Several disease states are characterized by resistance to the pressor effects of the vasoconstrictor hormone angiotensin II (AII). Because hormone-receptor interactions are required for hormone action, studies of receptor binding have been performed in a limited number of these conditions. In sodium depletion a decrease in receptor number appears to be responsible for the decreased response to AII. On the other hand, in potassium deficiency a decrease in receptor affinity for AII has been observed. Pregnancy, cirrhosis, and the nephrotic syndrome are also characterized by resistance to the pressor effects of AII. In this proposal, the mechanisms of AII resistance will be studied in vivo using conscious rats. A series of AII dose-pressor response studies will be performed to determine the role of activity of the renin-angiotensin system, prior receptor occupancy, presence of vasodilatory prostaglandins, and volume expansion in producing AII resistance. These findings will then be correlated with in vitro studies of vascular smooth muscle receptor binding of AII using a radioreceptor assay. AII receptor number and receptor affinity will be determined. The role of elevation of AII levels, prostagladins, and volume expansion in smooth muscle AII receptor regulation will be studied. Studies of receptor binding of AII by vascular smooth cells in culture will be performed to study the phenomenon of receptor down regulation, the influence of ionic and hormonal milieu on receptor regulation, and the relationship of binding of AII with post-receptor events. These studies will further regulation. These studies will also result in a better understanding of the altered hemodynamic state of pregnancy, cirrhosis, and the nephrotic syndrome.
