Lack of beneficial effects of the NO-donor, molsidomine, in the L-NAME-induced pre-eclamptic syndrome in pregnant rats

1 In pregnant rats, chronic NO-synthase inhibition induces the development of a pre-eclamptic syndrome, characterized by an increase in maternal blood pressure, a loss of vascular refractoriness to presser stimuli, a reduction in litter size and a decrease in pups (and maternal) weight. We investigated whether a NO-donor, molsidomine, administered during NO synthase inhibition, could restore a normal pregnancy. 2 Pregnant rats were given daily, starting from day 14 of gestation, saline (controls), or L-NAME (50 mg kg(-1) d(-1)), or molsidomine (15 or 30 mg kg(-1) d(-1)), or the L-NAME + molsidomine combinations. Maternal blood pressure and body weight, litter size, pups weight and vascular reactivity to presser stimuli (angiotensin II, noradrenaline, electrical stimulation of the spinal cord) were investigated. 3 L-NAME alone, as compared to controls, increased maternal blood pressure, reduced litter size (-59%), increased foetal reabsorptions (+625%) and decreased foetal weight (-10%). Vascular reactivity to presser stimuli was enhanced. 4 Molsidomine alone, as compared to controls, dose-dependently decreased maternal blood pressure but had no effect on vascular reactivity and, whatever the dose, on foetal outcome. 5 The L-NAME-molsidomine combinations dose (of molsidomine)-dependently limited the rise in maternal blood pressure induced by L-NAME alone but unexpectedly, dose-dependently and significantly worsened pregnancy evolution, e.g., at 30 mg kg(-1) d(-1): litter size (-80%), foetal reabsorptions (+1025%), foetal weight (-24%). Vascular reactivity to presser stimuli was paradoxically further enhanced. 6 Thus, in a chronic NO deprivation-induced model of pre-eclampsia in rats, molsidomine, possibly because of its hypotensive action, worsens the foetal outcome, which questions the usefulness of NO-donors in pre-eclamptic women.