The role of mitochondrial K(ATP) channels in antiarrhythmic effects of ischaemic preconditioning in dogs.
1. In the canine a single brief (5 min) coronary artery occlusion protects the myocardium against the severe ventricular arrhythmias and reduces the ischaemic changes that result from a subsequent, more prolonged (25 min) occlusion. The main purpose of the present study was to examine whether mitochondrial K(ATP) channels are involved in this protection. 2. In chloralose-urethane anaesthetized dogs, preconditioning (PC) was induced by a single 5 min period occlusion of the left anterior descending (LAD) coronary artery, 20 min prior to a 25 min occlusion of the same artery. In some of these PC dogs 5-hydroxydecanoate (5-HD; 150 micro g kg(-1) min(-1) by intracoronary infusion) was given over a period of 30 min either before, or after PC. In other dogs the mitochondrial K(ATP) channel opener diazoxide (1 mg kg(-1); i.c.) was given, either alone or in the presence of 5-HD. Control dogs (infused with saline) were simply subjected to a 25 min occlusion and reperfusion. 3. Compared to controls, both PC and diazoxide significantly reduced the number of ventricular premature beats (VPBs; 295+/-67 to 89+/-28 and 19+/-11, respectively; P<0.05), the number of episodes of ventricular tachycardia (VT; 8.3+/-4.2 to 1.6+/-0.9 and 0.2+/-0.1; P<0.05) and the incidences of VT (100 to 43 and 33%; P<0.05) and ventricular fibrilation (VF; 60 to 0 and 17%; P<0.05) during the 25 min occlusion of the LAD. Further, 43% of the PC dogs and 58% of the diazoxide treated dogs survived the combined ischaemia-reperfusion insult (cp. 0% in the controls; P<0.05). The protection afforded by PC and diazoxide was abolished by 5-HD, especially when it was given prior to the PC occlusion. In the presence of 5-HD, three out of 10 dogs fibrillated during the PC occlusion and another three dogs died following reperfusion. Furthermore, there were no survivors in this group from the prolonged ischaemia/reperfusion insult. 5-HD given after PC only attenuated the antiarrhythmic protection. 4. Opening of mitoK(ATP) channels prior to ischaemia by preconditioning and diazoxide protects the myocardium against ischaemia and reperfusion-induced arrhythmias. This protection is abolished if the opening of these channels is prevented by the prior administration of 5-HD but only attenuated if 5-HD is given after preconditioning. The results indicate that opening of mitoK(ATP) channels prior to ischaemia is mandatory for protection against ischaemia and reperfusion-induced arrhythmias.
Végh
Agnes
A
Department of Pharmacology and Pharmacotherapy, University of Szeged, Albert Szent-Györgyi Faculty of Medicine, Dóm tér 12, P O Box 427, H-6701 Hungary. vegh@phcol.szote.u-szeged.hu
Parratt
James R
JR
D000818:Animals; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006880:Hydroxy Acids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000150:complications; D015221:Potassium Channels; D017180:Tachycardia, Ventricular / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C052853:5-hydroxydecanoic acid; D003981:Diazoxide