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

Satoshi Yamamoto, Noriko Matsumoto, Mitsuo Kanazawa, Marie Fujita, Masanori Takaoka, Cheryl E. Gariepy, Masashi Yanagisawa, Yasuo Matsumura

Research output: Contribution to journalArticle

31 Citations (Scopus)

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

Original languageEnglish (US)
Pages (from-to)302-309
Number of pages8
JournalCirculation
Volume111
Issue number3
DOIs
StatePublished - Jan 25 2005

Fingerprint

Endothelin B Receptors
Endothelins
Metrorrhagia
Norepinephrine
A 192621
Reperfusion
Endothelin-1
Ischemia
Sodium-Hydrogen Antiporter
Myocardial Reperfusion Injury
Ventricular Pressure
Reperfusion Injury
Myocardial Ischemia
Sprague Dawley Rats
Pharmacology
Pathology
Blood Pressure

Keywords

  • Endothelin
  • Ischemia
  • Norepinephrine
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts. / Yamamoto, Satoshi; Matsumoto, Noriko; Kanazawa, Mitsuo; Fujita, Marie; Takaoka, Masanori; Gariepy, Cheryl E.; Yanagisawa, Masashi; Matsumura, Yasuo.

In: Circulation, Vol. 111, No. 3, 25.01.2005, p. 302-309.

Research output: Contribution to journalArticle

Yamamoto, Satoshi ; Matsumoto, Noriko ; Kanazawa, Mitsuo ; Fujita, Marie ; Takaoka, Masanori ; Gariepy, Cheryl E. ; Yanagisawa, Masashi ; Matsumura, Yasuo. / Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts. In: Circulation. 2005 ; Vol. 111, No. 3. pp. 302-309.
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T1 - Different contributions of endothelin-A and endothelin-B receptors in postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

AU - Yamamoto, Satoshi

AU - Matsumoto, Noriko

AU - Kanazawa, Mitsuo

AU - Fujita, Marie

AU - Takaoka, Masanori

AU - Gariepy, Cheryl E.

AU - Yanagisawa, Masashi

AU - Matsumura, Yasuo

PY - 2005/1/25

Y1 - 2005/1/25

N2 - 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 ET B 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. ET A/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

AB - 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 ET B 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. ET A/NHE-mediated excessive NE overflow is contributive, at least in part, to postischemic cardiac dysfunction in rats.

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