Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats.

OBJECTIVE: To examine whether chronic administration of the natural hormone progesterone or a synthetic progestogen, medroxyprogesterone acetate, to ovariectomized rats affects the endothelial control of arterial tone in the isolated mesenteric artery. DESIGN: Sham-operated rats received a daily subcutaneous injection of solvent (sesame oil), whereas ovariectomized rats received either sesame oil, progesterone (22 mg kg/day), or medroxyprogesterone acetate (22 mg kg/day) for 4 weeks, according to their respective group. RESULTS: Phenylephrine-induced contractions were significantly increased (about 200% at 10 microM) by N-nitro-L-arginine, a nitric oxide synthase inhibitor, in intact mesenteric arterial rings from the sham-operated but not from the ovariectomized group. The progesterone but not the medroxyprogesterone treatment restored the potentiating effect of N-nitro-L-arginine on phenylephrine-induced contraction (about 180% at 10 microM). Contractions to phenylephrine were not affected by the combination of charybdotoxin plus apamin, two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses, in all groups. Acetylcholine induced endothelium-dependent relaxations, which were partially inhibited by N-nitro-L-arginine and abolished by the combination of N-nitro-L-arginine plus charybdotoxin and apamin, in all groups. Acetylcholine induced similar charybdotoxin and apamin-sensitive hyperpolarizations in intact mesenteric artery segments from all groups. CONCLUSIONS: Chronic administration of progesterone, but not medroxyprogesterone, to ovarictomized rats restores the endothelium-dependent attenuation of contractile responses to phenylephrine in mesenteric arterial rings through the endothelial formation of nitric oxide. Thus, an enhancement of the protective effect of endothelial cells on the arterial wall might contribute to the beneficial effect of certain progestogen-containing preparations during hormonal treatment.

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.