Role of endogenous endothelin-1 in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts.

Abstract

Endothelin-1 and norepinephrine are involved in myocardial ischemia/reperfusion injury. The aim of this study was to investigate the role of endogenously generated endothelin-1 in ischemia/reperfusion-induced norepinephrine overflow and cardiac dysfunction using a nonselective prototype of endothelin-converting enzyme (ECE) inhibitor, phosphoramidon, and a selective ECE inhibitor, SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl]benzenesulfonamide, monosodium salt). According to the Langendorff technique, isolated Sprague-Dawley rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Phosphoramidon and SM-19712 were perfused 30 min before ischemia and during reperfusion. Endothelin-1 level in left ventricle was increased by ischemia/reperfusion. This increase in left ventricular endothelin-1 level was suppressed by treatment with SM-19712. SM-19712 significantly improved ischemia/reperfusion-induced cardiac dysfunction such as decreased left ventricular developed pressure and dP/dt(max) and increased left ventricular end diastolic pressure. In addition, this agent suppressed excessive norepinephrine overflow in the coronary effluent from the post-ischemic heart. In contrast, treatment with phosphoramidon further enhanced left ventricular endothelin-1 level and norepinephrine overflow, and significantly worsened cardiac dysfunction after ischemia/reperfusion. These responses such as exaggerated norepinephrine overflow and the cardiac dysfunction observed after ischemia/reperfusion were markedly suppressed in the presence of a selective endothelin ET(A) receptor antagonist, ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid]. These findings indicate that cardiac endothelin-1 production is enhanced by ischemia/reperfusion, and this endogenously increased endothelin-1 is involved in post-ischemic norepinephrine overflow and cardiac dysfunction via the activation of endothelin ET(A) receptors.

• Authors: Masashi Tawa, Taiki Fukumoto, Mamoru Ohkita, Yasuo Matsumura
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 591 Issue 1-3 Pg. 182-8 (Sep 04 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18586023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Enzyme Inhibitors
• Glycopeptides
• Pyrrolidines
• Receptor, Endothelin A
• SM 19712
• Sulfonamides
• Sulfonylurea Compounds
• Aspartic Acid Endopeptidases
• Metalloendopeptidases
• Endothelin-Converting Enzymes
• phosphoramidon
• Atrasentan
• Norepinephrine

Topics

• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, metabolism)
• Atrasentan
• Endothelin-1 (metabolism)
• Endothelin-Converting Enzymes
• Enzyme Inhibitors (pharmacology)
• Glycopeptides (pharmacology)
• Male
• Metalloendopeptidases (antagonists & inhibitors, metabolism)
• Myocardial Ischemia (complications)
• Myocardial Reperfusion Injury (etiology, physiopathology)
• Norepinephrine (metabolism)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (drug effects, metabolism)
• Sulfonamides (pharmacology)
• Sulfonylurea Compounds (pharmacology)