Semester

Spring

Date of Graduation

1999

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Michael Mawhinney.

Abstract

The goal of this research was to determine the role of norepinephrine (NE) in androgen-dependent pubertal proliferation and adult terminal differentiation in normal male accessory sex organ smooth muscle. The guinea pig seminal vesicle served as a model as its unique anatomy allowed clean harvest of smooth muscle without epithelium.;Androgen significantly increased in vivo DNA synthesis, total DNA, and NE release and down-regulated protein kinase C (PKC) in prepubertal seminal vesicle smooth muscle (SVSM) relative to prepubertal orchiectomized controls. High performance liquid chromotography quantified NE release as an increased concentration of (1) endogenous NE-metabolite, 3,4-dihydroxyphenolglycol per NE, and (2) NE in vitro SVSM minces. Binding studies using [3H]RX821002, an alpha2-adrenoceptor antagonist, showed a concurrent four-fold decrease in alpha2-adrenoceptor concentration, indicating reduced feedback as a potential mechanism for the increase in norepinephrine release. In vivo NE-depletion of ≥99% by reserpine selectively antagonized the androgen-induced increases in SVSM-DNA (measured spectrofluorophotometrically) and protein kinase C (PKC) down-regulation (measured by gamma[32P]ATP transfer). Gel electrophoresis detected no apoptosis, supporting other evidence that cell number is proliferation-dependent. Cell culture experiments demonstrated that SVSM alpha1-adrenoceptors mediated the proliferative response to NE. Functional alpha1-adrenoceptor expression, exhibited by electrical field stimulation of SVSM neurons, correlated with the onset of androgen-induced proliferative response.;In terminally differentiated adult SVSM, elevated NE release and decreased alpha 2-adrenoceptor concentration were maintained from puberty and developed androgen-resistance. PKC, however, returned to prepubertal castrate control levels (Mariotti et al., 1992). Androgen withdrawal combined with NE depletion caused no reduction in adult SVSM-DNA relative to adult castrates. These findings suggest that while increased NE release plays an obligatory role in pubertal SVSM proliferation, NE release becomes uncoupled from the mitogenic response at or before PKC stable activation in adulthood.;Human benign prostatic hypertrophy (BPH) is a fibromuscular neoplasia. The data presented here suggest BPH may be due to defective uncoupling between sustained, androgen-induced NE release and PKC activation. New pharmacological therapies for BPH can be envisioned based on either antagonizing the reduction in presynaptic alpha2-adrenoceptors to prevent increased NE release or inducing PKC resistance to generate the normal amitotic state.

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