Mechanisms of action of nitrates

Abstract

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.

Effect of Isosorbide-5-Mononitrate on Exercise Performance and Clinical Status in Patients with Congestive Heart Failure

“…The beneficial effect of nitrates in heart failure involves several mechanisms, including a decrease in filling pressure, decrease in peripheral resistance, lessening of valvular regurgitation following a reduction in ventricular volume and a reduction in myocardial oxygen demand [21, 22, 23, 24, 25, 26, 27, 28]. Modulation of the endothelial NO pathway may be a useful target for pharmotherapeutic intervention in heart failure [29]and may result in an improvement in exercise performance [30].…”

Functional models of [Fe—S] nitrosyl proteins

“…Nitrates, which are the most well known NO do nors (glycerol trinitrate, pentaerythritol tetranitrate, nicorandil, NO aspirin, NO paracetamol), are still most widely used for treating symptoms of stenocardia. [46][47][48][49][50] The efficiency of these pharmaceuticals depends on the metabolism of the nitro group.…”

YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components

“…Although 1H-(1,2,4)oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) compound oxidizes several hemeproteins (7), it displays a higher selectivity for the sGC heme (8). Nitrovasodilators, such as glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate, can generate NO (9), which results in the formation of a nitrosyl heme of sGC and, thereby, activation of sGC. Although widely and successfully used for the treatment of congestive heart failure, angina pectoris, and myocardial infarction (10), nitrovasodilators can have a restricted application because patients may develop tolerance.…”