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


OBJECTIVE
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 micromol/l) or the specific PGHS-2 inhibitor NS-398 (10 micromol/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 micromol/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.
Armstrong
Stephen J
SJ
Department of Ob/Gyn and Physiology, 232 Heritage Medical Research Centre, Perinatal Research Centre, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Xu
Yi
Y
Davidge
Sandra T
ST
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D008469:Meclofenamic Acid / Q000494:pharmacology; D008593:Menopause / Q000502:physiology*; D008638:Mesenteric Arteries; D016210:Methacholine Chloride; D023421:Models, Animal; D009578:Nitrobenzenes / Q000494:pharmacology*; D010052:Ovariectomy; D010656:Phenylephrine; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000378:metabolism*; D011463:Prostaglandins H / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents
D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D011463:Prostaglandins H; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D016210:Methacholine Chloride; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010656:Phenylephrine; D008469:Meclofenamic Acid; C015014:azo analog I; D011451:Prostaglandin-Endoperoxide Synthases