title: Myocardial release of endothelin (ET) and enhanced ET(A) receptor-mediated coronary vasoconstriction after coronary thrombosis and thrombolysis in pigs.
abstract: We investigated changes in vascular reactivity to endothelin (ET) and local release of ET-like immunoreactivity (ET-LI) induced by myocardial ischemia and reperfusion in a pig model of coronary thrombosis and thrombolysis and studied the possible mechanisms producing the changed vascular reactivity to ET-1. We induced coronary thrombosis by inserting a copper coil into the left anterior descending coronary artery (LAD) and achieved thrombolysis with tissue plasminogen activator (t-PA). Vascular reactivity to ET-1 in the nonischemic and ischemic/reperfused LAD diagonal branches was evaluated in vitro. ET-LI was analyzed in plasma from the great cardiac vein and aorta for estimation of local release. The vasoconstrictor response to ET-1 was enhanced twofold (p < 0.01) in the ischemic/reperfused arteries as compared with the nonischemic arteries. The vasoconstriction induced by the ETB receptor agonist [Ala 1,3,11,15] ET-1 or serotonin was not significantly affected by ischemia/reperfusion. The ETA receptor antagonist BQ-123 reversed the ET-1-induced vascular contraction to a similar degree in ischemic/reperfused and control arteries. The ET-1-induced vasoconstriction of control arteries was not affected by inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA) or cyclooxygenase with indomethacin. During reperfusion, the myocardial venoarterial plasma concentration difference of ET-LI and blood flow increased, resulting in an increased overflow of ET-LI. Our results demonstrate that coronary thrombosis and thrombolysis evokes enhanced local release of ET-LI during the reperfusion period and increases the vasoconstrictor effects of ET-1 through a mechanism related to ETA receptor activation but unrelated to altered endothelial function. These changes may play a role in the development of ischemic/reperfusion injury and no-reflow phenomenon.
authors.affiliation: Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Q D
authors.initials: QD
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Uriuda
authors.forename: J
authors.initials: J
authors.lastname: Pernow
authors.forename: A
authors.initials: A
authors.lastname: Hemsén
authors.forename: P O
authors.initials: PO
authors.lastname: Sjöquist
authors.forename: L
authors.initials: L
authors.lastname: Rydén
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003328:Coronary Thrombosis / Q000503:physiopathology*; D003331:Coronary Vessels / Q000503:physiopathology*; D016232:Endothelins / Q000097:blood / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006339:Heart Rate; D066298:In Vitro Techniques; D008297:Male; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D013552:Swine; D015912:Thrombolytic Therapy; D014661:Vasoconstriction
chemical_list: D016232:Endothelins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin