Opening of mitochondrial KATP channel induces early and delayed cardioprotective effect: role of nitric oxide.
Opening of mitochondrial ATP-sensitive (mitoKATP) channel with diazoxide induces an early phase (EP) of cardioprotection. It is unknown whether diazoxide also induces a delayed phase (DP) of cardioprotection. Because nitric oxide (NO) modulates ATP sensitivity of the KATP channel, we hypothesized that NO may play a role in diazoxide-induced cardioprotection. Diazoxide (1 mg/kg) was administered either 30 min (for EP) or 24 h (DP) before 30 min of lethal ischemia. Blockers of mitoK(ATP) channel [5-hydroxydecanoate (5-HD)] or NO synthase [N(G)-nitro-L-arginine methyl ester (L-NAME)] were given 10 min before ischemia-reperfusion performed by 30 min of left anterior descending coronary artery occlusion and 3 h of reperfusion. A risk area (RA) was demarcated by Evans blue dye, and infarct size (IS) was measured by tetrazolium staining. Diazoxide caused a decrease in IS (%RA) from 27.8 +/- 4.2% in the vehicle group to 12.9 +/- 1.2% during EP and from 30.4 +/- 4. 2% in vehicle-treated rabbits to 19.6 +/- 2.4% during DP (P < 0.05). IS increased to 31.3 +/- 1.1% and 27.9 +/- 1.0% (EP) and 29.9 +/- 2. 3% and 35.1 +/- 1.8% (DP) with 5-HD and L-NAME, respectively (P < 0. 05). 5-HD and L-NAME caused no proischemic effect in controls. Diazoxide induced both early and delayed anti-ischemic effects via opening of mitoK(ATP) channels, which was NO dependent.
Ockaili
R
R
Division of Cardiology, Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Emani
V R
VR
Okubo
S
S
Brown
M
M
Krottapalli
K
K
Kukreja
R C
RC
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003331:Coronary Vessels / Q000503:physiopathology; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008928:Mitochondria / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D015221:Potassium Channels; D009569:Nitric Oxide; C052853:5-hydroxydecanoic acid; D000255:Adenosine Triphosphate; D003981:Diazoxide; D019331:NG-Nitroarginine Methyl Ester