Interactions of nitric oxide synthase inhibitors and dexamethasone with α‐adrenoceptor‐mediated responses in rat aorta

Ayotunde S O Adeagbo, Christopher Triggle

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The effects of NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐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. NA produced concentration‐dependent 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. Treatment with l‐NAME (1–30 μm), or l‐NMMA (10–500 μm), but not their d‐isomers, resulted in an endothelium‐dependent enhancement of NA‐induced contractions. Pre‐treatment, in vitro, with 0.5 μm dexamethasone neither directly potentiated, nor influenced l‐NAME‐induced potentiation of NA‐mediated contractions in endothelium‐intact rings; however, dexamethasone pretreatment reduced EC50 values for NA, and also prevented l‐NAME‐induced potentiation, in denuded rings equilibrated for 5 h under resting tension. 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. Following treatment with 5 or 50 nm phenoxybenzamine (PBZ), NA concentration‐response (C‐R) curves were shifted to the right with marked depression of maximal responses; 100 μm l‐NAME reversed the antagonism in both endothelium intact and denuded rings. However, 500 nm PBZ treatment resulted in complete abolition of the responses to NA, and contractions were not restored by either l‐NAME or l‐NMMA. 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 nm ritanserin, and 100 μm l‐NAME partially reversed the antagonism in intact but not denuded rings. 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. 1993 British Pharmacological Society

Original languageEnglish
Pages (from-to)495-501
Number of pages7
JournalBritish Journal of Pharmacology
Volume109
Issue number2
DOIs
Publication statusPublished - 1993
Externally publishedYes

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Nitric Oxide Synthase
Dexamethasone
Aorta
Norepinephrine
Endothelium
Phenoxybenzamine
Adrenergic Receptors
Smooth Muscle
Ritanserin
Prazosin
Phentolamine
Acetylcholine
Esters
Thorax
Endothelial Cells

Keywords

  • dexamethasone
  • inducible NO synthase
  • NO synthase inhibitors
  • Rat aorta
  • α‐adrenoceptors

ASJC Scopus subject areas

  • Pharmacology

Cite this

Interactions of nitric oxide synthase inhibitors and dexamethasone with α‐adrenoceptor‐mediated responses in rat aorta. / Adeagbo, Ayotunde S O; Triggle, Christopher.

In: British Journal of Pharmacology, Vol. 109, No. 2, 1993, p. 495-501.

Research output: Contribution to journalArticle

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AB - The effects of NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐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. NA produced concentration‐dependent 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. Treatment with l‐NAME (1–30 μm), or l‐NMMA (10–500 μm), but not their d‐isomers, resulted in an endothelium‐dependent enhancement of NA‐induced contractions. Pre‐treatment, in vitro, with 0.5 μm dexamethasone neither directly potentiated, nor influenced l‐NAME‐induced potentiation of NA‐mediated contractions in endothelium‐intact rings; however, dexamethasone pretreatment reduced EC50 values for NA, and also prevented l‐NAME‐induced potentiation, in denuded rings equilibrated for 5 h under resting tension. 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. Following treatment with 5 or 50 nm phenoxybenzamine (PBZ), NA concentration‐response (C‐R) curves were shifted to the right with marked depression of maximal responses; 100 μm l‐NAME reversed the antagonism in both endothelium intact and denuded rings. However, 500 nm PBZ treatment resulted in complete abolition of the responses to NA, and contractions were not restored by either l‐NAME or l‐NMMA. 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 nm ritanserin, and 100 μm l‐NAME partially reversed the antagonism in intact but not denuded rings. 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. 1993 British Pharmacological Society

KW - dexamethasone

KW - inducible NO synthase

KW - NO synthase inhibitors

KW - Rat aorta

KW - α‐adrenoceptors

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