The activity of molsidomine in experimental models of ischemic cardiac disease

Nitz, Rolf-Eberhard; Martorana, P. A.

doi:10.1016/0002-8703(85)90668-4

Cited by 7 publications

(6 citation statements)

References 31 publications

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“…Thus, the delayed ST segment elevation and AR% changes observed in molsidomine treated-dogs might reflect an anti-ischaemic effect of the drug, accounting for both the antifibrillatory action and the reduced number of ventricular premature beats observed in the present investigation. This interpretation fits with previous experiments in which a coronary collateral vasodilator action in hearts with coronary insufficiency (Hirata & Kikuchi, 1970), improved endocardial flow (Berdeaux et al, 1978), decreased infarct size after coronary artery ligation , and a significant anti-ischaemic effect after left anterior descending coronary artery controlled reduction of perfusion, as assessed by ST segment changes in multiple unipolar leads (Nitz & Martorana, 1985), have been documented with molsidomine. These results are also in accordance with clinical data showing that molsidomine reduces electrocardiographic signs of myocardial ischaemia in patients with coronary heart disease undergoing ergometric testing (Detry et al, 1981).…”

Section: Electrocardiographysupporting

confidence: 91%

“…In fact, as reported in previous experiments this effect was associated with an oxygen sparing action of the drug (Hirata & Kikuchi, 1970;Berdeaux et al, 1978;Fiedler, 1982). In particular, a normalization of ST segment displacements in unipolar epicardial leads has been found to parallel the decrease of preload in a canine model of ischaemia using a dosage of the drug similar to that administered in this investigation (Nitz & Martorana, 1985). Indeed, molsidomine is known to possess similar haemodynamic properties to those of nitrates (Majid et al, 1980).…”

Section: Haemodynamicssupporting

confidence: 83%

“…The 15.5% fall in cardiac output was not significant. Since it has been documented by Fiedler (1982) that no depressant effect ofmolsidomine on left ventricular haemodynamics follows a 0.10mgkg-' bolus dose of the drug, the non-significant effect of molsidomine on cardiac output presented here might be ascribed to its well known action on preload (Nitz & Martorana, 1985).…”

Section: Haemodynamicsmentioning

confidence: 60%

“…The time-action curve of this early antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes which are lowered and those against ventricular premature beats which are less in treated as compared to control dogs. These results need to be considered with regard to the experimental setup, taking into account the relevance of standard electrocardiographic changes as an index of pathophysiological precursors of lifethreatening ventricular arrhythmias (Kaplinsky et al, 1979;Menken et al, 1979;David et al, 1982;Jouve et al, 1986a) and the reported effects of molsidomine in improving directly or indirectly the oxygen supply in ischaemic areas ofthe left ventricle (Hirata & Kikuchi, 1970;Berdeaux et al, 1978;Fiedler, 1982;Fiedler et al, 1982;Nitz & Martorana, 1985 , 1985). In contrast, the antiplatelet effects of the drug do not seem to contribute importantly to these effects of the drug.…”

Section: Discussionmentioning

confidence: 99%

“…These include: a coronary collateral vasodilator action in hearts with coronary insufficiency (Hirata & Kikuchi, 1970), improved endocardial blood flow (Berdeaux et al, 1978), a reduction of both occlusive coronary artery thrombosis and myocardial ischaemia (Fiedler, 1982), decreased infarct size after coronary artery ligation , and an anti-ischaemic effect following controlled reduction of coronary perfusion as assessed by ST segment changes in multiple unipolar epicardial leads (Nitz & Martorana, 1985). Finally, a reduction in the incidence of post-Q The Macmillan Press Ltd 1986 reperfusion ventricular fibrillation in a non-controlled study was observed after left anterior descending coronary artery ligation in 8 dogs (Nitz & Martorana, 1985). Whether molsidomine is capable of preventing post-occlusion ventricular fibrillation and of reducing the mortality rate in acute coronary artery occlusion models, though of potentially clinical relevance, has not been previously ascertained.…”

Section: Post-ischaemic Electrocardiographic Changesmentioning

confidence: 99%

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Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Cano

Guillen

Jouve

et al. 1986

British J Pharmacology

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Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 μg kg−1 as an i.v. bolus −15 min prior to coronary occlusion – followed by an infusion of 0.05 μg kg−1 min−1). Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and ΔR% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post‐ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post‐occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate‐pressure product were lowered 10 min after the start of the drug; immediate post‐occlusion (3 min) ST segment changes (0.82 ± 0.52 vs 1.52 ± 0.78 mV, P < 0.025) and ΔR% changes (37 ± 50 vs 90 ± 84%, P < 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml−1. The time‐action curve of the antifibrillatory effect of molsidomine parallels those at the level of post‐ischaemic electrocardiographic changes.

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Section: Electrocardiographysupporting

confidence: 91%

Section: Haemodynamicssupporting

confidence: 83%

Section: Haemodynamicsmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Post-ischaemic Electrocardiographic Changesmentioning

confidence: 99%

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Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Cano

Guillen

Jouve

et al. 1986

British J Pharmacology

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

Szabó

2010

Burger's Medicinal Chemistry and Drug Discovery

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Nitric oxide ( NO ), carbon monoxide ( CO ), and hydrogen sulfide ( H 2 S ) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H 2 S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) and S ‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H 2 S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H 2 S donor molecules have also been identified, which are used in preclinical studies.

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SIN‐1 has no direct myocardial anti‐ischemic action

Kober

Bender

Vallbracht

et al. 1993

Clinical Cardiology

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Summary: Anti-ischemic drugs may develop their cardiac activity via peripheral (reduction in preload and/or afterload) or cardiac (cornnary vasculature, myocardial cell metabolism) effects. The aim of the study wa3 to investigate whether SIN-1, the active metabolite of molsidomine, develops a direct myocardial anti-ischemic property. Three groups of seven patients each were treated with 0.4 mg SIN-1 administered via either the intracoronary (IC) or intravenous (IV) route, or with placebo in a double-blind randomized investigation. SIN-1 had no influence on either the ischemic parameters in the surface electmcardiogmn (ECG) or the intracoronary ECG. There was also no change in peripheral or central hemodynamics or in the severity of angina following this low IC or N dosage. There is no evidence of a direct myocardial anti-ischemic response of SIN-1. The well known anti-ischemic activity of SIN-1 or molsidomine has to be attributed to the proven peripheral and cardiac vascular responses.

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The activity of molsidomine in experimental models of ischemic cardiac disease

Cited by 7 publications

References 31 publications

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs

SIN‐1 has no direct myocardial anti‐ischemic action

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The activity of molsidomine in experimental models of ischemic cardiac disease

Cited by 7 publications

References 31 publications

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs

SIN‐1 has no direct myocardial anti‐ischemic action

Contact Info

Product

Resources

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Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH₂Sand their Prodrugs