Effects of KATP channel blockade by glibenclamide on the warm-up phenomenon

Aims The increased tolerance to myocardial ischaemia observed during the second of two sequential exercise tests, i.e. the warm-up phenomenon, has been proposed as a clinical model of ischaemic preconditioning. As ATP-sensitive K+ channels appear to be a mediator of ischaemic preconditioning in both experimental and clinical studies, the aim of this study was to investigate the role of K-ATP channels in the warm-up phenomenon. Methods and Results Twenty-six patients with coronary artery disease were randomized to receive 10 mg oral glibenclamide, a selective ATP-sensitive K+ channel blocker. or placebo. Sixty minutes after glibenclamide or placebo administration, patients were given an infusion of 10% dextrose (8 ml . min(-1)) to correct glucose plasma levels or, respectively, an infusion of saline at the same infusion rate. Thirty minutes after the beginning of the infusions, both patient groups underwent two consecutive treadmill exercise tests, with a recovery period of 15 min to re-establish baseline conditions. Before exercise tests, blood glucose were similar in placebo and glibenclamide groups (96 +/- 10 vs 105 +/- 22 mg . 100 ml(-1), P = ns). After placebo administration, rate-pressure product at 1.5 mm ST-segment depression significantly increased during the second exercise test compared to the first (220 +/- 41 vs 186 +/- 29 beats . min(-1) . mmHg . 10(2), P<0.01), but it did not change after glibenclamide (191 +/- 34 vs 187 +/- 42 beats . min(-1) . mmHg . 10(2), P = ns), with a significant drug-test interaction (P=0.0091, at two-way ANOVA). Conclusions Glibenclamide, at a dose previously shown to abolish ischaemic preconditioning during coronary angioplasty, prevents the increase of ischaemic threshold observed during the second of two sequential exercise tests. These findings confirm that ischaemic preconditioning plays a key role in the warm-up phenomenon and that in this setting is, at least partially, mediated by activation of ATP-sensitive K+ channels.