Effects of ET(A) and ET(B) receptor blockade on post-ischemic cardiac dysfunction and norepinephrine overflow in isolated rat hearts.
We investigated the role of endothelin-A (ETA) and endothelin-B (ETB) receptors in ischemia/reperfusion-induced cardiac dysfunction and norepinephrine overflow using isolated rat hearts. According to the Langendorff technique, isolated hearts were subjected to 40 minutes of global ischemia followed by 30 minutes of reperfusion. Ischemia/reperfusion led to decreases in left ventricular developed pressure and coronary flow, and an increase in left ventricular end-diastolic pressure compared with pre-ischemic basal levels. An ETB receptor antagonist A-192621 at 1 microM worsened ischemia/reperfusion-induced cardiac dysfunction. In contrast, an ETA receptor antagonist ABT-627 at 5 microM with or without A-192621 improved the aforementioned cardiac dysfunction, to the same extent. Norepinephrine was massively released in coronary effluent from the hearts exposed to ischemia/ reperfusion. Treatment with ABT-627 significantly suppressed the norepinephrine overflow induced by the ischemia/reperfusion whereas A-192621 further enhanced it, which was completely abolished by the concomitant treatment with ABT-627. These results suggest that the detrimental effect of ETB receptor blockade on post-ischemic cardiac function is mediated by the ETA receptor-related action and that norepinephrine overflow from sympathetic nerve endings is closely related to the antagonist-induced functional changes of post-ischemic hearts.
Yamamoto
Satoshi
S
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
Matsumoto
Noriko
N
Kanazawa
Mitsuo
M
Fujita
Marie
M
Takaoka
Masanori
M
Matsumura
Yasuo
Y
D000818:Animals; D000077868:Atrasentan; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / 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 / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017725:Ventricular Pressure / Q000187:drug effects
C120508:A 192621; D002317:Cardiovascular Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000077868:Atrasentan; D009638:Norepinephrine