NHLBI CLINICAL INVESTIGATOR AWARD PROGRAM

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This award is sought to further develop the research skills of an individual whose long-term career goal is to become an independent investigator in areas related to volume homeostasis and hypertension in pregnancy. Experiments, designed to elucidate water handling and the role of vasopressin (AVP) during both normal and abnormal gestation will be performed under the sponsorship of Dr. M.D. Lindheimer as follows: I. Water Metabolism: The factors responsible for gestational decreases in both plasma osmolality (Posm) and thresholds for AVP secretion and drinking will be investigated. Serial blood pressure and Posm will be examined throughout pregnancy to determine whether the gestational decrement in mean arterial pressure may be responsible for alterations in osmoregulation while pseudopregnant rats will be studied to determine if the fetoplacental unit plays a specific role in these changes. The possibility that the renin-angiotensin system, prolactin and endorphins are involved will also be examined through administration of hormone to virgin animals and/or through inhibition of specific hormones in gravid animals. II. Hypertension: These studies aim to investigate the role of vasopressin and related hormonal systems in the control of blood pressure during pregnancy in (1) normotensive Wistar-Kyoto rats, (2) an animal model of human essential hypertension, i.e. the spontaneously hypertensive rat, and (3) an animal (rat) model of human preeclampsia. Experiments will be performed to determine the vascular reactivity to AVP, angiotensin II and catecholamines and in addition the contribution of each in the maintenance of blood pressure will be assessed through the administration of specific vascular blocking agents. In parallel experiments blood pressure, volume and levels of the above hormones will be measured in early, mid and late gestation. In human studies water handling, AVP secretion, plasma renin activity and catecholamines will be compared in normotensive women and in gravidas with mild hypertension using physiological stimuli such as water loading and restriction. Volume homeostasis, water handling and blood pressure control in pregnancy are poorly understood. Information gained from present investigations will contribute to a better understanding of these phenomena and may lead to improvement in the clinical management of hypertensive disorders complicating gestation.