Effect of i1 imidazoline receptor agonist, moxonidine, in nitric oxide-deficient hypertension in pregnant rats.
Decreased nitric oxide production has been reported in preeclampsia, which is also frequently associated with glucose intolerance. It was thus considered of interest to investigate the effects of moxonidine, a centrally acting antihypertensive drug that reduces insulin resistance, in a rat model of preeclampsia. Hypertension was induced in Wistar rats by dietary l-NNA (N(omega)-nitro-L-arginine, 0.063%, 31 mg/kg/d, days 13-19 of gestation) and, over the same period, moxonidine or vehicle was administered orally (2 mg/kg/d by gavage). On day 20, blood pressure was measured in the pentobarbital anesthetized animals, glucose tolerance was tested (2 g/kg glucose i.p.), and morphologic studies were conducted on the litter to determine the benefits with respect to fetal outcome. Hypertension was reduced with daily moxonidine treatment (P < 0.05). Basal plasma insulin and insulin/glucose index were decreased with moxonidine treatment evidencing improved insulin sensitivity in the control and l-NNA-treated pregnant rats (P < 0.05). After glucose challenge, plasma insulin increased in all the groups as expected and plasma insulin and insulin/glucose index were significantly higher in the l-NNA group than in the control, moxonidine, or l-NNA + moxonidine groups (P < 0.05 for time 60 minutes). Thus, moxonidine improved glucose tolerance in l-NNA-treated pregnant rats. Moreover, moxonidine treatment very effectively decreased the number of necroses (1 necrosis in 71 fetuses in the l-NNA + moxonidine group versus 15 necroses in 79 fetuses in the l-NNA group, P < 0.01). In conclusion, the 7-day treatment with moxonidine suppressed hypertension and reduced glucose intolerance and fetal necrosis, thus demonstrating the effectiveness of moxonidine in the preeclamptic model.
Gairard
Alexis
A
Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, Faculté de Pharmacie, Illkirch, France. gairard@aspirine.u-strasbg.fr
Lopez-Miranda
Visitacion
V
Pernot
Fanny
F
Beck
Jean F
JF
Coumaros
Geneviève
G
Van Overloop
Bruno
B
La Roche
Benoît
B
Koehl
Christian
C
Christen
Marie O
MO
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology; D005951:Glucose Tolerance Test; D046110:Hypertension, Pregnancy-Induced / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D009336:Necrosis; D009569:Nitric Oxide / Q000172:deficiency*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000819:agonists*; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D009569:Nitric Oxide; C043482:moxonidine; D019001:Nitric Oxide Synthase