E. Balcells et al., ANGIOTENSIN-II FORMATION IN DOG HEART IS MEDIATED BY DIFFERENT PATHWAYS IN-VIVO AND IN-VITRO, American journal of physiology. Heart and circulatory physiology, 40(2), 1996, pp. 417-421
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.