Mechanism of action of nitrates

Mechanism of action of nitrates

Nitrates get metabolised to form nitric oxide, which is a potent vasodilator. Nitric oxide is also the endothelium derived relaxing factor. Nitric oxide stimulates the enzyme guanylate cyclase, which causes the synthesis of cyclic guanosine monophosphate. Cyclic GMP is a second messenger which activates protein kinase. Protein kinases cause de-phosphorylation of myosin light chains in the smooth muscle cells. The contractile state of the smooth muscles is due to phosphorylation of the myosin light chains. Hence de-phosphorylation of these lead to relaxation of smooth muscle. The process is also mediated by extrusion of calcium from the cells. Vasodilatation reduces myocardial oxygen demand. The predominant action is on veins, causes venodilatation and decreased venous return to the heart. This lowers the myocardial preload and hence the myocardial oxygen demand. There is also an arterial dilatory effect, which reduces the after load. This effect occurs at a higher dose than that which produces venodilatation. Effect on coronary arteries is mainly on large conductance vessels rather than on the resistance vessels. This also enhances the flow to ischemic myocardium.

Organic nitrate esters commonly used in the treatment of angina are isosorbide dinitrate, isosorbide-5-mononitrate and glyceryl trinitrate. These organic nitrate esters also have a direct relaxant effect on vascular smooth muscles. The dilation of coronary vessels improve myocardial oxygenation. Nitrates also have an inhibitory effect on platelet aggregation [1].

Reference

1. K E Torfgård, J Ahlner. Mechanisms of action of nitrates. Cardiovasc Drugs Ther. 1994 Oct;8(5):701-17.