INTERACTIONS OF NITRIC-OXIDE SYNTHASE INHIBITORS AND DEXAMETHASONE WITH ALPHA-ADRENOCEPTOR-MEDIATED RESPONSES IN RAT AORTA

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 alpha-adreno ceptor antagonists, have been investigated in rat isolated thoracic ao rtic rings with/without endothelium. 2 NA produced concentration-depen dent contractions of isolated aortic rings with EC50 values of 2.41 +/ - 0.54 (n = 21) and 28.00 +/- 8.50 (n = 25) nM 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 muM), or L-NMMA (10-500 muM), but not t heir D-isomers, resulted in an endothelium-dependent enhancement of NA -induced contractions. Pre-treatment, in vitro, with 0.5 muM dexametha sone neither directly potentiated, nor influenced L-NAME-induced poten tiation of NA-mediated contractions in endothelium-intact rings; howev er, dexamethasone pretreatment reduced EC50 values for NA, and also pr evented L-NAME-induced potentiation, in denuded rings equilibrated for 5h under resting tension. 4 In both intact and denuded rings, phentol amine, prazosin and WB 4101 shifted NA concentration-response curves t o the right; L-NAME, and also L-NMMA, but not their D-isomers, reverse d the blockade as indicated by significant decreases in NA dose-ratios . In denuded rings, reversal by L-NAME or L-NMMA was prevented followi ng pretreatment with dexamethasone. 5 Following treatment with 5 or 50 nM phenoxybenzamine (PBZ), NA concentration-response (C-R) curves wer e shifted to the right with marked depression of maximal responses; 10 0 muM L-NAME reversed the antagonism in both endothelium intact and de nuded rings. However, 500 nM PBZ treatment resulted in complete abolit ion of the responses to NA, and contractions were not restored by eith er L-NAME or L-NMMA. 6 5-Hydroxytryptamine (5-HT)-induced contractions of aortic rings were potentiated by endothelium denudation and also b y L-, but not D-, NAME. 5-HT-induced contractions were non-competitive ly antagonized by 10 nM ritanserin, and 100 muM L-NAME partially rever sed the antagonism in intact but not denuded rings. 7 It is concluded that the inhibition of constitutive endothelial NO synthase and induci ble smooth muscle NO synthase accounts for the ability of L-NAME, and L-NMMA, to potentiate the effects of agonists and reduce a-adrenocepto r antagonism in endothelium-intact and denuded rings. Furthermore, end othelial cell removal/damage triggers the induction of a smooth muscle NO synthase.