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


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.
Gur
Serap
S
Department of Urology, Tulane Health Sciences Center, New Orleans, Louisiana 70112, USA.
Kadowitz
Philip J
PJ
Trost
Landon
L
Hellstrom
Wayne J G
WJ
D000368:Aged; D000577:Amides / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007172:Erectile Dysfunction / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000098:blood supply*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology
D000577:Amides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D011725:Pyridines; D013450:Sulfones; C108830:Y 27632; D009569:Nitric Oxide; D001120:Arginine; D000068677:Sildenafil Citrate