PHARMACOLOGICAL STUDIES OF HUMAN ERECTILE TISSUE

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.