Cardioprotection by K-ATP channels in wild-type hearts and hearts overexpressing A(1)-adenosine receptors

We studied the role of mitochondrial ATP-sensitive K+ (K-ATP) channels in m odifying functional responses to 20 min global ischemia and 30 min reperfus ion in wild-type mouse hearts and in hearts with similar to 250-fold overex pression of functionally coupled A(1)-adenosine receptors (A(1)ARs). In wil d-type hearts, time to onset of contracture (TOC) was 303 +/- 24 s, with a peak contracture of 89 +/- 5 mmHg. Diastolic pressure remained elevated at 52 +/- 6 mmHg after reperfusion, and developed pressure recovered to 40 +/- 6% of preischemia. A(1)AR overexpression markedly prolonged TOC to 517 +/- 84 s, reduced contracture to 64 +/- 6 mmHg, and improved recovery of diast olic (to 9 +/- 4 mmHg) and developed pressure (to 82 +/- 8%). 5-Hydroxydeca noate (5-HD; 100 mu M), a mitochondrial K-ATP blocker, did not alter ischem ic contracture in wild-type hearts, but increased diastolic pressure to 69 +/- 8 mmHg and reduced developed pressure to 10 +/- 5% during reperfusion. In transgenic hearts, 5-HD reduced TOC to 348 +/- 18 s, increased postische mic contracture to 53 +/- 4 mmHg, and reduced recovery of developed pressur e to 22 +/- 4%. In summary, these data are the first to demonstrate that en dogenous activation of K-ATP channels improves tolerance to ischemia-reperf usion in murine myocardium. This functional protection occurs without modif ication of ischemic contracture. The data also support a role for mitochond rial K-ATP channel activation in the pronounced cardioprotection afforded b y overexpression of myocardial A(1)ARs.