Blocked ETA receptors prevent ischemia and reperfusion injury in rat lungs.
The effects of endothelin (ET)-A (ETA)- and ETB-receptor agonist and antagonists were studied in isolated buffer-perfused rat lungs subjected to 45 min of ischemia followed by 105 min of reperfusion (I/R). For the I/R group after 30 and 90 min of reperfusion, the Kfc had increased three- and fivefold above control values, respectively (P < 0.01), and the number of circulating neutrophils in the perfusate decreased by 65 +/- 7.65%. Both an ETA-receptor antagonist (BQ-610) and an ETAB-receptor antagonist (PD-156707-0015) given before the ischemic period protected the lung endothelial barrier from injury associated with I/R. Also, these compounds attenuated the I/R-induced neutrophil accumulation in the lung (31.94 +/- 4.16 and 34.38 +/- 1.05%, respectively; P < 0.01 compared with I/R). Neither an ETB-receptor agonist (IRL-1620) nor an ETB-receptor antagonist (IRL-1038) affected the I/R-induced endothelial injury. In addition, they did not alter the number of circulating polymorphonuclear cells during I/R. ET-1 administration alone caused a dose-dependent increase in pulmonary arterial pressure, but no measurable increase in microvascular permeability occurred. We conclude that ET-1 is involved in I/R-induced lung endothelial injury and speculate that it acts in concert with some other coactivator(s), most likely platelet-activating factor, through ETA receptors. This mechanism requires polymorphonuclear leukocyte activation with subsequent release of oxygen radicals and/or expression of adhesive molecules on the neutrophil surface.
Khimenko
P L
PL
Department of Physiology, College of Medicine, University of South Alabama, Mobile 36688, USA.
Moore
T M
TM
Taylor
A E
AE
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology; D066298:In Vitro Techniques; D007958:Leukocyte Count; D008171:Lung Diseases / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D011652:Pulmonary Circulation / Q000502:physiology; D011669:Pulmonary Wedge Pressure / Q000502:physiology; D051381:Rats; D017466:Receptors, Endothelin / Q000819:agonists; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin