Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts.

Abstract

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.

• Authors: Masashi Tawa, Taiki Fukumoto, Mamoru Ohkita, Naoto Yamashita, Ayman Geddawy, Takeshi Imamura, Kazuhide Ayajiki, Tomio Okamura, Yasuo Matsumura
• Journal: Hypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 34 Issue 2 Pg. 218-24 (Feb 2011) ISSN: 1348-4214 [Electronic] England
• PMID: 21048781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• A 192621
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Pyrrolidines
• SM 19712
• Sulfonamides
• Sulfonylurea Compounds
• Aspartic Acid Endopeptidases
• Metalloendopeptidases
• Endothelin-Converting Enzymes
• Atrasentan
• Norepinephrine

Topics

• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors)
• Atrasentan
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (administration & dosage, antagonists & inhibitors, physiology)
• Endothelin-Converting Enzymes
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Myocardial Reperfusion Injury (drug therapy, physiopathology)
• Norepinephrine (antagonists & inhibitors)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides (pharmacology)
• Sulfonylurea Compounds (pharmacology)
• Ventricular Dysfunction, Left (drug therapy, physiopathology)