Angiotensin-converting enzyme inhibition potentiates angiotensin II type 1receptor effects on renal bradykinin and cGMP

Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by anta gonizing Ang II at its type 1 (AT(1)) receptors and diverting Ang II to its counterregulatory type 2 (AT(2)) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors b lock the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interst itial fluid (RIF) BK levels. We used a microdialysis technique to recover B K and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawle y rats infused for 60 minutes with the AT(1) receptor blocker valsartan (0. 17 mg/kg per minute), with the active metabolite of the ACE inhibitor benaz epril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT(2) re ceptor blocker PD 123,319 (50 mug/kg per minute) alone or combined. Each an imal served as its own control. RIF BK and cGMP levels increased significan tly over I hour in response to valsartan, benazeprilate, or both but not to a vehicle control (P<0.01). The combined benazeprilate-valsartan effect wa s greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) po tentiate each other, and we postulate that such combinations may be benefic ial in clinical states marked by Ang II elevation, such as chronic heart fa ilure, postinfarction left ventricular dysfunction, and hypertension.