title: Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts.
abstract: BACKGROUND
  Endothelin (ET)-1 and norepinephrine (NE) are involved in myocardial ischemia/reperfusion injury. We investigated the role of ET-1 in ischemia/reperfusion-induced NE overflow and cardiac dysfunction using a selective ET(A) receptor antagonist (ABT-627), a selective ET(B) receptor antagonist (A-192621), and the spotting lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene.
  
  
  RESULTS
  According to the Langendorff technique, isolated hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. In Sprague-Dawley rat hearts, ischemia/reperfusion-induced cardiac dysfunctions such as decreased left ventricular developed pressure and coronary flow and increased left ventricular end-diastolic pressure were worsened by treatment with A-192621. This agent enhanced excessive NE overflow in the coronary effluent from the postischemic heart. In contrast, treatment with ABT-627, in the absence or presence of A-192621, significantly improved postischemic cardiac dysfunction and markedly suppressed NE overflow to the same extent. Postischemic cardiac dysfunction and NE overflow in the heart of ET(B) receptor-deficient homozygous (sl/sl) rats were highly observed compared with cases in wild-type rats, and exaggerated responses to ischemia/reperfusion in sl/sl rats were abolished by ABT-627 treatment. Exogenously applied ET-1 produced severe cardiac dysfunction and a significant increase in NE overflow in a dose-dependent manner, but these responses were markedly suppressed in the presence of 5-N-ethyl-N-isopropyl-amiloride, an inhibitor of the Na+/H+ exchanger (NHE).
  
  
  CONCLUSIONS
  Pharmacological blockade or genetic deficiency of ET(B) receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET(A) receptor activation. ET(A)/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.
authors.affiliation: Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kanazawa
authors.forename: Marie
authors.initials: M
authors.lastname: Fujita
authors.forename: Masanori
authors.initials: M
authors.lastname: Takaoka
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Gariepy
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000077868:Atrasentan; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D017353:Gene Deletion; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000235:genetics / Q000502:physiology*; D012039:Regional Blood Flow; D017725:Ventricular Pressure
chemical_list: C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000584:Amiloride; D000077868:Atrasentan; C039614:ethylisopropylamiloride; D009638:Norepinephrine