Activation and potentiation of the NO/cGMP pathway by NG-hydroxyl-L-arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing.
1 When nitric oxide synthase (NOS) produces NO from N(G)-hydroxy-L-arginine (OH-arginine) instead of L-arginine, the total requirement of molecular oxygen and NADPH to form NO is reduced. The aim of this work was to evaluate the effects of OH-arginine on the contractility of rabbit corpus cavernosum (RCC) and to compare the capacities of L-arginine and OH-arginine to enhance NO-mediated responses under normoxic and hypoxic conditions and in ageing, as models of defective NO production. 2 OH-arginine, but not L-arginine, was able to relax phenylephrine-contracted rabbit trabecular smooth muscle. OH-arginine-induced relaxation was inhibited by the NOS-inhibitor, L-NNA (300 microM), and by the guanylyl cyclase inhibitor, ODQ (20 microM), while it was not affected by the cytochrome P450 oxygenase inhibitor, miconazole (0.1 mM). Administration of OH-arginine, but not L-arginine, produced a significant increment of cGMP accumulation in RCC tissue. 3 Relaxation elicited by OH-arginine (300 microM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 microM) in RCC was significantly enhanced by addition of OH-arginine (300 microM) in normoxic conditions, as well as under hypoxia, while L-arginine did not alter the effects of ACh on cGMP accumulation. 4 Endothelium-dependent and nitrergic nerve-mediated relaxations were both significantly reduced in RCC from aged animals (>20-months-old) when compared with young adult rabbits (5-months-old). Treatment with OH-arginine (300 microM) significantly potentiated endothelium-dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L-arginine (300 microM) did not have significant effects. 5 Results show that OH-arginine promotes NO-mediated relaxation of RCC and potentiates the NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. We propose that the use of OH-arginine could be of interest in the treatment of erectile dysfunction, at least in those secondary to defective NO production.
Angulo
Javier
J
Fundación para la Investigación y el Desarrollo en Andrología, Hospital Ramón y Cajal, Madrid, Spain.
Cuevas
Pedro
P
Fernández
Argentina
A
Gabancho
Sonia
S
Allona
Antonio
A
Martín-Morales
Antonio
A
Moncada
Ignacio
I
Sáenz de Tejada
Iñigo
I
D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006152:Cyclic GMP / Q000819:agonists / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017665:Hydroxyl Radical / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000819:agonists / Q000378:metabolism*; D010413:Penis / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D009569:Nitric Oxide; D017665:Hydroxyl Radical; D001120:Arginine; D006152:Cyclic GMP