Actions and interactions of NG‐substituted analogues of l‐arginine on NANC neurotransmission in the bovine retractor penis and rat anococcygeus muscles

The effects and interactions of a series of N G ‐substituted analogues of l ‐arginine known to inhibit nitric oxide synthase were examined on non‐adrenergic, non‐cholinergic (NANC) neurotransmission in the bovine retractor penis (BRP) and rat anococcygeus muscles. Treatment of BRP muscle strips with either N G ‐nitro l ‐arginine ( l ‐NOARG: 0.1–10 μ m ) or N G ‐nitro l ‐arginine meythl ester ( l ‐NAME; 0.1–100 μ m ) produced a concentration‐dependent blockade of NANC relaxation: blockade was complete at the highest concentration of each. Pretreatment with l ‐arginine (1–10 m m ) had no effect on NANC relaxation by itself, but inhibited, in a concentration‐dependent manner, the subsequent ability of both l ‐NOARG (0.1–300 μ m ) and l ‐NAME (0.1–1 m m ) to produce blockade. l ‐Arginine (1–10 m m ) reversed established submaximal blockade of NANC relaxation induced by l ‐NOARG (1 μ m ) or l ‐NAME (1 μ m ), but had little effect on maximal blockade induced by these agents. In contrast to l ‐NOARG and l ‐NAME, N G ‐monomethyl l ‐arginine ( l ‐NMMA; 1 μ m ‐1 m m ) had no effect by itself on NANC relaxation of the BRP. l ‐NMMA (0.1–1 m m ) did, however, like l ‐arginine, inhibit, in a concentration‐dependent manner, the subsequent ability of both l ‐NOARG (0.1–1 m m ) and l ‐NAME (0.1–3 m m ) to produce blockade, but was more potent. As with l ‐arginine, l ‐NMMA (0.1–1 m m ) reversed established submaximal blockade of NANC relaxation induced by l ‐NOARG (1 μ m ) or l ‐NAME (1 μ m ), but had little effect on maximal blockade induced by these agents. In contrast to the effects on BRP, treatment of rat anococcygeus muscle with either l ‐NOARG (0.1–10 μ m ) or l ‐NMMA (1–100 μ m ) produced concentration‐dependent inhibition of NANC relaxation: the maximal inhibition induced by l ‐NOARG and l ‐NMMA was 100% and 40.1 ± 5.9% ( n = 8), respectively. l ‐Arginine (1–10 m m ) reversed established submaximal inhibition of NANC relaxation induced by l ‐NOARG (1 μ m ), had little effect on maximal blockade by this agent, and reversed maximal blockade induced by l ‐NMMA (100 μ m ). In the presence of partial blockade of NANC relaxation on rat anococcygeus by a maximal concentration of l ‐NMMA (100 μ m ), subsequent blockade by l ‐NOARG (0.1–100 μ m ) was inhibited. l ‐NMMA (100 μ m ) produced a partial reversal of established submaximal blockade of NANC relaxation induced by l ‐NOARG (1 μ m ), but had little effect on maximal blockade induced by this agent. These findings suggest a complex series of interactions between l ‐arginine and certain of its N G ‐substituted analogues that are commonly used to inhibit nitric oxide synthase. The most striking new finding is that l ‐NMMA does not block NANC relaxation in the BRP, but acts with greater potency than the endogenous substrate, l ‐arginine, to inhibit the blockade induced by l ‐NOARG or l ‐NAME. Even on rat anococcygeus where l ‐NMMA acts as a partial blocker of NANC relaxation, further blockade by l ‐NOARG is inhibited.