We postulated that guanosine 3',5'-cyclic monophosphate (cGMP), a cellular mediator of vascular smooth muscle relaxation, might mediate maternal renal and cardiovascular hemodynamic adaptation to pregnancy. Because extracellular levels of cGMP most likely reflect intracellular production, we began our investigation of this hypothesis by measuring the plasma concentration, urinary excretion, and metabolic clearance rates of cGMP during pregnancy in rats. Plasma cGMP was significantly elevated during mid- and late pregnancy, whereas urinary excretion of cGMP was increased throughout pregnancy. The fractional excretion of cGMP by the kidneys was 0.90 +/- 0.15 in the nonpregnant condition. In contrast, plasma levels of adenosine 3',5'-cyclic monophosphate were unchanged during pregnancy, and its urinary excretion rose slightly, reaching significance only on gestational day 20. There was also a significant rise in urinary excretion of cGMP throughout pseudopregnancy. The metabolic clearance rate of cGMP measured in chronically instrumented rats before, during, and after pregnancy was not significantly altered during gestation. The elevated plasma level of cGMP during gestation in rats, in the face of an unchanged metabolic clearance, reflects augmented tissue(s) production of cGMP, although enhanced cellular efflux may contribute. Because cGMP is a second messenger for several vasodilatory hormones, our data are consistent with the hypothesis that vascular production of cGMP may increase during pregnancy and thereby contribute to maternal renal and cardiovascular vasodilation. (Most investigators have not observed increment of plasma atrial natriuretic peptide in rat gestation; therefore this hormone is an unlikely first messenger for the elevated extracellular levels of cGMP that we have observed. Finally, pseudopregnant rats also showed enhanced urinary excretion of cGMP, which suggests that the proliferative activity that accompanies fetoplacental maturation, as well as hormones elaborated by the fetoplacental unit, is not necessary for the rise in urinary excretion of cGMP observed during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)