Impotence is a common disorder that can have a profound impact in the well being of the individual. It is estimated that 10 million American men suffer from impotence. The overall aim of this proposal is to investigate the basic mechanisms regulating senile erection. The specific aims of this proposal include: 1) Study of the physiological mechanisms that control smooth muscle tone in the penile helicine arteries. These blood vessels act as resistant arteries regulating blood flow in the cavernous bodies of the penis. To date there is no information available on the local physiological mechanisms that regulate these blood vessels. 2) Characterization of neurogenic relaxation of trabecular smooth muscle. The neurogenic relaxation of trabecular smooth muscle is controlled by nerves that release acetylcholine and, an as yet not fully identified, nonadrenergic noncholinergic neurotransmitter. We will study the physiological mechanisms that modulate the release of acetylcholine and the putative nonadrenergic noncholinergic neurotransmitter, vasoactive intestinal polypeptide. We will investigate the intracellular second messenger mechanisms activated during neurogenic relaxation. Also, we will investigate the possibility that neurotransmitters released by nerve terminals reach the endothelium, causing the release of endothelium-derived substances, which contribute to the relaxation of penile smooth muscle. 3) Characterize the possible role of the novel peptide endothelin in the control of penile smooth muscle. The physiological mechanisms that maintain penile flaccidity are not completely understood. It is hypothesized that endothelin has a role in the control of penile flaccidity. We will characterize the biological activity of endothelin in penile smooth muscle and the receptors for endothelin in corpus cavernosum tissue. A better knowledge of the physiology of penile erection may improve our understanding of the pathophysiological mechanisms which lead to impotence. In particular, establishment of the physiological interactions of nerves and endothelium in the regulation of penile smooth muscle relaxation may explain the high prevalence of impotence in disorders associated with endothelial injury such as hypercholesterolemia and diabetes mellitus. Also, better understanding of these physiological mechanisms can lead to improved forms of treatment, including the development of better drugs for intracorporal injection as well as oral drags for the treatment of impotence.