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Angiotensin-converting enzyme inhibitor captopril reverses the adverse cardiovascular effects of polymerized
Tao Li1, Ronghua Zhou, Yusheng Yao
11 Laboratory of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University , Chengdu, China .
Insights
High-dose hemoglobin-based oxygen carriers (HBOCs) worsen cardiac injury by constricting arteries and damaging cells. The ACE inhibitor captopril protects against these effects by reducing oxidative stress and improving nitric oxide availability.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biomedical Engineering
Background:
- Cell-free hemoglobin-based oxygen carriers (HBOCs) are investigated for oxygen transport but may pose cardiovascular risks.
- Previous studies suggest HBOCs can induce adverse effects, including myocardial infarction and death.
Purpose of the Study:
- To investigate the protective effect of an angiotensin-converting enzyme (ACE) inhibitor on HBOC-induced cardiovascular toxicity.
- To elucidate the mechanisms underlying HBOC-induced endothelial dysfunction and myocardial injury.
Main Methods:
- A canine cardiopulmonary bypass model was used to assess cardiac ischemia/reperfusion injury.
- Isolated coronary arteries and human umbilical vein endothelial cells were exposed to HBOCs and/or captopril.
- NAD(P)H oxidase expression, reactive oxygen species (ROS) production, and vascular function were measured.
Main Results:
- High-dose HBOC aggravated cardiac ischemia/reperfusion injury, causing coronary artery constriction and impaired cardiac function.
- HBOC induced endothelial dysfunction, increased endothelial cell necrosis/apoptosis, and elevated ROS production via NAD(P)H oxidase.
- The ACE inhibitor captopril suppressed these adverse effects, preserved nitric oxide (NO) bioavailability, and its effects were dependent on ROS and NAD(P)H oxidase inhibition.
Conclusions:
- Captopril effectively alleviates high-dose HBOC-induced endothelial dysfunction and myocardial toxicity.
- The protective mechanisms involve downregulating NAD(P)H oxidase overproduction and enhancing vascular NO bioavailability.
- These findings highlight the potential of ACE inhibitors to mitigate HBOC-related cardiovascular adverse events.
Aim:
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.
Innovation And Conclusion:
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.
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