Testosterone positively regulates functional responses and nitric oxide expression in the isolated human corpus cavernosum.

BACKGROUND: Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied. OBJECTIVES: To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and nitric oxide-independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway. MATERIALS AND METHODS: Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays. RESULTS: Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression. CONCLUSION: This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men.

Imatinib mesylate (Gleevec) as protein-tyrosine kinase inhibitor elicits smooth muscle relaxation in isolated human prostatic tissue.

OBJECTIVE: To evaluate the mechanism of action of imatinib mesylate (Gleevec), a protein tyrosine kinase inhibitor on the human prostate with benign prostatic hyperplasia. METHODS: Prostate samples were obtained from 16 patients with benign prostatic hyperplasia (mean age 68.3 ± 1.9 years), who had undergone transurethral prostatectomy. In tissue bath studies, cumulative concentration-response curves were constructed for imatinib after precontraction with 120 mM KCl. Imatinib-induced relaxation was quantitated in tissues treated with l-N(G)-Nitroarginine Methyl Ester (l-NAME) (an inhibitor of nitric oxide synthase) or 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylyl cyclase inhibitor). Two K+ channel blockers (adenosine triphosphate [K(ATP)] and Large-conductance Ca(2+)-activated K(+) channels [BK(Ca2+)] channels) were also evaluated as antagonists of imatinib-induced relaxation and repeated in the presence of the α-adrenergic receptor blocker alfuzosin. An electrical field stimulation (1-20 Hz, 5 ms, 5 seconds, 60 V)-induced contractile response was performed on strips incubated with imatinib (10(-3) M). RESULTS: KCl-induced contractions in human prostatic tissue were significantly inhibited by imatinib (maximal response 84.9 ± 4.5%) and were attenuated by l-NAME (42%, P < .001) and ODQ (43%, P < .001). This relaxant effect was also suppressed by glibenclamide (adenosine triphosphate-sensitive K+ channel blocker, 41%, P < .001) and tetraethylammonium (BK(Ca2+) channel blocker, 24%, P < .05). CONCLUSION: Imatinib induced prostatic smooth muscle relaxation in vitro. This effect was suppressed by l-NAME and ODQ, showing a dependence on the nitric oxide-cyclic guanosine monophosphate pathway and modulated by the K(ATP) and BK(Ca2+) K+ channels. Our findings suggest that imatinib can augment relaxation of human prostatic tissues by way of a novel ligand-protein tyrosine kinase signaling pathway.