Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan

The development of very specific blockers for the angiotensin II type 1 (AT (1)) receptor made it possible to examine the contribution of angiotensin I I to normal control mechanisms and disease with a specificity beyond what A CE inhibitors could provide. In the present study, we explored the contribu tion of angiotensin II to 2 renal mechanisms: renal hemodynamics and the sh ort feedback loop, in which angiotensin II acts as a determinant of renin r elease. To make that comparison, we studied healthy volunteers in balance o n a 10-mmol sodium intake to activate the renin:system. Our goal was to com pare the relation between the dose of candesartan, an AT(1) receptor blocke r, and the renal hemodynamic and hormonal responses. A second goal was to a scertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-so dium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with th e 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. Th e 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 th e 16-mg dose 4 hours earlier than the other subjects. On the basis of the d ifference in the relation between dose and response and the relationship be tween time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkab le rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evid ence for non-ACE-dependent angiotensin II generation in the kidney.