Effect of combined K(ATP) channel activation and Na(+)/H(+) exchange inhibition on infarct size in rabbits.
We tested if combining treatment with cariporide, an Na(+)/H(+) exchange inhibitor, and diazoxide, a mitochondrial ATP-sensitive K(+) (K(ATP)) channel opener, would reduce myocardial infarct size (IS) to a greater extent than either intervention alone. Four groups of rabbits were studied (n = 10 each): cariporide (0.3 mg/kg), diazoxide (10 mg/kg), both drugs, and saline control, given 15 min before a 30-min coronary artery occlusion and 3 h reperfusion. IS in controls comprised 47 +/- 6% of the risk region. Cariporide reduced IS by 55% compared with control (21 +/- 3%), but diazoxide did not significantly reduce IS compared with controls (37 +/- 6%). Combined treatment resulted in an IS of 18 +/- 5%. Also we determined that diazoxide did not potentiate a subthreshold dose of cariporide nor did a mitochondrial K(ATP) channel blocker, 5-hydroxydecanoate (5-HD), prevent cariporide from reducing IS. Thus cariporide reduced necrosis by >50% in this model, both in the presence and absence of K(ATP) channel blockade. There was no significant difference in IS reduction between the group receiving cariporide alone and the group receiving combined treatment. Because the effect of cariporide was not blocked by 5-HD, it is unlikely that K(ATP) channels play a role as an end effector in cariporide's mechanism.
Hale
S L
SL
Division of Cardiology, The Heart Institute of Good Samaritan Hospital Los Angeles, California 90017, USA. sharon.hale@attglobal.net
Kloner
R A
RA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate; D006880:Hydroxy Acids / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009336:Necrosis; D015221:Potassium Channels / Q000819:agonists* / Q000502:physiology; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006146:Guanidines; D006880:Hydroxy Acids; D015221:Potassium Channels; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D014665:Vasodilator Agents; C052853:5-hydroxydecanoic acid; C093373:cariporide; D003981:Diazoxide