The Effects of Molsidomine and Its Metabolite SIN-1 on Coronary Vessel Tone, Platelet Aggregation, and Eicosanoid Formation In Vitro???Inhibition of 12-HPETE Biosynthesis

Darius, Harald; Ahland, B; Rücker, W.; Klaus, W; Ba, Peskar; Schrör, Karsten

doi:10.1097/00005344-198401000-00018

Cited by 37 publications

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“…It was surprising that both SIN-I and molsidomine were able to inhibit the activation of PMNs in vitro, since in previous studies molsidomine showed no platelet antiaggregatory properties when incubated with platelet-rich plasma in vitro [5]; nor did it exert any vasodilator activity when applied to isolated vascular strips in an organ bath [1,5]. Molsidomine has hitherto been regarded as a prodrug that had to be enzymatically metabolized by the liver to SIN-I, which was then converted non-enzymatically into the vasoactive compound SIN-1A, releasing a free nitric oxide group, and thus activating the soluble guanylate cyclase.…”

Section: Discussionmentioning

confidence: 99%

“…During myocardial ischaemia circulating platelets and PMNs are activated and release a variety of mediators, some of which are potent vasoconstrictors (such as TXAz, 5-HT, or leucotrienes) and some of which increase vascular permeability (LTB4 and PAF) or damage endothelial cells (TXAz and superoxide anions). Molsidomine inhibits platelet aggregation as well as cyclo-oxygenase-and lipoxygenase-dependent product formation in platelets [5]. The platelet inhibitory effects of molsidomine has been demonstrated in humans in several independent studies ex vivo and in vivo [12,13,14].…”

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to the concentrations necessary to inhibit platelet aggregation and ATP secretion in vitro, which are in the range of 1-10 btmol. 1-1 [5].…”

Section: Discussionmentioning

confidence: 99%

“…This profibrinolytic effect has been confirmed in a placebo-controlled, randomized trial in volunteers [3] and in patients with peripheral arterial disease [4]. Inhibition of platelet aggregation, ATP-secretion, and synthesis of the products of cyclo-oxygenation and lipoxygenation have also been reported [5]. These results, taken together with the increased fibrinolytic potential, may explain the antithrombotic effects of molsidomine and SIN-I in canine models of coronary artery thrombosis [6].…”

mentioning

confidence: 82%

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The effects of the nitric oxide donors molsidomine and SIN-1 on human polymorphonuclear leucocyte functionin vitro andex vivo

Darius

Grodzínska²,

Meyer

1992

Eur J Clin Pharmacol

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The nitrovasodilator and nitric oxide donor molsidomine and its metabolite SIN-I dilate vascular smooth muscle and inhibit platelet activation by increasing intracellular concentrations of cyclic GMP. We have therefore studied the effects of molsidomine and SIN-I on isolated human polymorphonuclear leucocytes (PMN) in vitro and ex vivo. In vitro molsidomine dose-dependently reduced beta-glucuronidase release and the generation of superoxide anions from non-activated and from FMLP- or PAF-stimulated human PMNs. SIN-I was equally effective in reducing beta-glucuronidase release and totally inhibited oxygen radical generation at a concentration of 580 mumol.l-1. In a double-blind, placebo-controlled, randomized trial we also studied beta-glucuronidase release and the generation of superoxide anions from isolated PMNs. Blood was drawn from 12 healthy volunteers before and 3 h after oral molsidomine (16 mg) or placebo. There was no statistically significant difference in beta-glucuronidase release and superoxide anion formation when the PMNs were isolated before or after molsidomine or placebo. This was the case for non-activated, as well as FMLP- or PAF-stimulated PMNs. Thus, the nitric oxide donors molsidomine and its metabolite SIN-I caused a dose-dependent inhibition of PMN functions in vitro, but no significant inhibition when the PMNs were isolated after oral molsidomine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to the concentrations necessary to inhibit platelet aggregation and ATP secretion in vitro, which are in the range of 1-10 btmol. 1-1 [5].…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 82%

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The effects of the nitric oxide donors molsidomine and SIN-1 on human polymorphonuclear leucocyte functionin vitro andex vivo

Darius

Grodzínska²,

Meyer

1992

Eur J Clin Pharmacol

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“…In particular, sodium nitroprusside and SIN-1 increase the content of cyclic GMP in platelets and inhibit aggregation in vivo and in vitro as well as the production of thromboxane A2 by the cells (Basista et al, 1985;Block et al, 1982;Darius et al, 1984;Gerzer et al, 1989;Wirthumer-Hoche et al, 1984;Yamakado , 1982). The inhibition of the conversion of labelled arachidonic acid to thromboxane B2 is much less pronounced with isosorbide dinitrate than with SIN-1, nitroglycerin or isosorbide-5-mononitrate (WirthumerHoche et al, 1984).…”

Section: Differences and Similarities Between Exogenous And Endogenoumentioning

confidence: 99%

Endogenous and exogenous nitrates and their role in myocardial ischaemia.

1992

Brit J Clinical Pharma

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1. Although nitrates have been prescribed in patients with angina pectoris for more than a century, their mechanism of action has only been understood recently. 2. The discovery of the endogenous nitrovasodilator nitric oxide, which is formed in endothelial cells by the enzyme nitric oxide synthase, has greatly expanded our knowledge. Nitric oxide, if released from endothelial cells can interact with vascular smooth muscle as well as circulating blood cells such as platelets. Nitric oxide activates soluble guanylate cyclase, which in turn leads to an intracellular increase in cyclic GMP. In vascular smooth muscle, this causes vasorelaxation, in platelets dysaggregation and prevention of platelet adhesion. This protective pathway both reduces the effects of vasoconstrictor substances, can produce profound vasodilation, if activated appropriately and acts as a regulator of platelet‐vessel wall interaction. In addition, nitric oxide inhibits the production and action of endothelin, a 21 amino acid vasoconstrictor peptide formed by endothelial cells. 3. Exogenous nitrovasodilators also exert their action by releasing nitric oxide from the molecule. Their action is particularly pronounced in blood vessels with a low basal production of nitric oxide and is enhanced after removal of the endothelium. In coronary artery disease, the formation of endothelium‐derived nitric oxide is reduced, its breakdown is increased, but only at later stages, is the action of endogenous and therapeutic nitrates depressed. 4. Hence, nitrates are an appropriate therapeutic tool in patients with coronary artery disease to substitute the effects of the impaired activity of the endothelial L‐ arginine/nitric oxide pathway.

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Molsidomine: Alternative Approaches To Treat Myocardial Ischemia

Nitz¹,

Fiedler²

1987

Pharmacotherapy

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The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.

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The Effects of Molsidomine and Its Metabolite SIN-1 on Coronary Vessel Tone, Platelet Aggregation, and Eicosanoid Formation In Vitro???Inhibition of 12-HPETE Biosynthesis

Cited by 37 publications

References 0 publications

The effects of the nitric oxide donors molsidomine and SIN-1 on human polymorphonuclear leucocyte functionin vitro andex vivo

The effects of the nitric oxide donors molsidomine and SIN-1 on human polymorphonuclear leucocyte functionin vitro andex vivo

Endogenous and exogenous nitrates and their role in myocardial ischaemia.

Molsidomine: Alternative Approaches To Treat Myocardial Ischemia

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