To assess the effects of the presence of the uteroplacental circulation on the systemic arterial pressure, blood volume, and cardiac output during pregnancy, we measured those variables and plasma renin activity (PRA) during a 30-min period before and after occlusion of the uterine circulation. After uterine vascular occlusion, pregnant rabbits (n = 7) experienced a drop in mean arterial pressure of 8.7%, heart rate of 9.5%, cardiac output of 30.2%, and hematocrit of 18.2% (each with P less than 0.05). Stroke volume decreased an average of 29.7%; however, it did not reach significance. PRA and venous pressure did not change significantly from the control period (P greater than 0.1). Nonpregnant rabbits did not experience changes in arterial or venous pressures, hematocrit, heart rate, cardiac output, or PRA after closure of the uterine circulation. To exclude the possibility that the findings were secondary to the release of toxic products to the peritoneal cavity by the ischemic pregnant uterus, we also studied the effect of closure of the uterine circulation in five anesthetized pregnant guinea pigs. These animals' uteri were exteriorized and maintained in a sealed plastic container during the experiment. In these animals, arterial pressure decreased 15.6% by 10 min (P less than 0.05). The finding of a significant decrease in arterial pressure and heart rate is compatible with the idea that the uterine circulation produces a substance with a short half-life that has a significant direct effect on the heart and/or systemic vascular tone.