ANGIOTENSIN-II FORMATION IN DOG HEART IS MEDIATED BY DIFFERENT PATHWAYS IN-VIVO AND IN-VITRO

Angiotensin-converting enzyme (ACE) inhibitors (I) have beneficial eff ects that are presumably mediated by decreased angiotensin II (ANG II) production. However, in vitro assays in human heart extracts have dem onstrated that >75% of ANG II-forming enzyme activity was not inhibite d by captopril (Cap) and therefore did not appear to be related to ACE but was inhibited by chymostatin, suggesting that it was predominantl y chymase-like activity. Previous work in our laboratory has demonstra ted a similar relative contribution of ACE and chymase-like activity t oward ANG II formation in vitro in dog heart tissue extracts. Accordin gly, we compared Cap-inhibitable ANG II formation in vitro in heart ti ssue of five adult mongrel dogs to the in vivo Cap-inhibitable, ANG II -forming activity across the myocardial bed in four open-chest, adult mongrel dogs. In vitro studies demonstrated that only 6 +/- 2% of ANG II formation was inhibited by Cap from heart tissue extracts of the le ft ventricular midwall. In in vivo studies, ANC I (0.5 nmol/min) follo wed by ANG I plus the ACE inhibitor Cap (0.1 mu mol/min) was infused i nto the left anterior descending artery, and ANG II was assayed in the proximal aorta and coronary sinus. The arterial-venous (A-V) differen ce of ANG II across the myocardial circulation increased significantly during ANG I infusion (-13.4 +/- 23.5 to 142.8 +/- 71.4 pg/ml; P < 0. 03). Subsequent coinfusion of Cap with ANG I significantly decreased t he myocardial A-V difference of ANG II by 60 +/- 18% (P < 0.05). Thus, in contrast to the in vitro situation, ANG II formation in vivo is in hibited significantly by Cap in the normal dog heart. This comparison of in vivo and in vitro conversion of ANG I to ANG II by ACE and chyma se-like activity suggests that in vitro assays may underestimate the f unctional contribution of ACE to intracardiac ANG II formation.