Human penile erection is predominantly a vascular event mediated by the autonomic nervous system, which activates distinct membrane receptors on vascular smooth muscle in the penile corpora. Since vascular tone in vivo is the resultant of a complex and constantly changing hormonal milieu, equilibrium between agonists and receptors may rarely occur in the penile corpora. Therefore, assessment of the nature of response generation over time to both single and multiple receptor activation, is crucial to a better understanding of how corporal vascular tone is modulated in vivo. We will utilize novel kinetic protocols to evaluate the time- dependent nature of response generation in freshly excised human erectile tissue in vitro, and use this system as a model of the complex hormonal interactions that occur in the penile corpora in vivo. The long-term goal of this proposal is to characterize the pharmacology of the receptors that modulate the concatenation of events which result in normal penile tumescence, rigidity, and detumescence, and to identify mechanisms that may be involved in the erectile dysfunction associated with disease and chronic drug therapy in man.
The specific aims of this proposal are: 1) To assess generation of the contract tile response to single agonist activation of the alpha-l adrenergic and prostaglandin F2 alpha receptors, using kinetic protocols that separate the total contractile response into its two components, the phasic and tonic response. A simple data transformation reveals four kinetic parameters, two of which describe the phasic response (Ro and K decay) and two the tonic response (Kobs and Req). We also will examine the effects of prostanoids and metabolic inhibitors on the generation of spontaneous oscillations and maintenance of basal tissue tone; 2) To use kinetic protocols to examine the multiple receptor interactions which occur during simultaneous activation of distinct and functionally synergistic membrane receptors coupled to contraction; and 3) To study the genetic characteristics of the multiple receptor interactions that occur due to activation of distinct and functionally antagonistic membrane receptors.
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