The exact regulatory mechanisms of smooth muscle contractility are not yet known. There is considerable evidence that cyclic GMP exerts an important fundamental influence on regulation. The mechanisms by which cyclic GMP mediates this action remain to be elucidated. There are four classes of hormones, drugs, and other agents which elevate cyclic GMP levels. These include nitrovasodilators (nitroglycerin, sodium nitroprusside, etc.), endothelium-dependent vasodilators (thrombin, ATP, acetylcholine, etc.), contractile agents (norepinephrine, KCl, etc.) and the peptides released from the atria (atriopeptins). Thus, a variety of drugs, hormones, and other agents, some of which act through specific receptors, elevate cyclic GMP levels. However, depending upon the agent and tissue under investigation, the elevated cyclic GMP levels may be associated with contraction, relaxation or no change in tension. To explain this variability we propose that functionally distinct pools of cyclic GMP may exist, one or more of which induces inhibition of contraction. We suggest that the pools may be identified, in part, on the basis of their ability to activate cyclic GMP-dependent protein kinase and induce the phosphorylation of specific proteins. The long-term aim of this proposal is to identify, characterize and eventually isolate those proteins associated with inhibition of contraction. It is hoped that these studies will shed light on the mechanism of regulation of smooth muscle contractility by cyclic GMP. Those drugs and hormones which appear to function through the formation of cyclic GMP are extremely important therapeutic modalities. For example, the nitrovasodilators are the mainstay of therapy in the treatment of coronary vasospasm, angina, congestive heart failure and hypertensive emergencies. Clinical trials are currently in progress in the use of atriopeptins and their derivatives for the treatment of congestive heart failure and hypertension and the indications are promising. Pathophysiological situations in which changes in the endothelium occur may lead to a change in regulation of cyclic GMP in the vasculature which could relate to the disease process. Therefore, an understanding of the mechanism by which cyclic GMP regulates smooth muscle contractility is important for better understanding of the pathophysiology which underlies vascular disease and to the rational development of more efficacious and specific drug therapy.
