The development of very specific blockers for the angiotensin II type 1 (AT(1)) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT(1) receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142+/-13 mL. min(-1). 1.73 m(-2)) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3+/-1.6 ng. L(-1). s(-1); 55.0+/-5.6 ng angiotensin I. mL(-1). h(-1)) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non-ACE-dependent angiotensin II generation in the kidney.