application) It is currently accepted that the mechanism of vascular and trabecular smooth muscle relaxation in the penis required for penile erection depends upon nitric oxide. This novel biochemical mediator is well understood to be synthesized and released from nerve terminals within the erectile tissue of the penis. Some evidence also exists for its release from the endothelial component of the erectile tissue. As nitric oxide exerts such a significant role in the physiology of the penis, it would be pertinent to also understand the control mechanisms effecting its release and action in this organ. It is entirely conceivable that nitric oxide operates much like other mediators which are neither released constantly or unchangeably but are precisely regulated by modulatory substances. Regulation of the nitric oxide signal transduction pathway in the penis may significantly affect erectile tissue function and dysfunction. An improved understanding of the regulatory basis for nitric oxide effects in the penis would be expected to advance the biochemical and pharmacological approaches to promote erectile tissue function and dysfunction. An improved understanding of the regulatory basis for nitric oxide effects in the penis would be expected to advance the biochemical and pharmacologic approaches to promote erectile integrity and to minimize structural and functional damage involving the erectile tissue of the penis. Such an advance is welcomed in view of the established 10-20 percent rate of erectile dysfunction present in the American male population. This research proposal centers on two primary objectives, the regulatory basis for nitric oxide in the physiology of the penis and that possibly influencing penile pathophysiology.
Specific aims are: (1) to examine the effects of selective an combined nitric oxide synthase isoform deletions on penile erections in genetically altered mutant mice and determine whether compensatory mechanisms develop which preserve erectile function in these mice; (2) to investigate the effects of stimulation and inhibition of neural and humoral factors commonly associated with erectile function and dysfunction on the maintenance of penile erections in mutant mice with selecting and combined deletions of nitric oxide synthase isoforms; and (3) to evaluate neurotrophic mechanisms that may result in physiologic upregulation of nitric oxide synthase in the penis applying neurotrophin delivery to experiments paradigms of erectile dysfunction. The experimental strategies employed by this proposal prominently feature a mutant mouse paradigm in which nitric oxide synthase genes are genetically disrupted. Consequences of this model on erectile function at baseline and following perturbations such as androgen withdrawal, neurotransmitter stimulation, neurotrophin exposure, and diabetogenesis will be studied using immunoblot analysis to confirm nitric oxide synthase expressions, immunohistochemistry to confirm nitric oxide synthase localizations, nitric oxide synthase assay to confirm nitric oxide synthase activity, and both physiologic erection and isometric tension studies of isolated erectile tissue to determine the effects of erectile function.
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