Activation and potentiation of the NO/cGMP pathway by NG‐hydroxyl‐L‐arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing

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Abstract
When nitric oxide synthase (NOS) produces NO from NG‐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. 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 μM), and by the guanylyl cyclase inhibitor, ODQ (20 μM), 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. Relaxation elicited by OH‐arginine (300 μM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 μM) in RCC was significantly enhanced by addition of OH‐arginine (300 μM) in normoxic conditions, as well as under hypoxia, while L‐arginine did not alter the effects of ACh on cGMP accumulation. 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 μM) significantly potentiated endothelium‐dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L‐arginine (300 μM) did not have significant effects. 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. British Journal of Pharmacology (2003) 138, 63–70. doi:10.1038/sj.bjp.0705027