Contractile recovery of heart muscle after hypothermic hypoxia is improved by nicorandil via mitochondrial K(ATP) channels.
BACKGROUND
The ATP-sensitive potassium channel (K(ATP)) opener nicorandil used instead of potassium in hypothermic cardioplegia significantly improves preservation of cardiac function and energetics in the in situ heart preparation. The present study, therefore, examines the effect of nicorandil at different temperatures and the role of sarcolemmal and mitochondrial K(ATP) channels under ex vivo conditions using contractile force (CF) and action potential duration (APD) as end points.


METHODS
Guinea-pig papillary muscles at 37, 27, or 22 degrees C (1Hz) were exposed to nicorandil 0.2-1.1 mM. The contributions of K(ATP) channel subtypes in cardioprotection were examined using mitochondrial (mito) (0.1 mM) or non-selective (1.0 mM) concentrations of nicorandil, mito K(ATP) blocker 5-hydroxyl decanoate (5HD, 300 microM) or sarcolemmal (sarc) K(ATP) blocker HMR1098 (30 microM) before and during 140 min of hypothermic (22 degrees C) glucose-free hypoxia.


RESULTS
Nicorandil >0.5 mM shortened the APD, and this was abolished by hypothermia and HMR1098 but not by 5HD. Nicorandil in both tested concentrations preserved contractile force after hypoxia-reoxygenation significantly better than control (73.7+/-4.4% and 75.8+/-3.9% vs 40.6+/-2.6%, n=6 in each group). Protection was blocked by 5HD but not by HMR1098. 5HD and HMR1098 alone did not change recovery of contractile force compared to control.


CONCLUSIONS
Shortening of APD and activation of sarc K(ATP) by nicorandil were not related to myocardial protection. Thus, the mito K(ATP) seems to play a significant role in cardioprotection compared to the sarc K(ATP) also when substrate depletion and hypoxia are combined with hypothermia.
Steensrud
Tor
T
Department of Cardiothoracic and Vascular Surgery, University Hospital North Norway, P.O. Box 102, N-9038 Tromsø, Norway. tor.steensrud@unn.no
Jakobsen
Øyvind
Ø
Ytrehus
Kirsti
K
Sørlie
Dag G
DG
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006324:Heart Arrest, Induced / Q000379:methods; D007036:Hypothermia, Induced; D000860:Hypoxia / Q000503:physiopathology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D020108:Nicorandil / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013696:Temperature; D046509:Tissue Culture Techniques; D014665:Vasodilator Agents / Q000494:pharmacology
D002316:Cardiotonic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil