Enhanced vascular reactivity during inhibition of nitric oxide synthesis in pregnant rats.

Abstract

Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120+/-2, 124+/-5, 116+/-4, and 171+/-5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to alpha1-adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31+/-0.03 x 10(4) N/m2) and the high-KCl-induced active stress (0.55+/-0.09 x 10(4) N/m2) were smaller than those in virgin rats. By contrast, in the L-NAME-treated pregnant rats, the maximal phenylephrine-induced active stress (0.76+/-0.1 x 10(4) N/m2) was greater than that in virgin rats (0.52+/-0.1 x 10(4) N/m2), whereas the high-KCl-induced active stress (1.08+/-0.14 x 10(4) N/m2) was indistinguishable from that in virgin rats (1.03+/-0.14 x 10(4) N/m2). Treatment with L-NAME did not affect the phenylephrine-releasable Ca2+ stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to alpha-adrenergic stimulation, which can possibly be explained in part by enhanced Ca2+ entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca2+ and/or activation of a completely Ca2+-independent mechanism cannot be excluded.