This proposal seeks to expand our understanding of arterial smooth muscle control during pregnancy and investigate a working hypothesis of the mechanism for preeclamptic hypertension. There are likely multiple etiologies for preeclampsia, each producing symptoms by activation of a common pathway. If so, therapy should be directed at the pathway and not at an etiology. We hypothesize that preeclamptic hypertension results from the potentiation of multiple vasoconstrictors by platelet released serotonin in a microenvironment characterized by decreased serotonin catabolism and disruption of the normal checks and balances for vasoconstriction. Since preeclampsia occurs only during pregnancy, the hypothesis requires that arterial smooth muscle respond to stimulate during pregnancy differently than remote from pregnancy. Nine questions are posed. The first four are addressed using guinea pigs chronically instrumented so that blood pressure, heart rate, cardiac output, and uterine blood flow velocity are measured in a continuous fashion. Questions 5-9 are addressed using suspended isometric rings from guinea pig uterine and mesenteric arteries. Question 1: Does a subcontractile concentration of serotonin shift left the pressor response curve for either epinephrine (E), norepinephrine (NE), U46619 (a thromboxane mimic) or leukotriene C4 (the study agents) regardless of pregnancy status? Question 2: Does pretreatment with indomethacin alter the interaction between serotonin and the study agents regardless of pregnancy status? Question 3: Does a left shift in the pressor curve occur in the guinea pig after suppression of plasma renin activity by volume loading the animal as it does after pretreatment with indomethacin? Question 4: Does a low dose of aspirin reduce the A II pressor response in contrast to the increase which follows a high dose? Question 5: Does serotonin potentiation of the study drugs differ qualitatively or quantitatively between pregnant and nonpregnant animals and between vessels? Question 6: Does EDRF play a role in the pregnancy associated reduction of arterial smooth muscle responsiveness to the study agents? Question 7: Does pretreatment of the isometric suspended ring with indomethacin further shift the dose response curve to the left regardless of gravid state? Question 8: Does serotonergic potentiation result from a change in the delivery of calcium to the contractile mechanism or from a change in the receptor status? Question 9: Does the combination of serotonin with the other study agents stimulate prostacyclin release above that which would be expected by simply summing the prostacyclin released in response to the individual agents?