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Chronic inhibition of nitric-oxide synthase potentiates endothelium-dependent contractions in the rat aorta by augmenting the expression of cyclooxygenase-2.
J Pharmacol Exp Ther. 2010 Aug; 334(2):373-80.JP

Abstract

Acute inhibition of nitric-oxide synthase (NOS) unmasks the release of endothelium-derived contracting factors (EDCFs). The present study investigated whether chronic inhibition of NOS modulates endothelium-dependent contractions. Eighteen-week-old male Sprague-Dawley rats were treated by daily gavage for 6 weeks with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (60 mg/kg) or vehicle (distilled water; 1 ml/kg). Chronic treatment with L-NAME increased arterial blood pressure. Isometric tension was measured in aortic rings with or without endothelium. Endothelium-dependent relaxations to acetylcholine and the calcium ionophore 5-(methylamino)-2-[(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)-ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid (A23187) were reduced in preparations from L-NAME-treated rats. The reduction in relaxation to A23187 was partially reversed by L-arginine (1 mM). In quiescent aortic rings, A23187 caused contractions in the presence of L-NAME and intact endothelium. The A23187-induced contractions were greater in rings from the L-NAME-treated rats than in those from the control group. These contractions were abolished by the cyclooxygenase (COX)-2 inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS-398) and the thromboxane-prostanoid (TP) receptor antagonist 3-((6R)-6-{[(4-chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)propanoate (S18886), but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560). Chronic L-NAME treatment reduced the level of nitric oxide in the plasma but increased COX activity in the aortic rings. Western blotting and immunohistochemical staining showed that endothelial NOS expression was reduced in the aortae of the chronic L-NAME-treated group. COX-1 expression was augmented slightly, whereas COX-2 expression was up-regulated markedly. The TP receptor expression was comparable with control. These experiments demonstrate that chronic NOS inhibition increases endothelium-dependent contractions of the rat aorta by inducing COX-2 expression and augmenting the production of EDCF.

Authors+Show Affiliations

Department of Pharmacology and Pharmacy, University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong. rykman@hku.hk.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20444882

Citation

Qu, Chen, et al. "Chronic Inhibition of Nitric-oxide Synthase Potentiates Endothelium-dependent Contractions in the Rat Aorta By Augmenting the Expression of Cyclooxygenase-2." The Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 2, 2010, pp. 373-80.
Qu C, Leung SW, Vanhoutte PM, et al. Chronic inhibition of nitric-oxide synthase potentiates endothelium-dependent contractions in the rat aorta by augmenting the expression of cyclooxygenase-2. J Pharmacol Exp Ther. 2010;334(2):373-80.
Qu, C., Leung, S. W., Vanhoutte, P. M., & Man, R. Y. (2010). Chronic inhibition of nitric-oxide synthase potentiates endothelium-dependent contractions in the rat aorta by augmenting the expression of cyclooxygenase-2. The Journal of Pharmacology and Experimental Therapeutics, 334(2), 373-80. https://doi.org/10.1124/jpet.110.167098
Qu C, et al. Chronic Inhibition of Nitric-oxide Synthase Potentiates Endothelium-dependent Contractions in the Rat Aorta By Augmenting the Expression of Cyclooxygenase-2. J Pharmacol Exp Ther. 2010;334(2):373-80. PubMed PMID: 20444882.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic inhibition of nitric-oxide synthase potentiates endothelium-dependent contractions in the rat aorta by augmenting the expression of cyclooxygenase-2. AU - Qu,Chen, AU - Leung,Susan W S, AU - Vanhoutte,Paul M, AU - Man,Ricky Y K, Y1 - 2010/05/05/ PY - 2010/5/7/entrez PY - 2010/5/7/pubmed PY - 2010/8/18/medline SP - 373 EP - 80 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 334 IS - 2 N2 - Acute inhibition of nitric-oxide synthase (NOS) unmasks the release of endothelium-derived contracting factors (EDCFs). The present study investigated whether chronic inhibition of NOS modulates endothelium-dependent contractions. Eighteen-week-old male Sprague-Dawley rats were treated by daily gavage for 6 weeks with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (60 mg/kg) or vehicle (distilled water; 1 ml/kg). Chronic treatment with L-NAME increased arterial blood pressure. Isometric tension was measured in aortic rings with or without endothelium. Endothelium-dependent relaxations to acetylcholine and the calcium ionophore 5-(methylamino)-2-[(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)-ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid (A23187) were reduced in preparations from L-NAME-treated rats. The reduction in relaxation to A23187 was partially reversed by L-arginine (1 mM). In quiescent aortic rings, A23187 caused contractions in the presence of L-NAME and intact endothelium. The A23187-induced contractions were greater in rings from the L-NAME-treated rats than in those from the control group. These contractions were abolished by the cyclooxygenase (COX)-2 inhibitor N-[2-cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS-398) and the thromboxane-prostanoid (TP) receptor antagonist 3-((6R)-6-{[(4-chlorophenyl)sulfonyl]amido}-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl)propanoate (S18886), but not by the COX-1 inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560). Chronic L-NAME treatment reduced the level of nitric oxide in the plasma but increased COX activity in the aortic rings. Western blotting and immunohistochemical staining showed that endothelial NOS expression was reduced in the aortae of the chronic L-NAME-treated group. COX-1 expression was augmented slightly, whereas COX-2 expression was up-regulated markedly. The TP receptor expression was comparable with control. These experiments demonstrate that chronic NOS inhibition increases endothelium-dependent contractions of the rat aorta by inducing COX-2 expression and augmenting the production of EDCF. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20444882/Chronic_inhibition_of_nitric_oxide_synthase_potentiates_endothelium_dependent_contractions_in_the_rat_aorta_by_augmenting_the_expression_of_cyclooxygenase_2_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20444882 DB - PRIME DP - Unbound Medicine ER -