Cardioprotective effect of enantiomers of cicletanine (BN50417, BN50418) in ischaemic/reperfused isolated working rat hearts: Interaction with glibenclamide

In the present study, interaction of the ATP-sensitive K+-channel blocker g libenclamide with enantiomers of the antihypertensive drug, cicletanine, wa s studied on ischaemic myocardial function, lactate-dehydrogenase (LDH) rel ease, and early reperfusion-induced ventricular fibrillation (VF). Isolated working rat hearts subjected to 10-min coronary artery occlusion followed by 2-min reperfusion were perfused with 1.5 x 10(-5)-6.0 x 10(-5) M D-cicle tanine[+] (BN50417) and L-cicletanine[-] (BN50418), respectively. Their int eraction with 10(-7) M glibenclamide was also studied. The most effective c oncentration of BN50418 (3 x 10-5 M) increased ischaemic aortic flow (AF) f rom its non-treated control value of 20.3 +/- 1.16 to 30.3 +/- 2.6 mi min(- 1) (P < 0.01), decreased left ventricular end-diastolic pressure (LVEDP) fr om 1.81 +/- 0.05 to 0.97 +/- 0.08 kPa (P < 0.001), attenuated ischaemia-ind uced increase in LDH leakage from 164 +/- 41 to 14.8 +/- 20 mU min(-1) g(-1 ) wet wt. (P < 0.01) at the 10th-min of coronary occlusion, and reduced VF upon reperfusion. Glibenclamide did not considerably affect cardiac perform ance, however, it inhibited the anti-ischaemic but not the antiarrhythmic e ffect of BN50418. BN50417 (3 x 10(-5) M) tended to improve ischaemic AF to 24.2 +/- 1.1 mi min(-1), and significantly attenuated ischaemia-induced inc rease in LVEDP to 1.3 +/- 0.08 kPa (P < 0.01), relative increase in LDH rel ease to 29.4 +/- 44 mU min(-1) g(-1) (P < 0.05), and alleviated reperfusion -induced VF. Glibenclamide abolished the anti-ischaemic and antiarrhythmic effect of BN50417. The cardioprotective effect of both enantiomers of cicle tanine involves a glibenclamide-sensitive mechanism, however, the antiarrhy thmic effect of BN50418 is not glibenclamide sensitive. BN50418 is the more potent enantiomer of cicletanine in terms of its cardioprotective effect. (C) 1999 The Italian Pharmacological Society.