Coronary Collateral Vasodilator Action of N-Ethoxycarbonyl-3-Morpholinosydnonimine (Sin-10) in Heart With Chronic Coronary Insufficiency in Dogs

Hirata, Minoru; Kikuchi, Katsuko

doi:10.1254/jjp.20.187

Cited by 18 publications

(9 citation statements)

References 13 publications

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“…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 vU Holzman, 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%

“…Other potentially useful pharmacological properties of molsidomine have been described in the dog. 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-reperfusion ventricular fibrillation in a non-controlled study was observed after left anterior descending coronary artery ligation in 8 dogs (Nitz & Martorana, 1985).…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Cano

Guillen

Jouve

et al. 1986

British J Pharmacology

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“…The fall in coronary flow after molsidomine was not accompanied by changes in coronary sinus blood oxygen content so that the flow reduction most likely reflects the consequences of reduced myocardial oxygen demand. These data, however, are not necessarily conflicting as the dogs in the earlier study (8) were chronically ischemic with ample time to develop functional coronary collateral vessels, whereas the acute, short-lasting coronary artery occlusion in the latter study (5) did not allow the hearts enough time to open collaterals for sufficient blood supply to the ischemic endocardial muscle. Hence, the intravenous administration of molsidomine does not directly affect the heart and coronary circulation.…”

Section: Discussionmentioning

confidence: 80%

“…The latter was recently shown for molsidomine as the result of longlasting venodilation (6,9) accompanied by a reduction in preload with little effects on afterload (1, 3,10). However, conflicting results exist with respect to molsidomine's effects upon coronary collateral vessels: whereas some investigators reported dilation of collateral vessels in canine hearts (1, 8,15), others could not establish changes in coronary collateral blood flow after molsidomine (5). As a contribution to these aspects of the mechanism of anti-anginal molsidomine actions, we have investigated the effects of the drug on the dog heart's non-constricted left coronary artery blood flow in acute experiments.…”

Section: Introductionmentioning

confidence: 96%

Effect of molsidomine on the coronary circulation in anesthetized dogs

Fiedler¹,

Nitz²

1982

Basic Res Cardiol

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The intravenous effects of molsidomine on the coronary circulation, myocardial oxygen consumption, and hemodynarnies were investigated in anesthetized, openchest dogs. Left coronary artery flow was reduced after drug administration, while coronary resistance remained unaffected. The coronary arteriovenous oxygen difference did not change after molsidomine. Myocardial oxygen consumption was significantly reduced. Stroke work of the heart was diminished. Molsidomine caused a dose-dependent decrease in aortic and left ventrieular pressures (afterload) as well as a sustained fall in left ventricular end-diastolic and mean pulmonary artery pressures (preload). Heart rate and contractility were only moderately affected. Stroke volume and cardiac output decreased significantly for the experimentation time, while total peripheral resistance increased after 0.25 mg/kg molsidornine.All observed effects of the drug can be explained by extracardiac effects: an increase in venous capacity. No direct effects of rnolsidomine on myocardial function could he noted. The fall in blood pressure was not induced by vasodilatation of peripheral arteriolar vessels but occurred as sequel of the reduced cardiac output following decreased ventricular filling. Molsidomine improved the oxygen supply-demand balance by decreasing external work of the heart and hence myocardial oxygen demand.

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“…This is very favourable with respect to the possible application of the drug in coronary heart disease for the following reasons: 1. This does not exclude an increase and a beneficial redistribution of myocardial blood flow supplied via collaterals (10). A concomitant, significant reduction in peripheral resistance is not desirable (24).…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic and myocardial effects of long-lasting venodilation in the conscious dog

Holtz¹,

Bassenge²,

Kolin³

1978

Basic Res Cardiol

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The effect of molsidomine-induced venodilation on cardiac preload was studied in conscious resting dogs, instrumented to analyze left ventricular function and myocardial perfusion. Direct effects on veins were studied during chloralose anesthesia by measuring regional venous capacitance changes with an induction angiometer. Kinetics of molsidomine-induced effects were compared to those induced by nitroglycerin and isosorbide dinitrate. This comparison was restricted to low i.v. dosages, causing only transient threshold effects on peripheral resistance and heart rate. During molsidomine-induced venous pooling, neither any direct effect on the coronary circulation nor any direct cardiac depressant activity of the drug was detected. 100 microgram/kg molsidomine caused a reduction of left ventricular preload by 5 mm Hg, lasting at least 4 hours. This effect was significantly more pronounced than that induced by 1 microgram/kg nitroglycerin or by 25 microgram/kg isosorbide dinitrate, lasting 2 min or 20 min, respectively. However, in raising regional venous capacitance, these nitrate dosages were equi-effective to 100 microgram/kg molsidomine, the effect of which was persistent and with a greater delay in onset. These results indicate that the lasting persistance of venodilation is a decisive factor for the amount of volume pooled in the capacitance system and, consequently, for the extent of preload reduction obtained. It is concluded, that lasting vasodilation, restricted to the veins, is beneficial for ventricular performance in ischemic heart disease.

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Coronary Collateral Vasodilator Action of N-Ethoxycarbonyl-3-Morpholinosydnonimine (Sin-10) in Heart With Chronic Coronary Insufficiency in Dogs

Cited by 18 publications

References 13 publications

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Effect of molsidomine on the coronary circulation in anesthetized dogs

Hemodynamic and myocardial effects of long-lasting venodilation in the conscious dog

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