Erectile dysfunction is a major health problem that has a dramatic impact on the quality of life of many men and their sexual partners. Moreover, erectile dysfunction represents a spectrum of disease, ranging from partial to complete impotence, and affecting an estimated 18-30 million American men greater than or equal to 40 years of age. Medical treatment of this prevalent disease resulted in 400,000 outpatient visits and 30,000 hospital admissions, at total cost of $146 million in 1985 alone. Incomplete corporal smooth muscle relaxation is now widely recognized as a significant etiologic factor in a large proportion of impotent men. The general consensus is that incomplete corporal smooth muscle relaxation severely compromises trapping of blood in the corporal sinuses (because of incomplete closure of the venous outflow), resulting in a lack of rigidity. This condition is commonly referred to as corporal veno- occlusive erectile dysfunction. In vitro studies have documented that isolated human corporal tissue strips and cultured corporal smooth muscle cells provide a valid model for studying at least some aspects of the modulation of corporal smooth muscle tone in vivo. Observations both in vitro and in vivo demonstrated that intercellular communication through gap junctions, and current flow through membrane ion channels (i.e., namely Ca & K channels) are important modulators of corporal smooth muscle tone, and therefore, of erectile capacity. It seems that regardless of the diversity of causes of erectile dysfunction related to incomplete corporal smooth muscle relaxation, their effects might still be explained via their direct or indirect impact on gap junctions, K channels or Ca channels. Thus, in many ways, the improved understanding, diagnosis and treatment of erectile dysfunction is largely dependent on more detailed knowledge of how physiologically relevant drugs modulate these primary effectors of corporal smooth muscle tone. To directly address this issue we shall: l: a) Conduct electrophysiological studies on enzymatically dispersed and cultured corporal smooth muscle cells to evaluate the role of intercellular current flow in propagating and amplifying signals in the corpora. b) Microinject cultured and enzymatically dissociated cells as well as isolated tissue strips with gap junction permeant dyes and second messenger molecules to assess the role of metabolic coupling in propagating and amplifying signals in the corpora. c) Conduct molecular biological and immunocytochemical studies to characterize gap junctions between smooth muscle cells in situ and in culture. 2) Use patch clamp techniques to characterize the K and Ca channels in enzymatically dispersed and cultured corporal smooth muscle cells. 3) Assess action potential generation in vitro, using the sucrose gap technique.
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