2/5.6) l/min (p < 0.01). This action of molsidomine corresponded to a complete overcoming (> 100%) of the benefit loss observed during the development of nitrate tolerance with respect to all above-mentioned hemodynamic parameters. Under parallel maintainance of nitroglycerin infusion (10 mg/h) these hemodynamic effects of molsidomine, i.e. at least 90% of the peak effect, lasted for 147 (130/182) minutes (median, 25%/75%-percentiles). Baseline values, i.e. a loss of at least 75% of the molsidomine effect, were only reached after 363 (319/412) minutes (median, 25%/75%-percentiles).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hemodynamic effect of molsidomine in coronary patients with heart failure with clinically manifest nitrate tolerance]. 832 79

A series of 5-deoxy-5-(4-substituted piperazin-1-yl)-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared and evaluated for oral anti-ischemic activities. Inhibition of lysine-vasopressin-induced T-wave elevation in the electrocardiogram (ECG) of rats (angina pectoris model) served as a primary assay. Optimum activity was observed for the compounds with the aryl-heteroatom (O,S, or N)-propyl group. Among them, the phenylthiopropyl-substituted compound 13 exhibited the most potent activity. Furthermore, intraduodenal administration (i.d.) of 13 tended to decrease left ventricular end-diastolic pressure (LVEDP) in a propranolol-induced heart failure model (dogs) and showed a potent protective effect against reperfusion arrhythmia in rats. Thus, 13 (KF 14124) is under further study as an orally active nitrate.
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PMID:1,4:3,6-Dianhydrohexitol nitrate derivatives. I. Synthesis and antianginal activity of alkylpiperazine derivatives. 837 Jan 9

A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.
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PMID:1,4:3,6-Dianhydrohexitol nitrate derivatives. II. Synthesis and antianginal activity of aryl- or arylcarbonylpiperazine derivatives. 837 Jan 10

The efficacy of nitrates versus that of angiotensin-converting enzyme (ACE) inhibitors in heart failure may be evaluated based on 3 treatment aims: hemodynamic improvement, symptom relief, and survival benefit. Nitrates used in conjunction with hydralazine produce a relatively large increase in stroke volume and a prominent reduction of left ventricular filling pressure, whereas ACE inhibitors produce a comparatively modest increase in stroke volume with a prominent reduction in filling pressure. The effect of these drugs on arterial compliance has been evaluated using a modified Windkessel model of the circulation to define their mechanism of action. Nitrates appear to affect the large arteries and arterial bed as well as the venous circulation. Intermediate-term response to therapy is often evaluated by changes in exercise tolerance. A review of multicenter trials reveals that, although both ACE inhibitors and hydralazine/nitrate have favorable hemodynamic actions, the effect of hydralazine/nitrate on exercise capacity appears to be slightly better. ACE inhibitors and nitrates both may reduce dysfunctional myocardial remodeling, as evaluated in a canine model of chronic left ventricular dysfunction. The increase in the ejection fraction by these drugs and the decrease of plasma norepinephrine levels by ACE inhibitors may contribute to improved long-term survival. It appears, therefore, that the long-term benefits of nitrates and ACE inhibitors in heart failure probably relate to their ability both to affect cardiac remodelling and to relax vascular smooth muscle.
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PMID:Nitrates versus angiotensin-converting enzyme inhibitors for congestive heart failure. 837 97

The clinical syndrome of congestive heart failure remains a therapeutic dilemma and challenge for the physician in 1992. This is a disease process that appears to be increasing in frequency and continues to carry an unacceptably high mortality rate. For years it has been well recognized that the combination of digoxin, Lasix and vasodilator therapy improved symptoms in these patients and decreased hospitalization, but did not increase survival. It was not until 1986 that the combination of digoxin, Lasix, Isordil, and hydralazine was shown to increase survival. Further significant improvement in quality of life and survival has recently been established in three large clinical trials, and it is now safe to say that the standard of care for symptomatic congestive heart failure in 1992 is digoxin, furosemide, and an ACE inhibitor, with the survival trials favoring the ACE inhibitor enalapril. The IV inotropic drug dobutamine remains the mainstay of pharmacological therapy for the treatment of severely refractory heart failure. Unfortunately, the phosphodiesterase inhibitors--amrinone, milrinone, and enoximone--have demonstrated unacceptable clinical side effects and have been withdrawn from further clinical study. In spite of these promising developments, the mortality and morbidity of congestive heart failure remains unacceptably high, and continued investigation in the new fields of pharmacology and the pathophysiology of congestive heart failure still must be aggressively pursued.
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PMID:Inotropic therapy of the failing myocardium. 841 61

Nitrate tolerance is a clinical problem in patients with coronary artery disease and heart failure. Human internal mammary arteries and saphenous veins obtained intraoperatively were suspended in organ chambers, and isometric tension was measured. In the artery, nitroglycerin elicited a potent relaxation, which was significantly diminished after prolonged incubation with nitroglycerin (10(-6) M, 1 h). In contrast, no tolerance occurred in saphenous vein under the same conditions. However, incubation with 10(-5) M nitroglycerin also developed tolerance. Compared to nitroglycerin, the new cysteine-containing mononitrate SPM 5185 exhibited a lower sensitivity but comparable maximal relaxation in arteries and veins. In nitroglycerin-tolerant arteries and veins, SPM 5185 caused relaxations similar to those under control conditions. Our results show that in isolated blood vessels, vascular nitrate tolerance occurs more readily in the mammary artery than in the saphenous vein. SPM 5185 seems to be less prone to the development of tolerance, which may be advantageous during chronic nitrate therapy.
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PMID:Development of nitrate tolerance in human arteries and veins: comparison of nitroglycerin and SPM 5185. 858 81


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