Progesterone up-regulates vasodilator effects of calcitonin gene–related peptide in N G-nitro- l-arginine methyl ester–induced hypertension

Abstract

OBJECTIVE: We recently reported that calcitonin gene–related peptide can reverse the hypertension produced by N G-nitro- l-arginine methyl ester in pregnant rats. In the current study we investigated whether these vasodilator effects of calcitonin gene–related peptide were progesterone dependent. STUDY DESIGN: Calcitonin gene–related peptide or N G-nitro- l-arginine methyl ester was infused through osmotic minipumps, either separately or in combination, to groups of five pregnant rats from day 17 of gestation until day 8 post partum or to nonpregnant ovariectomized rats for 8 days. Progesterone was injected during days 1 to 6 post partum and for 6 days after ovariectomy. Systolic blood pressure was measured daily. RESULTS: Animals receiving N G-nitro- l-arginine methyl ester exhibited significant elevations of blood pressure during pregnancy and post partum. Coadministration of calcitonin gene–related peptide to these rats reversed the hypertension during pregnancy but not during the postpartum period. At the dose used in this study calcitonin gene–related peptide administered alone was without significant effects on blood pressure. However, it reduced both the mortality and growth restriction of the fetus associated with N G-nitro- l-arginine methyl ester in these animals. Calcitonin gene–related peptide reversed the hypertension in N G-nitro- l-arginine methyl ester–infused postpartum rats during the periods of progesterone treatment only, and these effects were lost when progesterone treatment was stopped. Neither progesterone nor calcitonin gene–related peptide alone were effective. To further confirm these observations, progesterone effects were tested in ovariectomized adult rats. Similar to the findings in postpartum rats, calcitonin gene–related peptide completely reversed the elevation in blood pressure in N G-nitro- l-arginine methyl ester–treated rats receiving progesterone injections. The effects of calcitonin gene–related peptide were apparent only during the progesterone treatment period, and these effects were lost when progesterone treatment was stopped. Again, at these doses calcitonin gene–related peptide and progesterone were each ineffective alone. Conclusions: Calcitonin gene–related peptide reverses the N G-nitro- l-arginine methyl ester–induced hypertension during pregnancy, when progesterone levels are elevated, but not post partum or in ovariectomized nonpregnant rats. The blood pressure–lowering effects of calcitonin gene–related peptide were restored in both postpartum and ovariectomized rats with progesterone treatment. Therefore we conclude that progesterone modulates vasodilator effects of calcitonin gene–related peptide in hypertensive rats. (Am J Obstet Gynecol 1997;176:894-900.)