Coordinate interaction between ATP-sensitive K+ channel and Na+, K+-ATPase modulates ischemic preconditioning.
BACKGROUND
We reported that digoxin abolishes the infarct size (IS)-limiting effect of ischemic preconditioning (IPC). Because ATP-sensitive K+ (KATP) channels are involved in IPC, we studied whether Na+,K+-ATPase and KATP channels functionally interact, thereby modulating IPC.


RESULTS
Rabbits received 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. IPC was elicited by 5 minutes of occlusion followed by 10 minutes of reperfusion. The IS, expressed as a percentage of the area at risk, was 40.2+/-2.8% in control and 39.8+/-5.0% in digoxin pretreatment rabbits. Both IPC and pretreatment with cromakalim, a KATP channel opener, reduced IS to 11.8+/-1.8% and 13.4+/-2.6% (P<0. 05 versus control). Digoxin abolished the reduction in IS induced by IPC (33.5+/-3.3%), whereas it did not change that induced by cromakalim (18.8+/-3.0%). In patch-clamp experiments, digoxin was found to inhibit the opening of KATP channels in single ventricular myocytes in which ATP depletion had been induced by metabolic stress. In contrast, digoxin had little effect on the channel opening induced by cromakalim. Moreover, the inhibitory action of digoxin on channel activities was dependent on subsarcolemmal ATP concentration.


CONCLUSIONS
The IS-limiting effect of IPC is modulated by an interaction between KATP channels and Na+,K+-ATPase through subsarcolemmal ATP.
Haruna
T
T
Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
Horie
M
M
Kouchi
I
I
Nawada
R
R
Tsuchiya
K
K
Akao
M
M
Otani
H
H
Murakami
T
T
Sasayama
S
S
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019806:Cromakalim / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology*; D005260:Female; D019157:Ischemic Preconditioning, Myocardial; D009203:Myocardial Infarction / Q000473:pathology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology*; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D002316:Cardiotonic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase