The Role of Myocardial K ATP ‐Channel Blockade in the Protective Effects of Glibenclamide against Ischaemia in the Rat Heart

Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of K ATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of K ATP channels, opening of these K ATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 μmol.l −1 ; n=5), the K ATP channel openers pinacidil (1 μmol.l −1 ; n=5) and diazoxide (30 μmol.l −1 ; n=5), the combination of glibenclamide with pinacidil (n=5) and glibenclamide with diazoxide (n=5), and vehicle (n=8). Both pinacidil and diazoxide significantly increased coronary blood flow 2–3 times, which was abolished by glibenclamide pre‐ and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks K ATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2±2.9% during vehicle. Glibenclamide reduced the cardiac functional loss to 4.3±1.2% (P<0.01). Interestingly, both pinacidil and diazoxide reduced the cardiac functional loss to 4.0±1.5% (P<0.01) and 2.9±1.4% (P<0.001), respectively. The combination pinacidil+glibenclamide resulted in additional protection compared with the individual components (0.6±0.1 versus 4.0±1.5%, P<0.05). Thus, in contrast to its effect on coronary vascular tone, the glibenclamide‐induced improvement of postischaemic cardiac function may not be mediated through blockade of the K ATP channel. Alternative mechanisms may be operative, such as uncoupling of the mitochondrial respiratory chain, thereby preconditioning the hearts against stunning.