Abstract
This study analyzes the role of angiotensin II (Ang II), via AT1 receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg · day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg · day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording; COX-2 expression by Western blot and reverse transcription-polymerase chain reaction; prostaglandin (PG)I2, PGF2α, 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion () by lucigenin chemiluminescence; and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) at 1 μM reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF2α, PGI2, 8-isoprostane, and
production, and MDA levels were higher in SHR, but TAS was similar in both strains. Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS-398 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF2α, PGI2, 8-isoprostane, and
production and MDA levels in SHR. Ang II (0.1 μM) induced COX-2 expression in VSMC from SHR that was reduced by 30 μM apocynin and 100 μM allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT1 receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.
Footnotes
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This study was supported by Ministerio de Educacíon y Ciencia Grants (SAF2003-00633 and SAF2006-02376, Fondo de Investigaciones Sanitarias Grant (PIOY1917), and Red Temática de Investigación Cardiovascular Grant (RD06/0014/0011). Part of this work was presented at the 15th European Meeting on Hypertension; 2005 17–21 Jun; Milan, Italy. European Society of Hypertension, Milan, Italy.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.115287.
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ABBREVIATIONS: COX, cyclooxygenase; Ang II, angiotensin II; ROS, reactive oxygen species; VSMC, vascular smooth muscle cell(s); SHR, spontaneously hypertensive rat(s); WKY, Wistar Kyoto; HH, hydralazine-hydrochlorothiazide; MDA, malondialdehyde; TAS, total antioxidant status; NS-398, N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide; RT-PCR, reverse transcription-polymerase chain reaction; PG, prostaglandin; ANOVA, analysis of variance; SQ 29,548, [1S-[1α,2β(5Z)3β,4α]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxobicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid.
- Received October 10, 2006.
- Accepted January 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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