The following proposal will investigate the role that activity of the renin-angiotensin system (RAS) during development plays in determining adult cardiovascular and body fluid homeostasis in normotensive and hypertensive rats. Specifically, we will test the hypothesis that increased activity of the RAS during the preweanling period of development plays an initiating role in the development of hypertension in spontaneously hypertensive rats (SHR). This hypothesis is based is based on the fact that increased activity of the central and peripheral RAS is present prior to the rapid rise in arterial pressure in juvenile SHR and our recent finding that blockade of the AT1 receptor during preweanling development decreases blood pressure in adult SHR, but is not effective if treatment is delayed until the juvenile period of development. In addition, blockade of the RAS during preweanling development was found to produce long-term alterations in the regulation of body fluid balance in both WKY and SHR, although the blockade was only effective in reducing adult blood pressure in SHR. Because the central and peripheral RAS play a very consistent role in the maintenance of blood pressure and hydromineral balance, our findings suggest that activity of the RAS during preweanling development determines the maintenance of body fluid balance into adulthood and that increased activity of this system early in life may predispose the SHR towards hypertension. Therefore, the central and peripheral mechanisms through which preweanling RAS blockade produces long-term influences on body fluid and cardiovascular regulation will be investigated in this proposal.
