Lack of beneficial effects on 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 pressor 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 pressor 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 pressor stimuli was enhanced. 4. Molsidomine alone, as compared to controls, dose-dependently decreased maternal blood pressure but had no effect 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 pressor 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.
Richer
C
C
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Boulanger
H
H
Es-Slami
S
S
Giudicelli
J F
JF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors; D005260:Female; D005333:Fetus / Q000098:blood supply / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008981:Molsidomine / Q000627:therapeutic use*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000517:prevention & control*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester