Optimizing nitric oxide production by time dependent L-arginine administration in isolated human corpus cavernosum

Abstract

Purpose: We investigated the relaxant effects of repetitive administration of L-arginine, the substrate for nitric oxide, at hourly intervals and elucidated its mechanism of action in human corpus cavernosum.

Materials and methods: Samples of human corpus cavernosum were suspended in an organ chamber for measurements of isometric tension. After precontraction with phenylephrine (10 microM), concentration-response curves were performed for L-arginine at 2-hour intervals (1 to 10 hours). Underlying mechanisms of relaxation were evaluated by inhibitory and stimulatory agents.

Results: After a brief incubation period of 1 to 4 hours L-arginine (0.1 to 1,000 microM) but not D-arginine induced minor changes in HCC. In contrast, when incubation time was increased to 6 to 10 hours L-arginine evoked detectable human corpus cavernosum relaxation proportional to concentration and time. Relaxation was significantly attenuated by the nitric oxide synthase inhibitor L-NAME, the blocker of soluble guanylyl cyclase ODQ and the blocker of small conductance Ca2+ activated K+ channels apamin, and partially by the inducible nitric oxide synthase inhibitor aminoguanidine and the cyclic guanosine 5'-monophosphate dependent protein kinase G inhibitor Rp-8-pCPT-cGMPS. Relaxation was potentiated in the presence of the membrane permeable cyclic guanosine 5'-monophosphate analogue 8-bromo-cyclic guanosine 5'-monophosphate, the Rho-kinase inhibitor Y-27632 and the phosphodiesterase-5 inhibitor sildenafil.

Conclusions: These observations demonstrate that L-arginine induces slow and prolonged relaxation of human corpus cavernosum. This may occur by restoring the endogenous amino acid pool for nitric oxide synthesis and by nitric oxide-soluble guanylyl cyclase-protein kinase G signaling involving the activation of KCa channels or by inhibiting the up-regulated RhoA/Rho-kinase pathway. The use of sildenafil combined with L-arginine further facilitates erections and it may benefit men with more severe erectile dysfunction.