oxadiazoles and Heart-Failure

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.. The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.. The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Diastole; Female; Heart Failure; Humans; Hypertension; Japan; Male; Middle Aged; Multicenter Studies as Topic; Oxadiazoles; Randomized Controlled Trials as Topic; Recovery of Function; Stroke Volume; Tetrazoles; Time Factors; Treatment Outcome; Vascular Stiffness; Ventricular Dysfunction, Left; Ventricular Function, Left; Young Adult

The effect of vasodilator Molsidomine (M) vs placebo on left ventricular dimensions and function measured by echocardiography was evaluated in a randomized study on 23 patients (pts) with refractory congestive heart failure (R CF) (NYHA class III-IV). The pts were randomized in two groups: group A (12 pts) received M, group B received an identical appearing placebo. Adequate echocardiograms were obtained before and one hour after 2 tablets of M (4 mg) or P; left ventricular end-diastolic and end-systolic diameters (LVEDD and LVESD), mean rate of circumferential shortening and left ventricular fractional shortening were calculated on the echocardiograms obtained. At the same time mean arterial pressure (MAP) and heart rate were measured. In group A, the single-dose test induced a significant reduction in LVEDD (74.1 +/- 7.2 to 72.1 +/- 7.1 mm; p less than 0.01), in LVESD (64.4 +/- 8.4 to 61.6 +/- 7.4 mm; p less than 0.01) and in MAP (96.5 +/- 8.3 to 85.4 +/- 7.2 mmHg; p less than 0.05). No significant changes were noted in the other parameters. Moreover, changes of parameters evaluated in group A between pts with idiopathic cardiomyopathy and pts with ischemic heart disease showed no statistical differences. Thus, acute Molsidomine therapy is effective in reducing left ventricular diameters and MAP in pts with RCF without changes of echocardiographic contractility indexes.

Topics: Adult; Aged; Blood Pressure; Double-Blind Method; Drug Evaluation; Echocardiography; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Molsidomine; Myocardial Contraction; Oxadiazoles; Random Allocation; Sydnones; Vasodilator Agents

The effects of molsidomine were studied in seven patients with refractory congestive heart failure by means of two-dimensional echocardiography. Four milligrams of molsidomine or placebo was sublingually administered in a double-blind crossover manner. End-diastolic dimension, end-systolic dimension, and mean velocity of circumferential fiber shortening were measured just below the mitral valve before drug or placebo administration and 1 hour later. No significant changes were observed with placebo. Heart rate and mean arterial pressure were not significantly modified with Molsidomine (80 to 83 bpm and 100 to 97 mm Hg, respectively). The reduction in end-diastolic dimension (67 to 61 mm; 9%; P less than 0.01) was slightly greater than the decline in end-systolic dimension (59 to 54 mm; 8%; p less than 0.01). The mean velocity of circumferential fiber shortening increased from 0.4 to 0.5 sec-1 but did not achieve statistical significance. Thus sublingual administration of molsidomine in patients with chronic heart failure reduces end-diastolic more than end-systolic dimension without effect on blood pressure, suggesting a predominant action on cardiac preload.

Topics: Echocardiography; Female; Heart Failure; Heart Ventricles; Humans; Male; Molsidomine; Myocardial Contraction; Oxadiazoles; Sydnones; Vasodilator Agents

Molsidomine, similar to nitrates, improves myocardial blood flow in hypoperfused, poststenotic myocardial regions, reduces left ventricular pressure and volumes, and leads to improvement in impaired regional wall motion. In patients with chronic, stable anginal pectoris who underwent long-term treatment with 2 mg of molsidomine three times daily there were reductions in ST segment depression of 45% and 9% at 1 and 3 hours after administration, respectively, and slight but statistically significant reductions in the rates of anginal attacks and nitrate consumption of 16% and 18%. Administration of 3 mg three times daily did not render more significant effects. Doubling the frequency of administration--that is, 2 mg six times daily--led to reductions in the rates of anginal attacks and nitrate consumption of 38% and 36%, respectively, and 4 mg led to a more marked reduction in ST segment depression of 57%. With administration of 8 mg of sustained-release molsidomine, a prolonged antiischemic effect was documented with reductions in ST segment depression of 74% at 1 hour and 31% at 8 hours after medication. In patients with congestive heart failure, 1 hour after administration of 4 mg of molsidomine there were significant reductions in systolic and diastolic pulmonary artery pressures of 25% and 30%, respectively. After 7 days of continuous treatment with 4 mg of molsidomine four times daily, comparable reductions in pulmonary artery pressure were observed. Thus molsidomine, in adequate dosages, elicits an unequivocal anti-ischemic and antianginal effect as well as a salutary reduction in left ventricular filling pressure.

Topics: Angina Pectoris; Blood Pressure; Clinical Trials as Topic; Drug Administration Schedule; Electrocardiography; Heart Failure; Heart Rate; Humans; Molsidomine; Nitrates; Oxadiazoles; Pulmonary Artery; Sydnones; Vasodilator Agents

The effect of molsidomine on hemodynamic properties was studied in 10 patients with chronic congestive heart failure in New York Heart Association functional classes III and IV. Ten patients with the same degree of heart failure served as control subjects. All patients were receiving standard therapy with digitalis and diuretics. Administration of a single dose of 4 mg of molsidomine orally in the initial phase resulted in significant decreases of pulmonary artery pressure, pulmonary capillary pressure, and right atrial pressure at rest and during exercise (p less than 0.01 and p less than 0.01, respectively). After long-term oral treatment with 4 mg of molsidomine three times daily over a period of 3 weeks, single dose administration of 4 mg of molsidomine orally again caused significant decreases of pulmonary artery, pulmonary capillary, and right atrial pressure at rest and during exercise (range p less than 0.01 to p less than 0.02). Cardiac output, heart rate, systemic arterial pressure, pulmonary artery resistance, and systemic arterial resistance were essentially unchanged.

Topics: Blood Pressure; Cardiac Output; Clinical Trials as Topic; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Pulmonary Artery; Sydnones; Vascular Resistance; Vasodilator Agents

In this report we describe the clinical and hemodynamic response of refractory cardiac failure to molsidomine. In the first part of the study the hemodynamic effects of a single oral dose of 2 or 4 mg of molsidomine were compared with placebo control in 23 patients. In the second phase the dose 8 to 24 mg/24 hours was used in nine patients with functional class III or IV symptoms over an average period of 28 months (range 7 to 42 months); a hemodynamic control study was performed. These data demonstrate that molsidomine has a hemodynamic effect on pulmonary artery pressure for 5 to 6 hours, that the peak effect is reached between 1 and 1 1/2 hours after oral intake, and that the clinical and hemodynamic benefits of molsidomine may be maintained in the long term in patients with particularly severe cardiac failure. The conditions of seven patients were clinically improved with treatment; significant reductions in mean right atrial, pulmonary artery, and pulmonary capillary pressures were observed.

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Pulmonary Artery; Radiography; Sydnones; Time Factors; Vasodilator Agents

Molsidomine, one of the sydnonimine group of drugs; the object of this study was to evaluate its efforts in refractory cardiac failure. In the first part of the study, the haemodynamic effects of a single oral dose of 2 or 4 mg of molsidomine were compared with placebo controls in 23 patients. This showed molsidomine to be an active venous vasodilator reducing pulmonary artery and right atrial pressures without changing cardiac index or systemic pressures. The peak effect was observed after 1 to 1,5 hours. In the second phase, molsidomine was used in 9 patients aged 32 to 71 years (mean 47 +/- 12 years) over an average period of 19 months (3,5 to 42 months). The maintenance dose varied from 8 to 24 mg/24 hours. These patients had refractory cardiac failure secondary to primary cardiomyopathy with dilatation (6 cases) or ischemic heart disease (3 cases). The 9 patients were in functional classes IV (5 cases) or III (4 cases). Four patients were theoretically good indications for transplantation. Haemodynamic control was performed 1,8 +/- 5 months after a washout period of 8 hours, and after initial right heart catheterisation, the measurements were repeated 1 hour after oral administration of a 4 mg dose of molsidomine. Two patients did not respond initially to molsidomine; one died, the other remained in functional Class III. Another patient who responded initially was improved for over two years but died in cardiac failure after 42 months' treatment. The other six patients have been significantly improved and were in functional Class II at their last control.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Random Allocation; Sydnones; Vasodilator Agents

A double blind, crossover, random assignment study was undertaken in two 1-monthly stages following aw one-week wash-our period. Cyclo-ergometric tests were used to evaluate the antianginal effects of molsidomine compared with a placebo administered to 5 ambulatory patients with stable angina pectoris. After oral molsidomine (3 x 2 mg/day) the improvement of the evaluated parameters was significant: maximal exercise capacity, total workload, S-T segment depression. The therapeutic superiority of molsidomine compared to placebo is statistically significant. The effectiveness and tolerance observed in this clinical trial confirm the conclusions of numerous investigators.

Topics: Angina Pectoris; Clinical Trials as Topic; Double-Blind Method; Exercise Test; Female; Heart Failure; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Random Allocation; Sydnones

Topics: Clinical Trials as Topic; Female; Heart Aneurysm; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Myocardial Contraction; Myocardial Infarction; Oxadiazoles; Physical Endurance; Sydnones; Vasodilator Agents

There is certain evidence that high efficacy of beta-adrenoblockers with alpha-adrenoblocking effect (vasodilating beta-blockers) in congestive heart failure (CHF) can be explained by their effect on nitric oxide (NO) metabolism. In this context, the possible effects of carvedilol and proxodolol on the NO level in different organs have been studied on CHF model. The heart failure was modeled in rats by ligation of the coronary artery. Operated animals were divided into experimental groups treated with carvedilol or proxodolol and the untreated (control) group. In addition, a group of sham-operated animals was formed. After 28 days of treatment, the NO level was measured in heart, liver, and kidneys using the EPR method with spin trap. It was found that, in carvedilol-treated group, the NO level in liver is significantly lower than in other groups, which can be explained by the inhibitory action of carvedilol on the NO metabolism in this organ. The NO levels in myocardium and kidney in the control group were higher than in the sham-operated group, which confirms previous findings that the NO levels increases in CHF. Both drugs significantly decreased the NO concentration in myocardium and kidney tissue compared to control animals.

Topics: Adrenergic beta-Antagonists; Animals; Carbazoles; Carvedilol; Heart Failure; Male; Nitric Oxide; Organ Specificity; Oxadiazoles; Propanolamines; Rats; Rats, Wistar

Inhibition of myocardial fatty acid oxidation has been suggested as a therapeutic approach for improving cardiac function in chronic heart failure (HF). The novel piperazine derivative CVT-4325 was shown to inhibit fatty acid oxidation in cardiac mitochondria and in isolated perfused rat hearts. In the present study, we tested the hemodynamic and metabolic effects of acute intravenous CVT-4325 in dogs with HF.. HF (LV ejection fraction

Topics: Animals; Chronic Disease; Disease Models, Animal; Dogs; Fatty Acids; Heart Failure; Injections, Intravenous; Myocardium; Oxadiazoles; Oxygen Consumption; Piperazines; Stroke Volume; Ventricular Function, Left

Topics: Animals; Energy Metabolism; Fatty Acids; Heart Failure; Humans; Oxadiazoles; Oxygen Consumption

Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Cardiomyopathy, Dilated; Cricetinae; Cytoskeletal Proteins; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Enalapril; Endothelium, Vascular; Enzyme Inhibitors; Heart Failure; Hemodynamics; Male; Membrane Glycoproteins; Mesocricetus; Myocardial Contraction; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitrites; Oxadiazoles; Quinoxalines; Rabbits; Sarcoglycans; Ultrasonography; Vasoconstriction; Ventricular Remodeling

beta-adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR) during beta-adrenergic stimulation.. Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca(2+) spark frequency (CaSpF, reflecting resting RyR openings) and Ca(2+) transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 micromol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca(2+) transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca(2+) load).. iNOS/NO depresses beta-adrenergic-stimulated RyR function through a cGMP-independent pathway (eg, NO- and/or peroxynitrite-dependent redox modification). This mechanism limits beta-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

Topics: Animals; Calcium; Colforsin; Cyclic GMP; Enzyme Inhibitors; Guanidines; Guanylate Cyclase; Heart Failure; Heart Ventricles; Humans; Lipopolysaccharides; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxadiazoles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Sarcoplasmic Reticulum

Doxorubicin (DXR) is an effective antitumor agent in a wide spectrum of neoplasms. Chronic treatment is associated with cardiomyopathy and characteristic myocardial ultrastructural changes, which include swelling of the t tubules. Accordingly, we investigated excitation-contraction coupling in cardiomyopathic rat heart resulting from chronic DXR treatment. Using the whole-cell patch clamp technique, we studied the L-type calcium channel in single cells enzymatically isolated from normal (CTRL) and DXR rat hearts. Despite similar cell dimensions, the total membrane capacitance was significantly smaller in the DXR cells (138 +/- 9 pF) than in the CTRL cells (169 +/- 11 pF) (mean +/- SEM, n = 9, P less than 0.05). The mean current and the current density-voltage relationships of the CTRL and the DXR cells were significantly different (n = 9, P less than 0.001) with the maximal peak L-type calcium current (ICa) density increased from 6.4 +/- 0.9 in CTRL cells to 10.5 +/- 2.4 microA/cm2 in the DXR cells (P less than 0.05). There was no shift either in the current-voltage relationship or the steady-state inactivation curve in the two cell groups. However, the fast time constant of inactivation was increased at a membrane voltage of -10 to 10 mV. Calcium channel antagonist equilibrium binding assays using [3H]-PN200-110 revealed no difference in the maximal receptor binding capacity (CTRL, 194 +/- 27 and DXR 211 +/- 24 fmol/mg protein; P greater than 0.05, n = 6) and in receptor affinity (CTRL, 0.15 +/- 0.05 and DXR 0.13 +/- 0.03 nM; P less than 0.05). These data suggest that a decrease in effective capacitance might be associated with t-tubular damage. Despite this decrease, ICa was increased in the DXR cells. Such an increase may result from an alteration in the properties of the calcium channels and/or recruitment of "hibernating" channels in the remaining surface and t-tubular membranes.

Topics: Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Doxorubicin; Electric Conductivity; Female; Heart Failure; In Vitro Techniques; Isradipine; Oxadiazoles; Rats; Rats, Inbred Strains

We studied the acute hemodynamic effects of PN 200-110, a newly available calcium antagonist, in 12 patients with severe congestive heart failure. Measurements of cardiac performance were obtained by a right heart catheter before and after administration of 5 and 15 mg of PN. Peak drug effects occurred 1-2 h following the administration of PN 200-110 and were dose related. The 15-mg dose reduced mean arterial pressure (MAP) from 90 +/- 11 to 75 +/- 6 mm Hg (mean +/- SD) (p less than 0.001) and decreased systemic vascular resistance (SVR) from 1,740 +/- 500 to 995 +/- 300 dynes X s X cm-5 (p less than 0.01). Stroke volume index (SVI) increased from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001), and cardiac index (CI) rose from 2.1 +/- .3 to 2.8 +/- .6 L/m2 (p less than 0.01). Pulmonary arterial wedge pressure (PAW) changed insignificantly. Seven patients performed graded supine exercise at identical workloads before and after treatment. When peak exercise values were compared, the addition of PN 200-110 further reduced SVR from 1,282 +/- 461 to 936 +/- 356 dynes X s X cm-5 (p less than 0.01) and increased CI from 3.3 +/- 1.1 to 4.3 +/- 1.3 L/m2 (p less than 0.01). Only minor, self-limiting side effects were noticed during acute administration. Of the seven patients discharged on PN 200-110 and followed for at least 6 months, six reported substantial relief of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Calcium Channel Blockers; Female; Heart Failure; Hemodynamics; Humans; Isradipine; Male; Middle Aged; Oxadiazoles; Physical Exertion

PN 200-110 (isradipine), a dihydropyridine derivative, is a newly available calcium antagonist with potent vasodilatory properties. To determine if PN 200-110 might benefit patients with congestive heart failure (CHF), its acute hemodynamic effects were evaluated in a group of 12 patients with severe CHF. Measurements of cardiac performance were obtained after oral administration of placebo and 15 mg of PN 200-110. Placebo resulted in no significant changes in any of the variables. PN 200-110 decreased mean arterial pressure from 94 +/- 14 (mean +/- standard deviation) to 77 +/- 7 mm Hg (p less than 0.001) and increased both cardiac index from 2.1 +/- 0.4 to 2.8 +/- 0.6 liters/m2 (p less than 0.01) and stroke volume index from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001). Systemic vascular resistance was reduced from 1,726 +/- 563 to 1,099 +/- 370 dynes s cm-5 (p less than 0.01). Neither heart rate nor pulmonary artery wedge pressure changed significantly. Of the 7 patients discharged receiving PN 200-110, 6 improved clinically and there was evidence of a substantial reduction in cardiothoracic ratio on chest x-ray in some patients. No serious side effects were encountered. Vasodilation with PN 200-110 can improve cardiac performance acutely in patients with CHF. Although this clinical experience is encouraging, carefully performed long-term trials must be done to determine the value of this drug in the management of patients with CHF.

Topics: Adult; Aged; Calcium Channel Blockers; Female; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Isradipine; Male; Middle Aged; Oxadiazoles; Time Factors

Topics: Adult; Female; Heart Failure; Heart Valve Diseases; Humans; Male; Middle Aged; Molsidomine; Nifedipine; Oxadiazoles; Rheumatic Heart Disease; Sydnones; Vasodilator Agents

Acute haemodynamic effects of molsidomine, antianginal drug with vasodilator properties, were evaluated in 12 male patients with chronic congestive heart failure in New York Heart Association functional class 3 or 4 (mean age 56 +/- 7 years; ischemic heart disease in 8 cases, dilated cardiomyopathy in 3 cases, heart disease of combined aetiology in 1 case). After sublingual molsidomine (4 mg: 6 cases; 8 mg: 6 cases) the following haemodynamic changes were observed: mean right atrial pressure - 35% (p less than 0.01), left ventricular filling pressure -30% (p less than 0.01), total pulmonary resistance -33% (p less than 0.01), pulmonary arteriolar resistance -32% (p less than 0.01), cardiac index -6% (p less than 0.05), stroke volume index -12% (p less than 0.05), stroke work index +18% (p less than 0.01), heart rate -6% (p less than 0.01), double product -10% (p less than 0.01) (Fig. 3). Peak haemodynamic effect was reached between 30 and 90 minutes, lasting till 180 minutes. Molsidomine acutely reduced preload, did not show side effects and was well tolerated. These results suggest that molsidomine might be used in the treatment of chronic congestive heart failure, especially if characterized by an increased right and left ventricular filling pressure.

Topics: Administration, Oral; Adult; Aged; Blood Pressure; Cardiac Catheterization; Cardiac Output; Chronic Disease; Heart Failure; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Pulmonary Artery; Sydnones; Vasodilator Agents

Topics: Coronary Disease; Heart Failure; Humans; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

We have used equilibrium gated blood pool scintigraphy to evaluate the hemodynamic effects and duration of action of molsidomine, a new peripheral vasodilator antianginal drug, after sublingual administration (4 mg) in five patients with heart failure. The following parameters were studied at rest and 10, 60, and 240 minutes after drug administration: left and right ventricular ejection fractions, end-diastolic and end-systolic volumes, stroke volume, heart rate, and cardiac index. Systolic and diastolic blood pressures were determined by cuff measurement. Statistically significant (p less than 0.05) changes were observed after 10 minutes for left ventricular ejection fraction (+26.2%), left and right end-diastolic volume (-12.4% and -15.2%), left ventricular end-systolic volume (-15%), and cardiac index (+7.9%); after 60 minutes for left ventricular ejection fraction (+49%), left ventricular systolic volume (+30.5%), cardiac index (+29.7%), systolic blood pressure (-7.9%), and right ventricular end-diastolic volume (-14.3%); and after 240 minutes for cardiac index (+23.9%), systolic blood pressure (-6.3%), and right ventricular ejection fraction (+23.1%). No changes in heart rate were observed. No patient experienced any side effect. We conclude that the hemodynamic improvement observed with molsidomine can be prolonged and results both from preload and afterload reduction.

Topics: Adult; Aged; Cardiac Output; Heart Failure; Hemodynamics; Humans; Middle Aged; Molsidomine; Oxadiazoles; Radionuclide Imaging; Stroke Volume; Sydnones; Time Factors; Vasodilator Agents

The short-term hemodynamic effects of molsidomine (4 mg sublingually) were evaluated in 13 patients with congestive heart failure following acute myocardial infarction. Right heart catheterization was performed by means of a Swan-Ganz thermodilution catheter. Hemodynamic measurements were made 30, 60, 120, and 180 minutes after the administration of the drug. Molsidomine significantly reduced systolic blood pressure from 121.5 +/- 3.3 (mean +/- SEM) to 111.1 +/- 2.9 mm Hg (p less than 0.001) after 60 minutes, mean right atrial pressure from 6.1 +/- 1 to 2.6 +/- 0.6 mm Hg (p less than 0.0001), mean pulmonary arterial pressure from 29.8 +/- 1.9 to 20.1 +/- 1.3 mm Hg (p less than 0.0001), and left ventricular filling pressure from 20.3 +/- 0.6 to 12.2 +/- 0.7 mm Hg (p less than 0.0001). No significant change occurred in heart rate, diastolic and mean blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, systemic vascular resistance, and pulmonary vascular resistance. No side effects were seen after the administration of molsidomine.

Topics: Aged; Female; Heart Failure; Hemodynamics; Humans; Male; Molsidomine; Myocardial Infarction; Oxadiazoles; Sydnones; Time Factors; Vasodilator Agents

Central hemodynamic effects of 0.05 mg/kg molsidomine were examined in 60 patients with decompensated mitral disease dwelling at low and medium altitudes. M-echocardiography was used to assess hemodynamic shifts. The assessments were made during the diagnostic probing of a pulmonary artery in 23 cases. Hemodynamic efficacy of molsidomine was more pronounced up in the mountains. Rationale are given for expanding indications for peripheral vasodilators (molsidomine) in highlanders with congestive heart failure.

Topics: Adolescent; Adult; Altitude; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Myocardial Contraction; Oxadiazoles; Sydnones

We studied the effects of molsidomine on hemodynamic properties and blood gas levels in eight patients with acute myocardial infarction and left heart failure. One hour after an 8 mg intravenous bolus injection, pulmonary wedge pressure and right atrial pressure decreased, respectively, from 30 +/- 9 to 23 +/- 12 mm Hg (p less than 0.01) and from 10.4 +/- 3.6 to 7.8 +/- 4.0 mm Hg (p less than 0.05) without significant changes in heart rate, cardiac index, or systemic blood pressure. There was a mild decrease in arterial oxygen tension (from 61 +/- 15 to 56 +/- 6 mm Hg), but it was not significant. The drug induced no adverse effects. Intravenous bolus injection of molsidomine rapidly relieves pulmonary congestion in patients with acute myocardial infarction.

Topics: Aged; Carbon Dioxide; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Myocardial Infarction; Oxadiazoles; Oxygen; Sydnones; Vasodilator Agents

The hemodynamic effects of a new drug: molsidomine (M) were evaluated in 9 patients with congestive myocardiopathy. To that end, with a 4-channel Swan-Ganz catheter and cardiac output computer, the following hemodynamic parameters were measured in the control condition (CC) and 5, 15 and 30 minutes after sublingual administration of 4 mg of M: heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), cardiac index (CI), stroke volume index (SVI), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and the stroke work index (SWI). Comparing the data in CC and at the end of the study, we found a decrease of 80 +/- 5 to 76 +/- 5 b/m (p less than 0.01) in HR, of 91 +/- 4 to 84 +/- 4 mmHg (p less than 0.01) in MAP and of 3087 +/- 151 to 2758 +/- 131 d/c/s-5 in SVR (p less than 0.02); a drop in PWP of 27 +/- 3 to 20 +/- 3 mmHg (p less than 0.001) and in PVR of 1367 +/- 293 to 1115 +/- 256 d/c/s-5 (p less than 0.001); an increase in SVI of 31 +/- 3 to 34 +/- 2 ml/b/m2 (p less than 0.05) and non-significant changes in CI of 2380 +/- 96 to 2459 +/- 82 ml/m2 (p less than 0.03) and in the SWI of 34 +/- 4 to 37 +/- 4 gm/m2 (p less than 0.1). We conclude that in patients with severe heart failure, the fundamental effects of M appears to be vasodilation in both pulmonary and systemic circulations demonstrated by a fall in PWP, PVR, MAP and SVR together with a mild increase in SVI without significant changes in CI and SWI.

Topics: Adolescent; Adult; Aged; Blood Pressure; Cardiomyopathy, Dilated; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Pulmonary Wedge Pressure; Stroke Volume; Sydnones; Vascular Resistance; Vasodilator Agents

Topics: Adult; Aged; Chronic Disease; Drug Evaluation; Heart Failure; Hemodynamics; Humans; Middle Aged; Molsidomine; Oxadiazoles; Rheumatic Heart Disease; Sydnones; Vasodilator Agents

Haemodynamic monitoring, using a Swan-Ganz balloon catheter, was done in 14 patients with pump failure associated with acute myocardial infarction, before and for 8 h after single 6 mg oral dose of molsidomine. The following changes effects were found: HR fell by 1.6 to 4.7% (significant at 4th hour; p less than 0.05); SBP was 8.4% lower after 1 h (p less than 0.05); PCP was decreased by approximately 30%, a significant effect that lasted for 8 hours (p less than 0.002). CI did not change significantly, although individual analysis showed it to have increased in 6 out of 12 cases. Stroke volume index was increased by about 6% (significant after 1 h, p less than 0.025). The left ventricular stroke work index also increased from 9.8 to 24.5% (significant after 1 and 4 h, p less than 0.01 and 0.025). These findings show the beneficial haemodynamic effects of molsidomine in pump failure complicating acute myocardial infarction.

Topics: Aged; Antihypertensive Agents; Cardiac Catheterization; Cardiac Output; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Myocardial Infarction; Oxadiazoles; Stroke Volume; Sydnones; Vascular Resistance

A haemodynamic study was performed in 12 men aged between 28 and 64 years, including 8 with clinical signs of congestive cardiac failure and an ejection fraction of less than 50 per cent. The pulmonary artery pressure, capillary pressure, left ventricular pressure, cardiac output and the arterial and venous oxygen tensions were measured before (T 0) and after sublingual administration of 4 mg of molsidomine (T 15, T 30, T 45, T 60 min) and 3 minutes after a dose of 0.6 mg sublingual trinitrine (given immediately after the measurements made at T 60). The haemodynamic modifications were very significant at the 30th minute and reached a plateau between the 45th and 60th minute. The left and right ventricular filling pressures fell by more than 25 per cent, the aortic pressure fell by 17 per cent. There was a mild decrease (8 per cent) in the cardiac index and the systolic index, without any significant change in the heart rate. The reduction in the cardiac index and the systolic index was not significant in patients with cardiac failure and an ejection fraction of less than 50 per cent. The peripheral vascular resistance fell by 9 per cent. Finally, there was a significant reduction in the cardiac work and power and especially in the pressure-time index per beat and per minute. The administration of 0.6 mg of sublingual trinitrine induced an additional reduction in the aortic pressure with acceleration of the heart rate and a slight increase in the cardiac output, but no additional venodilator effect was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Mouth Floor; Nitroglycerin; Oxadiazoles; Sydnones; Tablets

The unloading mechanisms and side of peripheral action of the new antianginal drug molsidomine was compared with isosorbide dinitrate (ISDN) in 14 patients with acute myocardial infarction using a Swan-Ganz catheter and venous occlusion plethysmography. Sublingual molsidomine (2-4 mg) increased calf venous capacitance (CVC) (0.42 +/- 0.18 to 0.64 +/- 0.09 ml/100 ml, p less than 0.05) from 30 to 240 minutes, while simultaneously lowering of PCWP (25.9 +/- 4.9 to 15.8 +/- 7.3 mmHg, p less than 0.05) and CVP (9.3 +/- 3.7 to 5.8 +/- 3.5 cmH2O, p less than 0.05). Calf blood flow (CBF), calf vascular resistance (CVR), CI, TSPR and SWI were not affected significantly. Molsidomine reduced preload more than 240 minutes after its administration. Sublingual ISDN increased CBF into the initial 15 minutes (1.19 +/- 0.49 to 1.83 +/- 0.98 ml/100ml/min, p less than 0.05) and CVC from 5 to 60 minutes (0.42 +/- 0.19 to 0.68 +/- 0.24 ml/100ml p less than 0.01) while simultaneously lowering PCWP (24.3 +/- 2.2 to 14.6 +/- 4.5 mmHg, p less than 0.01) and CVP (9.0 +/- 2.8 to 5.5 +/- 3.5 cmH2O, p less than 0.05). Neither drug affected cardiac index, blood pressure or systemic vascular resistance. These data suggest that molsidomine significantly lowered elevated preload (PCWP/PCP) by dilating venous capacitance vessels. Its length of action was 240 minutes compared with 60 minutes obtained with ISDN, which suggests this new agent may be of marked benefit in the AMI patients suffering from backward failure uncomplicated by forward failure in whom continued preload reduction is necessary. (Results are expressed as the mean +/- standard deviation).

Topics: Adult; Aged; Blood Circulation; Blood Flow Velocity; Central Venous Pressure; Female; Heart Failure; Hemodynamics; Humans; Isosorbide Dinitrate; Male; Middle Aged; Molsidomine; Myocardial Infarction; Oxadiazoles; Plethysmography; Pulmonary Wedge Pressure; Sydnones

Systemic arterial compliance was measured in 20 patients with left ventricular failure due to congestive cardiomyopathy. The method consisted in evaluating arterial compliance by analysing the exponential fall of the arterial pressure curve on a simple visco-elastic model. In the patient group, significant correlations were found between arterial compliance and age (r = 0,64 ; p less than 0,01) and arterial compliance and systolic blood pressure (r = -0,58 ; p less than 0,001). These relationships suggest that arterial compliance depends on the height of the systolic blood pressure and/or the elasticity of the arterial walls. Two groups of patients were defined : Group I (10 patients) given a single oral dose of 7,5 mg of nitroglycerine (Lenitral), and Group II (10 patients) giben a single oral dose of 4 mg N ethoxycarbonyl-3-morpholinosydnonomine (Molsidomine). There was no significant difference in the hemodynamic parameters or arterial compliance between the two groups before administration of these drugs. However, systolic blood pressure was significantly lower (p less than 0,01) and compliance significantly higher (p less than 0,05) after treatment in Group II. In Group I, nitroglycerine caused a significant increase in compliance (p less than 0,01), a significant decrease in systolic (p less than 0,02) and mean blood pressure (p less than 0,05) whilst heart rate, cardiac output and total systemic resistance remained unchanged. In Group II, Molsidomine caused a significant increase in arterial compliance (p less than 0,01), a decrease in systolic (p less than 0,001), diastolic (p less than 0,01) and mean blood pressure (p less than 0,01) and in cardiac output (p less than 0,01), whilst heart rate and total systemic resistance remained unchanged. This study shows that both drugs studied had significant effects on the walls of the large arteries.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Heart Failure; Humans; Male; Middle Aged; Molsidomine; Nitroglycerin; Oxadiazoles; Sydnones

Topics: Aged; Chronic Disease; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Molsidomine; Morpholines; Oxadiazoles; Sydnones

Topics: Aged; Chronic Disease; Female; Heart Failure; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones