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 glibenclamide with enantiomers of the antihypertensive drug, cicletanine, was studied on ischaemic myocardial function, lactate-dehydrogenase (LDH) release, 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 1.5x10(-5)-6.0x10(-5)M D-cicletanine[+] (BN50417) and L-cicletanine[-] (BN50418), respectively. Their interaction with 10(-7) M glibenclamide was also studied. The most effective concentration of BN50418 (3x10(-5) M) increased ischaemic aortic flow (AF) from its non-treated control value of 20.3+/-1.16 to 30.3+/-2.6 ml min-1(P<0.01), decreased left ventricular end-diastolic pressure (LVEDP) from 1.81+/-0.05 to 0.97+/-0.08 kPa (P<0.001), attenuated ischaemia-induced increase in LDH leakage from 164+/-41 to 14.8+/-20 mU min-1g-1 wet wt. (P<0.01) at the 10th-min of coronary occlusion, and reduced VF upon reperfusion. Glibenclamide did not considerably affect cardiac performance, however, it inhibited the anti-ischaemic but not the antiarrhythmic effect of BN50418. BN50417 (3x10(-5) M) tended to improve ischaemic AF to 24.2+/-1.1 ml min-1, and significantly attenuated ischaemia-induced increase in LVEDP to 1.3+/-0.08 kPa (P<0.01), relative increase in LDH release to 29.4+/-44 mU min-1g-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 cicletanine involves a glibenclamide-sensitive mechanism, however, the antiarrhythmic effect of BN50418 is not glibenclamide sensitive. BN50418 is the more potent enantiomer of cicletanine in terms of its cardioprotective effect.
Ferdinandy
P
P
Department of Biochemistry, Albert Szent-Györgyi University, Medical School, Szeged, H-6701, Hungary.
Szilvássy
Z
Z
Csont
T
T
Koltai
M
M
Droy-lefaix
M T
MT
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D004347:Drug Interactions; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D020011:Protective Agents / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D013237:Stereoisomerism; D014693:Ventricular Fibrillation
D000959:Antihypertensive Agents; D020011:Protective Agents; D011725:Pyridines; C038068:cicletanine; D007770:L-Lactate Dehydrogenase; D005905:Glyburide