Role of ATP-sensitive K+ channels in relaxation of penile resistance arteries.

OBJECTIVES: To investigate the functional presence of adenosine triphosphate (ATP)-sensitive potassium (K+) channels (K(ATP)) in penile resistance arteries by evaluating the relaxant effects of the selective K(ATP) channel openers, cromakalim and levcromakalim, and also the involvement of K(ATP) channels in the relaxation of two drugs currently used in the treatment of erectile dysfunction (ie, prostaglandin E1 [PGE1] and sildenafil). METHODS: Penile resistance arteries were dissected from the horse corpus cavernosum and mounted in microvascular myographs for isometric tension recording. The arteries were precontracted with phenylephrine, and the responses to several vasodilators were tested in the absence and presence of K+ channel blockers. RESULTS: Cromakalim and levcromakalim evoked complete concentration-dependent relaxations that were blocked by 3 microm of the selective K(ATP) channel inhibitor glibenclamide. Raising extracellular K+ (25 mM) inhibited the relaxations to PGE1 and to the selective inhibitor of the cyclic adenosine monophosphate-specific phosphodiesterase (PDE4) rolipram. At a concentration selective for calcium-activated K+(K(Ca)) channels (3 mM), tetraethylammonium inhibited rolipram responses but not those of PGE1. However, glibenclamide significantly reduced the relaxation to both PGE1 and rolipram, but not those induced by the selective inhibitor of the type 5 cyclic guanosine monophosphate-specific phosphodiesterase (PDE5). CONCLUSIONS: The present results suggest a functional role for K(ATP) channels in the relaxation of penile resistance arteries, as well as their differential involvement in the vasodilation to drugs used in the treatment of organic erectile dysfunction. They mediated relaxation to PGE1 and cyclic adenosine monophosphate-elevating agents, but not those of cyclic guanosine monophosphate-elevating agents such as sildenafil.

Mechanisms of prostaglandin E1-induced relaxation in penile resistance arteries.

PURPOSE: The current in vitro study was performed to investigate intracellular mechanisms underlying prostaglandin E1 (PGE1) elicited vasodilation in isolated penile resistance arteries and evaluate whether there may be interactions with the nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. MATERIALS AND METHODS: Second or third order branches of the horse deep intracavernous penile artery were mounted in microvascular myographs. The vasodilator effects of PGE1 and cyclic adenosine 3',5'-monophosphate (cAMP) elevating agents were evaluated in the absence and the presence of inhibitors of the adenylate cyclase/cAMP and the NO/cGMP pathways. RESULTS: PGE1, the adenylate cyclase activator forskolin, and the phosphodiesterase types 3 and 4 inhibitors milrinone and rolipram, respectively, dose dependently relaxed penile resistance arteries with rolipram being the most potent of the 4 relaxant agents. Threshold concentrations of rolipram markedly enhanced PGE1 elicited relaxations. The inhibition of cAMP dependent protein kinase decreased relaxant responses to PGE1, forskolin and rolipram. Neither mechanical endothelial cell removal nor the blockade of NO synthase or guanylate cyclase altered PGE1 relaxant responses. However, combined treatment with blockers of cAMP dependent protein kinase and cGMP dependent protein kinase unmasked an inhibitory effect of the latter on relaxations induced by PGE1 and forskolin. CONCLUSIONS: These results provide evidence for cAMP involvement in PGE1 elicited vasodilation of penile resistance arteries. They underline the importance of the adenylate cyclase/cAMP pathway in the relaxation of penile erectile tissue. Moreover, cAMP elevating agents seem to cross-activate cGMP dependent protein kinase, thus, interacting downstream with the NO/cGMP cascade.