Molsidomine: Alternative Approaches To Treat Myocardial Ischemia

Abstract

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.

Nitric Oxide Donors Increase Blood Flow and Reduce Brain Damage in Focal Ischemia: Evidence That Nitric Oxide is Beneficial in the Early Stages of Cerebral Ischemia

“…One potential problem with using these agents in stroke patients is that they produce hypotension. In pa tients with myocardial infarction, a condition in which NO donors appear to be beneficial, these he modynamic effects have been counteracted suc cessfully with vasoconstrictors (Nitz and Fiedler, 1987). A similar approach could be used in patients with acute cerebral ischemia.…”

Conventional and Novel Drug Therapeutics to Relief Myocardial Ischemia

“…Molsidomine is a nitric oxide donating vasodilator [32]. When compared with placebo, it reduced the incidence of anginal attacks, the use of sublingual nitrates, and increased exercise capacity in patients with stable angina [33,34].…”

Antagonist molecules in the treatment of angina

“…Molsidomine or N -ethoxycarbonyl-3-morpholinosydnonimine (SIN10) is a nitric oxide donating vasodilator [97] and has been used to treat angina. When compared with placebo, it reduced the incidence of anginal attacks, the use of sublingual nitrates, and increased exercise capacity in patients with stable angina [98].…”

“…As with the entire spectrum of coronary disease, optimal medical therapy and risk factor modification provides important prognostic and symptomatic benefit in these patients. A wide array of pharmacological armamentarium is now available to manage the patients with chronic stable angina as outlined in Table 1 [27, 31–36, 38–40, 42, 43, 45, 50, 51, 53, 54, 67, 72, 78, 80, 82–84, 87–92, 95, 97, 102, 107, 132–144]. …”