Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts.
Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET(A) receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1  nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt(max)) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET(B) receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET(A) receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET(B) receptors to exert its related beneficial actions.
Laboratory of Pathological and Molecular Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
Masashi
M
Tawa
Taiki
T
Fukumoto
Mamoru
M
Ohkita
Naoto
N
Yamashita
Ayman
A
Geddawy
Takeshi
T
Imamura
Kazuhide
K
Ayajiki
Tomio
T
Okamura
Yasuo
Y
Matsumura
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D000077868:Atrasentan; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072396:Endothelin-Converting Enzymes; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology
C120508:A 192621; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; C419789:SM 19712; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000077868:Atrasentan; D009638:Norepinephrine