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Cardiovascular Research 2004 61(2):333-338; doi:10.1016/j.cardiores.2003.11.009
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

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

Stephen J Armstrong, Yi Xu and Sandra T Davidge*

Department of Ob/Gyn and Physiology, 232 Heritage Medical Research Centre, Perinatal Research Centre, University of Alberta, Edmonton, AB, Canada T6G 2S2

* Corresponding author. Tel.: +1-780-492-1864; fax: +1-780-492-1308. sandra.davidge{at}ualberta.ca

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 1 week (n = 6) or 4 weeks (n = 6). Methacholine (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 µmol/l) or the specific PGHS-2 inhibitor NS-398 (10 µmol/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). PGH2/thromboxane inhibition (U-51605, 50 µmol/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.

KEYWORDS Aging; Mesenteric arteries; PGHS-2 inhibition; Prostaglandin; Female

Time for primary review 21 days


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