MECHANISMS OF ISCHEMIA-INDUCED CAVERNOSAL SMOOTH-MUSCLE RELAXATION IMPAIRMENT IN A RABBIT MODEL OF VASCULOGENIC ERECTILE DYSFUNCTION

Purpose: To determine the effects of hypercholesterolemia and atherosc lerosis-induced chronic cavernosal arterial insufficiency on cavernosa l smooth muscle tone, nitric oxide synthase (NOS) activity and caverno sal tissue synthesis of constrictor eicosanoids. To study whether inhi bition of the cyclooxygenase pathway by indomethacin and tissue treatm ent with nitric oxide (NO) precursor L-arginine improve hypercholester olemia and ischemia-induced impaired endothelium-dependent and neuroge nic relaxation of cavernosal tissue. Materials and Methods: New Zealan d White rabbits were divided into control (n = 10, fed a regular diet) , hypercholesterolemia (Hch, n = 13, fed a diet containing 0.5% choles terol) and chronic cavernosal ischemia (CCI, n = 14) groups. The CCI g roup underwent balloon deendothelialization of iliac arteries and rece ived a diet containing 0.5% cholesterol. After 16 weeks, we examined t he effects of Hch and balloon de-endothelialization induced arterial o cclusive disease on iliac arterial blood flow, reactivity of cavernosa l tissue, cavernosal NOS activity and cavernosal tissue synthesis of c onstrictor eicosanoids. Results: Histology revealed significant athero sclerotic arterial occlusive disease in the CCI group. Iliac artery bl ood now in the CCI group was significantly reduced compared with the c ontrol and Hch groups. In the Hch and CCI groups, endothelium-dependen t relaxation of cavernosal tissue to acetylcholine was significantly r educed compared with the control group. Electrical field stimulation-i nduced neurogenic relaxation and cavernosal NOS activity were signific antly reduced in the CCI group but not in the Hch group. The basal rel ease of cavernosal constrictor eicosanoids, prostaglandin F-2 alpha (P GF(2 alpha)) and thromboxane A(2) (TXA(2)) was significantly increased in the CCI group. Indomethacin increased endothelium-dependent relaxa tion in all groups and neurogenic relaxation in the CCI group,but fail ed to normalize the differences in relaxation between treated and cont rol groups. In the presence of indomethacin, L-arginine improved endot helium-dependent relaxation of cavernosal tissue in the Hch group but did not normalize endothelium-dependent or neurogenic relaxations in t he CCI group. Relaxation to NO donor sodium nitroprusside and papaveri ne was similar in cavernosal tissue from all groups. Conclusions: Impa irment of endothelium-dependent relaxation by Hch occurs secondary to disruption of the NO formation in cavernosal endothelium. Improvement of endothelium-dependent relaxation by L-arginine may suggest lack of availability of L-arginine in cavernosal tissue from the Hch animals. Impairment of endothelium-dependent and neurogenic relaxation by CCI o ccurs secondary to disruption of the NO formation due to an alteration in the expression or activity of NOS and increased output of constric tor eicosanoids in cavernosal tissue. These studies show that Hch and atherosclerosis-induced chronic cavernosal arterial insufficiency, bey ond decreasing cavernosal perfusion pressure, also adversely affect sm ooth muscle relaxation mechanisms in cavernosal tissue.