Effects of chronic PGHS-2 inhibition on PGHS-dependent vasoconstriction in the aged female rat

被引:3
作者
Armstrong, SJ [1 ]
Xu, Y [1 ]
Davidge, ST [1 ]
机构
[1] Univ Alberta, Dept Ob Gyn & Physiol, Heritage Med Res Ctr 232, Perinatal Res Ctr, Edmonton, AB T6G 2S2, Canada
关键词
aging; mesenteric arteries; PGHS-2; inhibition; prostaglandin; female;
D O I
10.1016/j.cardiores.2003.11.009
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: In menopause, aging and decreased estrogen levels are risk factors contributing to impaired vascular function. Previously, in a young ovariectomized rat model, we demonstrated an increase in prostaglandin H synthase (PGHS)-dependent vasoconstriction that could be prevented by estrogen replacement. Subsequently, we found that, with aging, estrogen acts through suppression of the PGHS-2 isoform. Hypothesis: Chronic PGHS-2 inhibition reduces PGHS-dependent vasoconstriction in aging. Methods: Ovariectomized, aged (12 months) Sprague-Dawley rats were treated with a placebo (n = 7), or the PGHS-2 inhibitor (NS-398, s.c. 3 mg/kg) for I week (n = 6) or 4 weeks (n = 6). Miethacholine (endothelium-dependent dilator) and phenylephrine (adrenergic constrictor) were used to assess vascular function in the absence or presence of the nonselective PGHS inhibitor, meclofenamate (1 mumol/l) or the specific PGHS-2 inhibitor NS-398 (10 mumol/l). Results: One week of chronic PGHS-2 inhibition abolished a PGHS-dependent shift in methacholine-induced relaxation, while modulation was still observed in phenylephrine constriction. Surprisingly, 4 weeks of PGHS-2 inhibition enhanced PGHS-dependent modulation of vasoconstriction (P < 0.05). PGH(2)/thromboxane inhibition (U-51605, 50 mumol/l) mimicked the results observed with PGHS inhibition among the groups. PGHS-2 expression increased with chronic PGHS-2 inhibition compared to control (P < 0.05). Conclusions: Our data indicate a paradoxical increase in PGHS-dependent vasoconstriction and PGHS-2 expression with prolonged inhibition of PGHS-2 activity. Hence, inhibitors of PGHS-2 activity may not be beneficial in counteracting the vascular dysfunction seen with aging and menopause. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:333 / 338
页数:6
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