Effect of Pregnancy on Vascular Cgmp Production and Vasorelaxation in the Rat

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Abstract
Objective: To determine whether vascular endothelium-derived relaxing factor (EDRF) activity is enhanced during gestation in the rat. Methods: Because cyclic guanosine 3′,5′-monophosphate (cGMP) is a second messenger which mediates vascular smooth muscle relaxation by EDRF, we measured basal and stimulated cGMP levels in isolated aortas from virgin and pregnant rats. Endothelium-dependent and -independent relaxation responses were also assessed in isolated aortas. Finally, endothelium-dependent and -independent hypotensive responses were tested in chronically instrumented, conscious virgin, and gravid rats. Results: (1) Basal levels of aortic cGMP were not significantly different between virgin and gravid rats, whether the vessels were incubated in the presence or absence of 0.1 mM 3-isobutyl-l-methyl-xanthine and 1.0 mM L-arginine. Further, reduced hemoglobin or endothelial removal decreased cGMP to the same level in the aortas from the two groups of rats. (2) Methacholine-stimulated production of cGMP was greater in aortas obtained from gravid rats than from virgin controls (P < 0.001), albeit at dosages which exceeded those required to produce half-maximal or even maximal in vitro relaxation. (3) Stimulated production of cGMP by histamine was less in the vessels from pregnant rats (P < 0.004), while that produced by ADP, bradykinin, mellitin, A23187, and sodium nitroprusside was not significantly different between the two groups of animals. (4) The relaxation responses of isolated aortic rings from gravid and virgin rats to both methacholine and sodium nitroprusside were comparable. (5) The peak hypotensive responses to methacholine, sodium nitroprusside, and isoproterenol were also similar between conscious pregnant and virgin rats. Conclusions: (1) Basal levels of cGMP in aortae isolated from virgin and pregnant rats are not significantly different, suggesting that basal production of nitric oxide by endothelial cell constitutive nitric oxide synthase is comparable, and that the inducible nitric oxide synthase is not expressed by this vessel during rat gestation. (2) The postreceptor pathways for EDRF and cGMP synthesis are comparable in aortas obtained from pregnant and virgin rats, and the differences in cGMP production by methacholine and histamine in these vessels from the two groups of rats may be due to gestational alterations of receptor function. (3) The physiological meaning of increased cGMP production observed in aortas of pregnant rats in response to methacholine is uncertain, because the in vitro relaxation and in vivo hypotensive responses to the agent were not significantly altered by gestation.