Nitrates. Mode of action at a cellular level.

The nitrates used therapeutically in angina pectoris and congestive heart failure are, from a chemical point of view, organic nitroesters. Their principal pharmacological effect is vascular smooth muscle relaxation, leading to vasodilation, which explains their therapeutic effects. Several mechanisms have been proposed for their mode of action at the cellular level, in order to explain vascular smooth muscle relaxation. Today, there is strong evidence that organic nitroesters stimulate the enzyme guanylate cyclase in the smooth muscle cell. This enzyme produces a cyclic nucleotide, cyclic guanosine-3',5'-monophosphate (cGMP), which in turn eventually lowers the free calcium concentration in the cytosol to induce relaxation. The exact mechanism by which the organic nitroesters stimulate guanylate cyclase is still obscure. Preliminary results from our laboratory indicate that there may be more than one mechanism responsible for the activation of the enzyme. Knowledge of the mode of action at the cellular level is probably important in order to understand the mechanism(s) behind the development of tolerance towards the organic nitroesters.