TY - JOUR
T1 - Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts
AU - Yamamoto, Satoshi
AU - Matsumoto, Noriko
AU - Kanazawa, Mitsuo
AU - Fujita, Marie
AU - Takaoka, Masanori
AU - Gariepy, Cheryl E.
AU - Yanagisawa, Masashi
AU - Matsumura, Yasuo
N1 - Funding Information:
Work in the laboratories is supported by Public Health Service Grants A1 19042, CA 16858, CA 22376, and CA 13696 to the Cancer Center from the National Institutes of Health and a grant from Becton-Dickinson,
PY - 2005/1/25
Y1 - 2005/1/25
N2 - 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 ETA 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 ETB 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 ETB 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 ETB receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ETA receptor activation. ET A/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.
AB - 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 ETA 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 ETB 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 ETB 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 ETB receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ETA receptor activation. ET A/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.
KW - Endothelin
KW - Ischemia
KW - Norepinephrine
KW - Reperfusion
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U2 - 10.1161/01.CIR.0000153351.86708.F7
DO - 10.1161/01.CIR.0000153351.86708.F7
M3 - Article
C2 - 15642760
AN - SCOPUS:12844261619
SN - 0009-7322
VL - 111
SP - 302
EP - 309
JO - Circulation
JF - Circulation
IS - 3
ER -