Adrenomedullin requires an intact nitric oxide system to function as an endogenous vasodilator in rat gestation.

OBJECTIVE: We hypothesize that administration of adrenomedullin (AM), an endogenous vasodilator, will ameliorate the hypertension and growth restriction associated with chronic nitric oxide inhibition induced by L-omega nitro-L-arginine methyl ester (L-NAME) infusion in pregnant rats. METHODS: Osmotic minipumps were inserted on day 14 of gestation to deliver continuously either AM, L-NAME, AM+L-NAME, or vehicle control. Systolic blood pressure was recorded daily in pregnant rats. Pregnant rats were either sacrificed on gestational days 15, 16, 17, 18, or 22, or they were allowed to deliver at term. The placentas from all of the treated groups were fixed for 24 hr in Bouin solution, sectioned, processed, embedded in paraffin, and stained with hematoxylin and eosin. The placentas were graded for the quality of fetal vessel development in the labyrinth. RESULTS: Systolic blood pressure was increased in AM+L-NAME-treated rats. The animals that delivered in the AM+L-NAME group exhibited decreased pup weight (L-NAME and AM+L-NAME, 5.2+/-0.1 compared with 6.4+/-0.1 g for both AM and controls, p<0.001) and increased pup mortality (AM+L-NAME, 44.4% compared with 16.7% in L-NAME, 0% in AM and 3.1% in controls, p<0.001 AM+L-NAME compared with controls). Increased decidual necrosis, necrosis in the labyrinth, and deficient fetal vessel development in the labyrinth was identified in the placentas treated with AM+L-NAME. CONCLUSIONS: Addition of the endogenous vasodilator AM to an L-NAME-induced state of chronic NO inhibition did not ameliorate hypertension and growth restriction.

Placental and fetal growth and development in late rat gestation is dependent on adrenomedullin.

Adrenomedullin is a potent, endogenous vasodilator peptide synthesized and secreted by diverse locations such as adrenal glands, lungs, kidneys, vascular smooth muscle, and endothelium. Homozygous deletion of the adrenomedullin gene is embryonic lethal. We hypothesized that adrenomedullin has an important role in placental and fetal growth and development in rat pregnancy. The current study evaluated maternal systolic blood pressure, litter size, placental and pup weight, pup mortality, and placental pathology in pregnant rats following continuous in utero exposure to an adrenomedullin antagonist. Osmotic minipumps were inserted on Gestational Day 14 to continuously deliver either adrenomedullin, adrenomedullin antagonist, or vehicle control. Systolic blood pressure was recorded daily. Pregnant rats were killed on Gestational Day 15-18, 20, and/or 22 to evaluate placental development and fetal growth. The placentas were graded for the presence of necrosis in the decidua and fetal labyrinth as well as fetal vessel development in the labyrinth. A trend toward increased systolic blood pressure was noted between Gestational Days 17 and 20 in mothers treated with adrenomedullin antagonist, but the difference was not statistically significant. Antagonism of adrenomedullin function during rat pregnancy caused fetal growth restriction, decreased placental size, gross necrosis of placental margins and amniotic membranes, histologically deficient fetal vessel development in the labyrinth, and fetal edema. Adrenomedullin contributes to angiogenesis, functions as a growth factor, and helps regulate vascular tone during rat gestation.

Growth and fertility rates in the offspring of pregnant rats treated with L-omega nitro-L-arginine methyl ester (L-NAME), a nitric oxide inhibitor.

OBJECTIVE: The objective of this study was to determine neonatal growth, fertility, and blood pressure for offspring of pregnant rats following in utero exposure to L-omega nitro-L-arginine methyl ester (L-NAME). STUDY DESIGN: Osmotic mini-pumps were inserted on day 14 of gestation during the index pregnancy to deliver L-NAME (50 mg/day/rat) or a placebo control continuously. Pup weights were obtained longitudinally until postnatal day 76. Systolic blood pressures were measured on postnatal days 29 and 44. At 11 weeks of age, groups of females and males (control and L-NAME-exposed in utero) were housed in pairs for 14 days; females were assessed for mating with a sperm positive vaginal flush and subsequent establishment of pregnancy. Pup weight and systolic blood pressure are expressed as mean +/- standard error of the mean and compared by using the unpaired t test. P <.05 was considered statistically significant. RESULTS: Pups born to L-NAME-treated mothers were significantly smaller than controls (5.2 +/- 0.2 g and 6.5 +/- 0.1 g, respectively; P <.0001)). These differences persisted even at postnatal day 76. There was no difference in systolic blood pressure between control and L-NAME-exposed pups. Successful mating rates were as follows: 90% (9/10) in control females with control males, 67% (8/12) in control females with L-NAME males, 47% (7/15) in L-NAME females with control males, and 31% (4/13) in L-NAME females with L-NAME males, P =.007 (control versus L-NAME females). CONCLUSION: The offspring of pregnant rats with in utero exposure to L-NAME (prolonged nitric oxide inhibition) exhibited decreased neonatal weight, postnatal growth, and fertility.