Endothelin-1-induced reduction of myocardial infarct size by activation of ATP-sensitive potassium channels in a rabbit model of myocardial ischaemia and reperfusion.
1. This study examined whether endothelin-1 (ET-1) reduces infarct size in a rabbit model of acute coronary artery occlusion (60 min) and reperfusion (120 min). In addition, we investigated whether the observed cardioprotective effect of ET-1 was due to the activation of ATP-sensitive potassium (KATP) channels by using two selective antagonists, glibenclamide and sodium 5-hydroxydecanoate (5-HD). 2. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 60 min of coronary artery occlusion followed by 2 h of reperfusion was 55 +/- 4% (n = 11). ET-1 (0.3 nmol kg-1), administered as a bolus injection into the left ventricle, had no effect on infarct size (62 +/- 2%, n = 4). A lower dose of ET-1 (0.03 nmol kg-1) resulted in a significant reduction in infarct size (infarct size 43 +/- 3%; P < 0.05, n = 16). The higher dose (0.3 nmol kg-1), but not the lower dose of ET-1 caused a significant rise in blood pressure, pressure rate index and hence, myocardial oxygen consumption. 3. The reduction in infarct size afforded by ET-1 (0.03 nmol kg-1) was abolished by pretreatment of rabbits with the KATP channel inhibitors, glibenclamide (0.3 mg kg-1) and 5-HD (5 mg kg-1), (infarct size 59 +/- 3 and 63 +/- 4% respectively; n = 4-9). 4. We propose that ET-1 reduces infarct size by opening KATP channels.
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E J
EJ
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London.
Piper
J
J
Thiemermann
C
C
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000150:complications; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000150:complications; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000627:therapeutic use*; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications* / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012680:Sensitivity and Specificity
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D016232:Endothelins; D006880:Hydroxy Acids; D015221:Potassium Channels; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D005905:Glyburide