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

Abstract

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 ET(A) 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 ET(B) 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 ET(B) 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 ET(B) receptors is detrimental to the postischemic heart, and exaggerated cardiac pathology under the above conditions is mediated by ET(A) receptor activation. ET(A)/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

• Authors: Satoshi Yamamoto, Noriko Matsumoto, Mitsuo Kanazawa, Marie Fujita, Masanori Takaoka, Cheryl E Gariepy, Masashi Yanagisawa, Yasuo Matsumura
• Journal: Circulation (Circulation) Vol. 111 Issue 3 Pg. 302-9 (Jan 25 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 15642760 (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
• Receptor, Endothelin A
• Receptor, Endothelin B
• Amiloride
• Atrasentan
• ethylisopropylamiloride
• Norepinephrine

Topics

• Amiloride (analogs & derivatives, pharmacology)
• Animals
• Animals, Genetically Modified
• Atrasentan
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (physiology)
• Gene Deletion
• In Vitro Techniques
• Male
• Myocardial Ischemia (complications)
• Myocardial Reperfusion Injury (etiology, metabolism, physiopathology)
• Myocardium (metabolism)
• Norepinephrine (metabolism)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (physiology)
• Receptor, Endothelin B (genetics, physiology)
• Regional Blood Flow
• Ventricular Pressure