Angiotensin-converting enzyme inhibitor captopril reverses the adverse cardiovascular effects of polymerized hemoglobin.
OBJECTIVE
Cell-free hemoglobin-based oxygen carriers (HBOCs) may increase the risk of myocardial infarction and death. We studied the effect of an angiotensin-converting enzyme (ACE) inhibitor on HBOC-induced adverse cardiovascular outcomes and elucidated the underlying mechanisms.


RESULTS
With a dog cardiopulmonary bypass model, we demonstrated that a high-dose HBOC (3%, w/v) did not reduce-but aggravated-cardiac ischemia/reperfusion injury. Animals administered a high-dose HBOC experienced coronary artery constriction and depression of cardiac function. Exposure of isolated coronary arteries or human umbilical vein endothelial cells to high-dose HBOC caused impaired endothelium-dependent relaxation, increased endothelial cell necrosis/apoptosis, and elevated NAD(P)H oxidase expression (gp91(phox), p47(phox), p67(phox), and Nox1) and reactive oxygen species (ROS) production. All observed adverse outcomes could be suppressed by the ACE inhibitor captopril (100 μM). Co-incubation with free radical scavenger tempol or NAD(P)H oxidase inhibitor apocynin had no effect on captopril action, suggesting that the positive effects of captopril are ROS- and NAD(P)H oxidase dependent. ACE inhibition by captopril also contributed to these effects. In addition, bioavailable nitrite oxide (NO) reduced by high-dose HBOC was preserved by captopril. Furthermore, HBOC, at concentrations greater than 0.5%, inhibited large conductance Ca(2+)-activated K(+) channel currents in vascular smooth muscle cells in a dose-dependent manner, although captopril failed to improve current activity, providing additional evidence that captopril's effects are mediated by the endothelium, but not by the smooth muscle.


CONCLUSIONS
Captopril alleviates high-dose HBOC-induced endothelial dysfunction and myocardial toxicity, which is mediated by synergistic depression of NAD(P)H oxidase subunit overproduction and increases in vascular NO bioavailability.
1 Laboratory of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University , Chengdu, China .
Tao
T
Li
Ronghua
R
Zhou
Yusheng
Y
Yao
Qian
Q
Yang
Cheng
C
Zhou
Wei
W
Wu
Qian
Q
Li
Zhen
Z
You
Xiaolin
X
Zhao
Linhui
L
Yang
Chen
C
Li
Da
D
Zhu
Yanhua
Y
Qiu
Ming
M
Luo
Zhaoxia
Z
Tan
Huan
H
Li
Yanfang
Y
Chen
Gu
G
Gong
Yuan
Y
Feng
Ke
K
Dian
Jin
J
Liu
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002216:Captopril / Q000494:pharmacology*; D054715:Cardiotoxins / Q000633:toxicity*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006454:Hemoglobins / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000276:immunology; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014664:Vasodilation
D000806:Angiotensin-Converting Enzyme Inhibitors; D054715:Cardiotoxins; D006454:Hemoglobins; D024681:Potassium Channels, Calcium-Activated; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002216:Captopril; D019255:NADPH Oxidases