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Actions and interactions of N G ‐substituted analogues of l ‐arginine on NANC neurotransmission in the bovine retractor penis and rat anococcygeus muscles
Author(s) -
Martin William,
Gillespie John S.,
Gibson Ian F.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13469.x
Subject(s) - penis , arginine , neurotransmission , retractor , chemistry , neuroscience , anatomy , pharmacology , biology , medicine , biochemistry , surgery , receptor , amino acid
1 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. 2 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. 3 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. 4 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. 5 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 ). 6 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. 7 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.