Goals of this proposal (in response to the RFA on Hypertension in Pregnancy) are to assess the influence of atrial natriuretic- peptides (ANP) on fluid volume, kidney function and blood pressure during normal and hypertensive gestation. Experiments utilizing pregnant Sprague-Dawley, spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats have the following aims: 1) To assess serial)y ANP in relation to the progressive and marked increases in blood volume that occur during rodent pregnancy. Studies to be performed on animals subjected to volume manipulation (chronically: high or low Na diets, mineralocorticoids: acutely: saline loads or diuretics) include: a) Measurement of plasma and atrial ANP, the mRNA of ANP's preprohormone in the atrium, and other humoral volume markers i.e. aldosterone, renin activity, and vasopressin (AVP) levels. b) Determining ANP release in an in vitro atrial prepara- tion, examining hearts from animals treated as described above. 2) Determine if changes in the density and affinity of glomerular receptors for ANP and angiotensin II (two hormones with opposing effects on mesangial cell contractility) can explain the increase in glomerular filtration rate (GFR) during gestation (or lack of it in hypertensive animals). 3) Assess effects of administered ANP on GFR, Na excretion and blood pressure in awake chronically catheterized rodents. Finally we will take advantage of our ongoing studies of AVP release in gestation. 4) To measure circulating ANP throughout human pregnancy focusing on the influence of posture, tonicity, and acute volume expansion.

Hypotheses to be tested are: volume-sensing-ANP release relationships change in pregnancy and the absolute increments in volume are not "sensed" as excessive. Alterations in these relationships may explain pathophysiologic changes in volume, salt handling, and GFR during hypertensive gestations. Many of the discrepant results regarding ANP in human pregnancy reflect gestational stage studied and failure to control posture.

We have chosen to study the SHR because its pathophysiology resembles that of essential hypertension in humans, which is responsible for 50% of the hypertensive complications of gestation. Finally, this response to the solicited RFA represents an extension of applicants' ongoing research interests that center on the kidney and volume homeostasis in pregnancy.

R01HD024498

1988-02-01

1992-01-31