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

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Abstract
1 The effects and interactions of a series of NG-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. 2 Treatment of BRP muscle strips with either NG-nitro l-arginine (l-NOARG: 0.1–10 μm) or NG-nitro l-arginine meythl ester (l-NAME; 0.1–100 μm) produced a concentration-dependent blockade of NANC relaxation: blockade was complete at the highest concentration of each. 3 Pretreatment with l-arginine (1–10 mm) 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 μm) and l-NAME (0.1–1 mm) to produce blockade. l-Arginine (1–10 mm) reversed established submaximal blockade of NANC relaxation induced by l-NOARG (1 μm) or l-NAME (1 μm), but had little effect on maximal blockade induced by these agents. 4 In contrast to l-NOARG and l-NAME, NG-monomethyl l-arginine (l-NMMA; 1 μm-1 mm) had no effect by itself on NANC relaxation of the BRP. l-NMMA (0.1–1 mm) did, however, like l-arginine, inhibit, in a concentration-dependent manner, the subsequent ability of both l-NOARG (0.1–1 mm) and l-NAME (0.1–3 mm) to produce blockade, but was more potent. As with l-arginine, l-NMMA (0.1–1 mm) reversed established submaximal blockade of NANC relaxation induced by l-NOARG (1 μm) or l-NAME (1 μm), but had little effect on maximal blockade induced by these agents. 5 In contrast to the effects on BRP, treatment of rat anococcygeus muscle with either l-NOARG (0.1–10 μm) or l-NMMA (1–100 μm) 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 mm) reversed established submaximal inhibition of NANC relaxation induced by l-NOARG (1 μm), had little effect on maximal blockade by this agent, and reversed maximal blockade induced by l-NMMA (100 μm). 6 In the presence of partial blockade of NANC relaxation on rat anococcygeus by a maximal concentration of l-NMMA (100 μm), subsequent blockade by l-NOARG (0.1–100 μm) was inhibited. l-NMMA (100 μm) produced a partial reversal of established submaximal blockade of NANC relaxation induced by l-NOARG (1 μm), but had little effect on maximal blockade induced by this agent. 7 These findings suggest a complex series of interactions between l-arginine and certain of its NG-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.