Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

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 ETB 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. ETA/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.