Angiotensin II formation in the intact human heart. Predominance of the angiotensin-converting enzyme pathway.
It has been proposed that the contribution of myocardial tissue angiotensin converting enzyme (ACE) to angiotensin II (Ang II) formation in the human heart is low compared with non-ACE pathways. However, little is known about the actual in vivo contribution of these pathways to Ang II formation in the human heart. To examine angiotensin II formation in the intact human heart, we administered intracoronary 123I-labeled angiotensin I (Ang I) with and without intracoronary enalaprilat to orthotopic heart transplant recipients. The fractional conversion of Ang I to Ang II, calculated after separation of angiotensin peptides by HPLC, was 0.415 +/- 0.104 (n = 5, mean +/- SD). Enalaprilat reduced fractional conversion by 89%, to a value of 0.044 +/- 0.053 (n = 4, P = 0.002). In a separate study of explanted hearts, a newly developed in vitro Ang II-forming assay was used to examine cardiac tissue ACE activity independent of circulating components. ACE activity in solubilized left ventricular membrane preparations from failing hearts was 49.6 +/- 5.3 fmol 125I-Ang II formed per minute per milligram of protein (n = 8, +/- SE), and 35.9 +/- 4.8 fmol/min/mg from nonfailing human hearts (n = 7, P = 0.08). In the presence of 1 microM enalaprilat, ACE activity was reduced by 85%, to 7.3 +/- 1.4 fmol/min/mg in the failing group and to 4.6 +/- 1.3 fmol/min/mg in the nonfailing group (P < 0.001). We conclude that the predominant pathway for angiotensin II formation in the human heart is through ACE.
Zisman
L S
LS
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
Abraham
W T
WT
Meixell
G E
GE
Vamvakias
B N
BN
Quaife
R A
RA
Lowes
B D
BD
Roden
R L
RL
Peacock
S J
SJ
Groves
B M
BM
Raynolds
M V
MV
D000803:Angiotensin I / Q000302:isolation & purification / Q000378:metabolism*; D000804:Angiotensin II / Q000302:isolation & purification / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D015773:Enalaprilat / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D016027:Heart Transplantation / Q000502:physiology*; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008962:Models, Theoretical; D009206:Myocardium / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*
D007457:Iodine Radioisotopes; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat