PHARMACOLOGICAL STUDIES OF HUMAN ERECTILE TISSUE

Potassium (K) channels are important modulators of vascular smooth muscle tone. In isolated tissues and cultured cells derived from the trabecular smooth muscle of the human corpora, two K channel subtypes in particular, the maxi-K and K/ATP, respectively, have been identified. The activity of these two K channel subtypes is modulated by a host of physiologically relevant endogenous neurotransmitters, neuromodulators and hormones. These observations reflect that fact that these K channel subtypes are a convergence point for the regulation of both contractile and relaxation responses. As such, these K channels can be regarded as a final common effector of corporal smooth muscle tone, and thus, of erectile capacity. Therefore, it is likely that alterations in K channel function may be responsible, at least in part, for both the heightened corporal smooth muscle contractility and the impaired smooth muscle relaxation thought to be a prevalent aspect of erectile dysfunction in a large proportion of impotent men. The goal of this proposal is to explore and characterize the physiology and pathophysiology of the regulation and function of these two prominent K+ currents in isolated tissue strips and explant cultured and enzymatically dissociated smooth muscle cells derived from the corpus cavernosum of potent men, as well as men with organic erectile dysfunction. Specifically, we shall: 1) Evaluate the contribution of the maxi-K and K/ATP channels to contractile responses elicited by phenylephrine (PE) and endothelin-1 (ET-1) on isolated corporal tissue strips. 2) Evaluate the contribution of K channels to relaxation responses in isolated corporal smooth muscle strips precontracted with PE or ET-1. 3) Examine the effects of K channel activation/blockade on resting and receptor-mediated increases in intracellular calcium levels in enzymatically dissociated and cultured human corporal smooth muscle cells. 4) transfect isolated corporal tissue strips and cultured corporal smooth muscle cells with the human maxi-K channel cDNA (hSlo), and evaluate the effects of transfection .