C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.

Abstract

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables. Serial sampling indicated that granulocyte extraction was increased before the reductions in coronary blood flow and myocardial function and that all effects of C5a had resolved within 2 minutes of injection. In separate studies, we examined the effects of C5a on isolated epicardial coronary arteries (750-1,000 fim diameter) of pigs. There was no vasoconstriction after exposure to C5a in buffer or in whole blood. These studies indicate that, in the presence of normal perfusion pressures, C5a activation of granulocytes results in intravascular trapping in the myocardium. Furthermore, coronary blood flow is decreased to the extent that an imbalance between myocardial oxygen supply and demand occurs, resulting in impairment of myocardial function. (Circulation Research 1988:63:483-491)

Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow.

“…In addition, activated neutrophils may release vasoconstricting substances, which could contribute to progressive impairment of flow. 56 Thus, "delayed no-reflow"might signify a vicious cycle of reperfusion-induced vascular and myocyte injury, initiated by a sufficient degree of ischemic injury to "prime" the reaction and resulting in progressive tissue necrosis.…”

Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury

“…C5a mediates a broad range of biological activities such as promoting PMN chemotaxis and activation, mast cells degranulation, smooth muscle cell contraction and increased vascular permeability (59,60). The administration of C5a into coronary arteries of healthy pigs have produced an up to 40% reduced in regional coronary blood flow and decreased in local myocardial function, attributed by the aggregation of circulatory granulocytes in the microcirculation (61). Inhibition of complement with novel drugs such as the anti-C5 antibody Pexelizumab have yielded promising results in animal models of cardiovascular disease (6 -9), but so far this promise has yet to be translated into successful clinical applications for human patients with MI.…”

Myosin Light Chain Phosphorylation in Neutrophil-Stimulated Coronary Microvascular Leakage

“…33,34 The selection of C5a as the neutrophil activator was based on the finding that human C5a cross-reacts with porcine neutrophils, leading to respiratory burst and chemotaxis. 33 Furthermore, the fact that C5a exerts a minimal direct effect on porcine microvascular endothelium 33,35,36 makes it a unique probe for the study of neutrophil-dependent endothelial responses. Compared with C5a, the effects of platelet-activating factor (PAF) on neutrophil dynamics and permeability were examined in the same isolated microvessel model.…”