Effects of age and sex on cerebrovascular function in the rat middle cerebral artery

Background: Although the mechanisms underlying the beneficial effects of estrogen on cerebrovascular function are well known, the age-dependent deleterious effects of estrogen are largely unstudied. It was hypothesized that age and sex interact in modulating cerebrovascular reactivity to vasopressin (VP) by altering the role of prostanoids in vascular function. Methods: Female (F) Sprague-Dawley rats approximating key stages of "hormonal aging" in humans were studied: premenopausal (mature multigravid, MA, cyclic, 5-6 months) and postmenopausal (reproductively senescent, RS, acyclic, 10-12 months). Age-matched male (M) rats were also studied. Reactivity to VP (10(-12)-10(-7) M) was measured in pressurized middle cerebral artery segments in the absence or presence of selective inhibitors of COX-1 (SC560, SC, 1 M) or COX-2 (NS398, NS, 10 mu M). VP-stimulated release of PGI(2) and TXA(2) were measured using radioimmunoassay of 6-keto-PGF(1 alpha) and TXB2 (stable metabolites, pg/mg dry wt/45 min). Results: In M, there were no changes in VP-induced vasoconstriction with age. Further, there were no significant differences in basal or in low-or high-VP-stimulated PGI(2) or TXA(2) production in younger or older M. In contrast, there were marked differences in cerebrovascular reactivity and prostanoid release with advancing age in F. Older RS F exhibited reduced maximal constrictor responses to VP, which can be attributed to enhanced COX-1 derived dilator prostanoids. VP-induced vasoconstriction in younger MA F utilized both COX-1 and COX-2 derived constrictor prostanoids. Further, VP-stimulated PGI(2) and TXA(2) production was enhanced by endogenous estrogen and decreased with advancing age in F, but not in M rats. Conclusions: This is the first study to examine the effects of age and sex on the mechanisms underlying cerebrovascular reactivity to VP. Interestingly, VP-mediated constriction was reduced by age in F, but was unchanged in M rats. Additionally, it was observed that selective blockade of COX-1 or COX-2 produced age-dependent changes in cerebrovascular reactivity to VP and that VP-stimulated PGI(2) and TXA(2) production were enhanced by endogenous estrogen in younger F. A better understanding of the mechanisms by which estrogen exerts its effects may lead to new age-and sex-specific therapeutic agents for the prevention and/or treatment of cerebrovascular diseases.