EFFECTS OF THE ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONIST ZD7155 ON ANGIOTENSIN II-MEDIATED REGULATION OF RENIN SECRETION AND RENAL RENIN GENE-EXPRESSION, RENAL VASOCONSTRICTION, AND BLOOD-PRESSURE IN RATS

Angiotensin Ui receptors have recently been subclassified as type-1 or type-2 receptors. The in vitro and in vivo effects of blocking the an giotensin TI type-1 receptor with ZD7155, an angiotensin II type-1 sel ective receptor antagonist, have been studied in angiotensin Ii-mediat ed increases in cytosolic calcium in rat mesangial cells, in angiotens in II-induced renal and systemic vasoconstriction, and in angiotensin II-mediated regulation of renin secretion and renal renin gene express ion. ZD7155 completely blocked the ability of angiotensin II to elicit an increase in free intracellular calcium concentrations in rat mesan gial cells. In isolated perfused rat kidneys, ZD7155 completely abolis hed the angiotensin II-induced vasoconstriction and increased renin se cretion to 700% of baseline levels. Furthermore. ZD7155 decreased syst olic blood pressure by 16 mm Hg, increased plasma renin activity 3.7-f old, and stimulated renal renin gene expression 4.2-fold in Sprague-Da wley rats in vivo. Our results suggest that ZD7155 is a potent antagon ist of the angiotensin II type-1 receptor, which mediates angiotensin II-induced increases of free intracellular calcium concentrations in ( e.g., renal mesangial cells), constriction of the renal and systemic v asculature, and inhibition of renin secretion and synthesis.