Mode of action of nitrates with regard to vasodilatation and tolerance

Nitrovasodilators relax vascular smooth muscle by one common mechanism, the activation of soluble guanylate cyclase leading to increased formation of cGMP. The considerable differences in potency between various nitrovasodilators appear, at least in part, to be due to the different pathways of their transformation into activators of guanylate cyclase such as nitrous oxide or nitrosothiol. Major differences were also found in the ability of these compounds to induce tolerance in isolated bovine coronary artery strips. Although the mechanism of tolerance development is still not clarified, it appears likely that cysteine deficiency may be responsible for this phenomenon since this thiol appears to be required for the transformation of certain nitrovasodilators (e.g. nitroglycerin) into stimulators of guanylate cyclase and also in the final step of activation of this enzyme.