MECHANISMS OF ACTION OF NITRATES

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-S-mononitrat e 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 muscl es, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses per ipheral arteries, reduces preload and afterload, and thereby lowers my ocardial oxygen consumption. Inhibition of platelet aggregation is ano ther effect that is probably of therapeutic value. Effects on the cent ral nervous system and the myocardium have been shown but not scrutini zed for therapeutic importance. Both the relaxing effect on vascular s mooth 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 b y enzymes such as glutathione S-transferase, cytochrome P-450, and pos sibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various proces ses, the protein kinase lowers intracellular calcium; an increased upt ake to and a decreased release from intracellular stores seem to be pa rticularly important.