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(Circulation. 2005;111:302-309.)
© 2005 American Heart Association, Inc.

Heart Failure

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

Satoshi Yamamoto, MSc; Noriko Matsumoto, MSc; Mitsuo Kanazawa, BSc; Marie Fujita, BSc; Masanori Takaoka, PhD; Cheryl E. Gariepy, MD; Masashi Yanagisawa, MD, PhD; Yasuo Matsumura, PhD

From the Department of Pharmacology (S.Y., N.M., M.K., M.F., M.T., Y.M.), Osaka University of Pharmaceutical Sciences, Osaka, Japan; Department of Pediatrics (C.E.G.), University of Michigan, Ann Arbor, Mich; and Howard Hughes Medical Institute (M.Y.), Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Tex.

Reprint requests to Yasuo Matsumura, PhD, Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. E-mail matumrh{at}gly.oups.ac.jp

Received April 22, 2004; revision received August 10, 2004; accepted October 5, 2004.

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.

Methods and 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.

Key Words: endothelin • ischemia • norepinephrine • reperfusion

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