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Activated neutrophils aggravate endothelial dysfunction after reperfusion of the ischemic feline myocardium
1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Insights
Myocardial ischemia-reperfusion causes endothelial dysfunction, impairing blood vessel relaxation. Activated neutrophils worsen this dysfunction through superoxide radicals, highlighting a potential therapeutic target for heart attack recovery.
Area of Science:
- Cardiovascular Physiology
- Endothelial Function
- Ischemia-Reperfusion Injury
Background:
- Endothelial dysfunction, characterized by reduced endothelium-derived relaxing factor (EDRF) release, is a known consequence of myocardial ischemia-reperfusion.
- Understanding the mechanisms underlying this dysfunction is crucial for developing effective treatments for ischemic heart disease.
Purpose of the Study:
- To investigate the development and mechanisms of endothelial dysfunction following myocardial ischemia and reperfusion.
- To determine the role of neutrophils and superoxide radicals in exacerbating this dysfunction.
Main Methods:
- Isolated cat hearts were subjected to global ischemia followed by reperfusion using the Langendorff procedure.
- Coronary vasorelaxation was assessed using endothelium-dependent (acetylcholine) and endothelium-independent (nitroglycerin, NaNO2) vasodilators.
- The impact of activated neutrophils and specific inhibitors (superoxide dismutase, anti-CD18 antibody) on endothelial function was evaluated.
Main Results:
- Ischemia-reperfusion significantly impaired acetylcholine-induced coronary vasorelaxation, while nitroglycerin response remained intact.
- Isolated coronary artery rings exhibited similar endothelial dysfunction.
- Infusion of activated neutrophils exacerbated acetylcholine-induced vasodilation impairment.
- Superoxide dismutase and an anti-CD18 antibody attenuated neutrophil-mediated endothelial dysfunction.
Conclusions:
- Endothelial dysfunction is an early event after myocardial reperfusion.
- Activated neutrophils, via superoxide radical production, significantly aggravate this dysfunction.
- Targeting neutrophils and superoxide radicals may offer a therapeutic strategy to mitigate ischemia-reperfusion injury.
Abstract:
Endothelial dysfunction, as evidenced by decreased stimulated release of endothelium-derived relaxing factor (EDRF), occurs after reperfusion of the ischemic myocardium. To better understand this endothelial dysfunction, isolated cat hearts were perfused under constant flow by the Langendorff procedure with Krebs-Henseleit solution devoid of blood cells. Following global ischemia (90 minutes) and reperfusion (20 minutes), coronary vasorelaxation to the endothelium-dependent vasodilator acetylcholine (ACh) was 70 +/- 3% of initial values (p less than 0.01) compared with 90 +/- 4% in nonischemic control perfused hearts. No decrement occurred in response to the endothelium-independent vasodilator nitroglycerin (NTG). Coronary artery rings isolated from the ischemic left circumflex coronary artery showed a similar degree of endothelial dysfunction to ACh, with normal relaxation in response to NaNO2. Autologous cat neutrophils (100 million cells), activated with 100 nmol/L f-met-leu-phe infused into the heart directly before and throughout reperfusion, resulted in a further decrement in ACh-induced vasodilation, to 55 +/- 5% of initial response, with no effect on NTG-induced vasodilation. Similar results were obtained with coronary artery rings isolated from perfused cat hearts and exposed to neutrophils. This neutrophil-enhanced endothelial dysfunction was inhibited by human superoxide dismutase as well as by an antibody to the adherence glycoprotein complex CD-18 (i.e., MAbR 15.7). Therefore endothelial dysfunction occurs initially upon reperfusion of the previously ischemic heart and is aggravated by superoxide radicals produced by activated neutrophils.