title: Cyclooxygenase-1 inhibition attenuates angiotensin II-salt hypertension and neurogenic pressor activity in the rat.
abstract: Cyclooxygenase (COX)-derived prostanoids contribute to angiotensin II (ANG II) hypertension (HTN). However, the specific mechanisms by which prostanoids act are unclear. ANG II-induced HTN is caused partly by increased sympathetic nervous system activity, especially in a setting of high dietary salt intake. This study tested the hypothesis that COX-derived prostanoids cause ANG II-salt sympathoexcitation and HTN. Experiments were conducted in conscious rats. Infusion of ANG II (150 ng·kg(-1)·min(-1) sc) caused a marked HTN in rats on 2% salt diet, but a much smaller increase in blood pressure in rats on 0.4% salt diet. The nonselective COX inhibitor ketoprofen (2 mg/kg sc) given throughout the ANG-II infusion period attenuated HTN development in rats on 2% NaCl diet, but not in rats on 0.4% NaCl diet. The acute depressor response to ganglion blockade was used to assess neurogenic pressor activity in rats on 2% NaCl diet. Ketoprofen-treated rats showed a smaller fall in arterial pressure in response to ganglion blockade during ANG-II infusion than did nontreated controls. In additional experiments, ketoprofen-treated rats exhibited smaller increases in plasma norepinephrine levels and whole body norepinephrine spillover than we previously reported in ANG II-salt HTN. Finally, the effects of the selective COX-1 inhibitor SC560 (10 mg·kg(-1)·day(-1) ip) and the selective COX-2 inhibitor nimesulide (10 mg·kg(-1)·day(-1) ip) were investigated. Treatment with SC560 but not nimesulide significantly reduced blood pressure and the depressor response to ganglion blockade in ANG II-salt HTN rats. The results suggest that COX-1 products are critical for sympathoexcitation and the full development of ANG II-salt HTN in rats.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan.
authors.forename: Ninitha
authors.initials: N
authors.lastname: Asirvatham-Jeyaraj
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: King
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Northcott
authors.forename: Shivanshu
authors.initials: S
authors.lastname: Madan
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Fink
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005730:Ganglionic Blockers / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005730:Ganglionic Blockers; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D017673:Sodium Chloride, Dietary; D013449:Sulfonamides; D000804:Angiotensin II; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; C012655:nimesulide; D009638:Norepinephrine
keywords: angiotensin II; cyclooxygenase; hypertension; salt; sympathetic