Few studies have examined the potential effects of childbirth on the responses of the female vasculature - especially the resistance microvasculature of non-reproductive tissues. In the present study we have investigated the response of mesenteric microvascular resistance vessels to estrogen (E2), an important vasoactive hormone. Vessels were obtained from either nulliparous or postpartum female Sprague-Dawley rats, and isometric tension studies were performed. We found that E2 induced a concentration-dependent, endothelium-independent relaxation of microvessels precontracted with 10 -5 M phenylephrine; however, E2-induced relaxation was reduced by nearly half in vessels from postpartum animals compared to nulliparous controls. Inhibiting nitric oxide synthase activity with 10-4 M l-NMMA or l-NPA (which exhibits selectivity for type 1 or nNOS) attenuated the relaxation effect of E2 on arteries from nulliparous animals. In contrast, l-NPA had little effect on arteries from postpartum animals, suggesting a reduced influence of nNOS after parturition. Moreover, expression of nNOS protein in microvessels was decreased 39% in the postpartum state compared to arteries from nulliparous animals. We propose that the impaired E2-induced relaxation response of microvessels from postpartum animals reflects a downregulation of NO production due to lower nNOS expressed in vascular smooth muscle cells. We measured a 73% decrease in serum E2 levels in the postpartum state compared to nulliparous animals. Because E2 has been shown to increase nNOS protein expression, we propose that lower E2 levels after parturition decrease expression of nNOS, leading to a reduced vasodilatory capacity of resistance microvessels.