title: Endothelin in the mechanism of endothelial injury and neutrophil adhesion in the post-ischemic guinea-pig heart.
abstract: This study addressed the hypothesis that endothelin promotes neutrophil accumulation in ischemic/reperfused myocardium, not only via its direct effect on neutrophils, but also because it mediates post-ischemic endothelial injury. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/35 min reperfusion, and infusion of neutrophils between 15 and 25 min of reperfusion. The infusion of the endothelin ET(A)/ET(B) receptor antagonist, tezosentan, the endothelin ET(A) receptor antagonist, BQ 123 [cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu-], and superoxide dismutase was terminated at reperfusion, 5 min before the start of the neutrophil infusion, to avoid the contact of the drugs with neutrophils. Coronary flow responses to acetylcholine and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Neutrophil adhesion and endothelium glycocalyx ultrastructure were assessed in histological preparations. Ischemia/reperfusion resulted in a 54%-impaired acetylcholine response, endothelium glycocalyx disruption, and enhanced neutrophil adhesion (21.6% of microvessels contained neutrophils vs. 2.6% in sham group), the latter prevented by a selectin blocker, sulfatide, 20 microg/ml. These alterations were completely prevented by 0.5 and 5 nM, but not 0.05 nM, tezosentan, and were greatly attenuated by BQ 123, 1 and 10 nM. The glycocalyx-protective effect of these interventions preceded their effect on neutrophil adhesion. Superoxide dismutase, 150 IU/ml, reported before by us to protect post-ischemic endothelium glycocalyx, here prevented the post-ischemic endothelial dysfunction and neutrophil adhesion. The data imply that neutrophil adhesion in ischemic/reperfused guinea-pig heart is a selectin-dependent process, secondary to mostly endothelin ET(A) receptor- and free radical-mediated functional and/or structural changes in the coronary endothelium. Thus, endothelin ET(A)/ET(B) as well as ET(A) receptor antagonists may be useful in attenuation of the inflammatory response in ischemic/reperfused heart. The antagonists may be effective because of their direct effect on neutrophils, as demonstrated by others, and because they provide endothelial protection, as demonstrated here.
authors.affiliation: Department of Clinical Physiology, Medical Center of Postgraduate Education, Marymoncka 99, 01-813, Warsaw, Poland
authors.forename: Michał
authors.initials: M
authors.lastname: Kurzelewski
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Czarnowska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Beresewicz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion; D016232:Endothelins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D006439:Hemodynamics; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009504:Neutrophils / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology
chemical_list: D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D000109:Acetylcholine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)