Oral losartan treatment improves microvascular endothelial function via nitric oxide-dependent mechanisms in women with a history of preeclampsia.

Abstract

Background: Women with a history of preeclampsia are at increased risk of developing cardiovascular disease compared with women who had a healthy pregnancy. One potential mechanism underlying this increased risk is microvascular endothelial dysfunction, characterized by reduced nitric oxide (NO)-dependent dilation and is mediated, in part, by increased vasoconstrictor sensitivity to angiotensin II, which persists postpartum. We hypothesized that systemic angiotensin II type 1 receptor (AT1R) inhibition via once-daily oral losartan treatment would 1) improve endothelium- and NO-dependent dilation, and 2) reduce angiotensin II-mediated vasoconstriction, in the microvasculature of women with a history of preeclampsia.

Methods: Eleven normotensive women, >12 weeks and ≤5 years postpartum, with a history of preeclampsia participated in a double-blind, placebo-controlled, crossover study. Following 6 weeks of placebo and losartan treatment (50 mg/day), we measured cutaneous vascular conductance responses to graded infusions of acetylcholine (ACh, 10-10-10-1M) alone or with 15mM NG nitro L-arginine methyl ester (L-NAME; NO-synthase inhibitor) to assess endothelium- and NO-dependent dilation, respectively. We also assessed microvascular vasoconstrictor responses to graded infusions of angiotensin II (10-20-10-4M) and norepinephrine (10-12-10-2M).

Results: Losartan treatment increased endothelium- (P<0.001) and NO-dependent (P<0.016) vasodilation compared with placebo. Losartan treatment also reduced angiotensin II-mediated vasoconstriction (P<0.001) compared with placebo, but had no effect on norepinephrine-mediated vasoconstriction (P=0.46).

Conclusions: These data suggest that systemic AT1R-inhibition with oral losartan is a viable, mechanism-specific approach to improve endothelial function and reduce vasoconstrictor sensitivity to angiotensin II in the microvasculature of healthy, normotensive women with a history of preeclampsia.