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Interactions of nitric oxide synthase inhibitors and dexamethasone with α‐adrenoceptor‐mediated responses in rat aorta
Author(s) -
Adeagbo Ayotunde S.O.,
Triggle Christopher R.
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.tb13597.x
Subject(s) - prazosin , omega n methylarginine , phenoxybenzamine , chemistry , phentolamine , acetylcholine , nitric oxide synthase , nitric oxide , endocrinology , dexamethasone , medicine , endothelium , pharmacology , propranolol , biochemistry , antagonist , receptor
1 The effects of N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) and N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA), their d ‐isomers, and dexamethasone on noradrenaline (NA)‐induced contractions and antagonism by α‐adrenoceptor antagonists, have been investigated in rat isolated thoracic aortic rings with/without endothelium. 2 NA produced concentration‐dependent contractions of isolated aortic rings with EC 50 values of 2.41 ± 0.54 ( n = 21) and 28.00 ± 8.50 ( n = 25) n m for endothelium‐denuded and ‐intact preparations respectively. Acetylcholine (ACh) relaxed NA‐precontracted rings with intact, but not those denuded of endothelium. 3 Treatment with l ‐NAME (1–30 μ m ), or l ‐NMMA (10–500 μ m ), but not their d ‐isomers, resulted in an endothelium‐dependent enhancement of NA‐induced contractions. Pre‐treatment, in vitro , with 0.5 μ m dexamethasone neither directly potentiated, nor influenced l ‐NAME‐induced potentiation of NA‐mediated contractions in endothelium‐intact rings; however, dexamethasone pretreatment reduced EC 50 values for NA, and also prevented l ‐NAME‐induced potentiation, in denuded rings equilibrated for 5 h under resting tension. 4 In both intact and denuded rings, phentolamine, prazosin and WB 4101 shifted NA concentration‐response curves to the right; l ‐NAME, and also l ‐NMMA, but not their d ‐isomers, reversed the blockade as indicated by significant decreases in NA dose‐ratios. In denuded rings, reversal by l ‐NAME or l ‐NMMA was prevented following pretreatment with dexamethasone. 5 Following treatment with 5 or 50 n m phenoxybenzamine (PBZ), NA concentration‐response (C‐R) curves were shifted to the right with marked depression of maximal responses; 100 μ m l ‐NAME reversed the antagonism in both endothelium intact and denuded rings. However, 500 n m PBZ treatment resulted in complete abolition of the responses to NA, and contractions were not restored by either l ‐NAME or l ‐NMMA. 6 5‐Hydroxytryptamine (5‐HT)‐induced contractions of aortic rings were potentiated by endothelium denudation and also by l ‐, but not d ‐, NAME. 5‐HT‐induced contractions were non‐competitively antagonized by 10 n m ritanserin, and 100 μ m l ‐NAME partially reversed the antagonism in intact but not denuded rings. 7 It is concluded that the inhibition of constitutive endothelial NO synthase and inducible smooth muscle NO synthase accounts for the ability of l ‐NAME, and l ‐NMMA, to potentiate the effects of agonists and reduce α‐adrenoceptor antagonism in endothelium‐intact and denuded rings. Furthermore, endothelial cell removal/damage triggers the induction of a smooth muscle NO synthase.