ACTIVATION OF ATP-DEPENDENT K- A FORCE-FREQUENCY-RELATIONSHIP STUDY( CHANNELS ENHANCES MYOCARDIAL PROTECTION DUE TO COLD HIGH POTASSIUM CARDIOPLEGIA )

The hypothesis that nicorandil might enhance myocardial protection due to cold St Thomas' Hospital (STH) solution ([K+](o)], 16 mmol/l) thro ugh opening of cardiac K-ATP channels was assessed in isometrically co ntracting guinea-pig papillary muscles submitted to 120 min of cardiop legic hypoxia followed by 60 min of normothermic reoxygenation. Right ventricular papillary muscles were paced (2 ms, 4 mA) in an organ bath and superfused with oxygenated (O-2 content 16 ml/l) Tyrode's solutio n (37 degrees C). The force-frequency relationship in the range 1600-3 00 ms cycle length (CL) was studied. Preparations were randomized to r eceive 120 min cold (20 degrees C), non-oxygenated (O-2 content 5 ml/l ) STH solution while continuously stimulated at 1600 ms CL, with: (1) saline (No-additive, n=12); (2) DMSO 1% (Vehicle, n=8); (3) nicorandil 1 mmol/l (n=8); (4) nicorandil 1 mmol/l plus glibenclamide 1 mu mol/l , the latter also given, before STH solution, in Tyrode's solution for 15 min (n=8); (5) glibenclamide 1 mu mol/l, also circulated, before S TH solution, in Trode's solution for 15 min (n=8); (6) nitroglycerin 1 00 mu mol/l (n=4); in addition, we studied: (7) STH solution with no-a dditive and no-pacing (n=4); (8) cold Tyrode's in place of cold STH so lution (n=4). Inotropic state was investigated by measuring: (i) veloc ity of developed tension (DT), obtained by dividing DT by time to peak tension; (ii) percentage (from pre-cardioplegia values) velocity chan ges of DT; (iii) log velocity of DT. Post-cardioplegic recovery of con tractility (including force-frequency relationship) was assessed in al l preparations: (a) 60 min after reoxygenation with Tyrode's solution; (b) after further 15 min superfusion with the positive inotropic agen t dobutamine (10 mu mol/l). In parallel experiments, action potential duration (APD) 50% changes induced by nicorandil or glibenclamide plus nicorandil in spontaneously beating atrial (n=4) or electrically driv en (1600 ms CL) ventricular (n=8) tissues during 10 min of STH solutio n were investigated. Based on force-frequency relationship, at 60 min reoxygenation, in absence of cardioplegia, the lowest recovery of myoc ardial contractility was seen (stunning). In STH solution, there was m oderate to severe stunning, which was unaffected by removing pacing du ring cardioplegia, or by vehicle or nitroglycerin. In contrast, nicora ndil improved recovery of contractility (F=3.01, P=0.0106). After dobu tamine, nicorandil preparations showed the highest positive inotropic response, which was completely offset by glibenclamide (F=3.47, P=0.00 46). Multivariate statistical analysis (at 1600 ms CL only) showed cor relations (0.59<multipIe r<0.71, P=0.00001) between log percent veloci ty of DT and the presence of nicorandil (at 60 min reoxggenation: prot ective) or glibenclamide (after dobutamine: detrimental) whereas nitro glycerin and the other covariates had no effect. In atrial tissue only , nicorandil accelerated substantially the shortening of APD 50% durin g cardioplegia, an effect prepented by pretreatment with glibenclamide . In conclusion, addition of nicorandil to cold STH solution improved Ventricular mechanical recovery after hypoxia and reoxygenation. This effect is likely to be due to K-ATP channel opening since it was preve nted by glibenclamide. Nicorandil action cannot be attributed to its n itrate-like properties since in this investigation nitroglycerin faile d to afford protection. Ventricular myocardial protection seems unrela ted to APD 50% shortening. (C) 1995 Academic Press Limited