Gene transfer of prepro-calcitonin gene-related peptide restores erectile function in the aged rat

Erectile dysfunction in the aging male is caused, in part, by inadequate re laxation of the corpora cavernosal smooth musculature. Calcitonin gene-rela ted peptide (CGRP), a peptide neurotrasmitter localized in the corpora cave rnosa, is down-regulated in the aging rat penis. We examined the hypothesis that this reduction in CGRP may contribute to decreased cavernosal smooth muscle relaxation. Therefore, we sought to determine whether adenoviral-med iated gene transfer of prepro-CGRP (AdRSVCGRP) could enhance erectile respo nses in aged rats. We found a significant decrease in CGRP concentrations a nd in cAMP and cGMP levels in aged rat cavernosal tissue compared to younge r rats. Aged rats also had significantly lower erectile function as determi ned by cavernosal nerve stimulation compared to younger rats. Five days aft er transfection with AdRSVCGRP, these aged rats had an approximately threef old increase in cavernosal CGRP levels compared to animals transfected with adenoviruses encoding nuclear-targeted beta -galactosidase (AdRSV beta gal ). The AdRSVCGRP-transfected animals also demonstrated an increase in CGRP mRNA and immunohistochemical localization of CGRP in the smooth muscle of t he corpora cavernosa. In addition, cAMP levels in the corpora cavernosa wer e significantly increased, whereas cGMP levels remained unchanged. Adenovir al transduction efficiency of p-galactosidase reporter gene was measured by chemi luminescence and was observed in cavernosal tissue 5 days after tran sfection with AdRSV beta gal. More importantly, 5 days after administration of AdRSVCGRP, a significant increase was observed in the erectile response to cavernosal nerve stimulation in the aged, rat, similar to the response observed in younger rats. These data suggest that in vivo adenoviral gene t ransfer of CGRP can physiologically improve erectile function in the aged r at.