Reinhard Brückner

Cardioprotective actions of KC 12291. I. Inhibition of voltage-gated Na+ channels in ischemia delays myocardial Na+ overload.

To characterize KC 12291 (1-(5-phenyl-1,2, 4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N-[2-(3,4-dimethoxy phenyl) ethyl] amino] propane hydrochloride), a newly synthezised inhibitor of voltage-gated Na+ channels, the effects of the agent on Na+ current and ischemia-induced Na+ overload were investigated in isolated cardiomyocytes, atria and saline-perfused hearts. As measured by the patch clamp technique, KC 12291 (1 microM) significantly reduced peak Na+ current after activation of voltage-gated Na+ channels in rat cardiomyocytes. Partial depolarization enhanced the inhibitory effects during steady state conditions of the channel. In isolated guinea pig atria, 1 microM KC 12291 had no effect on contractility under basal conditions but effectively delayed the onset and reduced the extent of anoxic contracture. The concentration-response curve was clearly shifted to the left when atria were partially depolarized by increased extracellular K+. As measured by 23Na NMR spectroscopy in isolated perfused guinea pig hearts, intracellular Na+ rose more than four-fold in a linear fashion during 60 min of low-flow ischemia. KC 12291 (1 microM) prevented Na+ overload within the initial 12 min of ischemia; thereafter the slope of Na+ accumulation was identical to controls. Electrical excitability of hearts, evaluated by intracardial ECG, completely ceased within 15 min after the onset of ischemia. KC 12291 (1 microM) accelerated this process by more than 6 min. The data provide first evidence that KC 12291 reduces Na+ influx through voltage-gated Na+ channels during ischemia and thus delays Na+ overload by enhancing the inexcitability of the heart.

Lack of Evidence of Areas of Slow Conduction Early After Radiofrequency Current Application at Porcine Atrial Myocardium

Electrophysiological sequelae after creation of atrial myocardial lesions by radiofrequency current (RFC) application have not been studied in vitro. During general anesthesia, a steerable 6 French electrode catheter, equipped with a thermistor at the 4‐mm tip electrode, was positioned at the lateral atrial aspect of the tricuspid valve annulus in 5 piglets (German Landrace, mean body weight 12.5 kg). Temperature‐guided (75°C) RFC (500 kHz) was delivered over 30 seconds. Forty‐ eight hours later, the hearts were removed and placed in ice‐cold Turner s solution. The right atria were dissected, and the RFC lesions with surrounding tissue were cut out and transferred to an organ bath according to Steiert. Preparations were superfused with Turner s solution at 37°C. Pacing of the viable tissue at the border of the preparations was accomplished at a cycle length of 500 ms. Whole atrial preparations ware impaled (76 to 150 impalements per specimen) with KC1 capillary microelectrodes containing 3 MKCl. In the surrounding viable tissue of the five preparations, mean maximum diastolic transmembrane potential ranged from −61.3 to −63.7 mV, mean action potential duration at 90% repolarization ranged from 135.2 to 156.1 ms, and mean maximum upstroke velocity of phase 0 of the action potential was between 104.7 and 112.9 V/sec. Statistical analysis revealed no significant differences among all 3 variables. No intracellular action potential was recorded from the surface of all 5 lesions. The surrounding tissue was sharply demarcated, with unaltered transmomhrane action potential characteristics in the vicinity of the lesions. Areas of slow conduction were not observed. Lack of evidence of areas of slow conduction after RFC application to the atrial myocardium may imply that this technique is safe regarding occurrence of atrial tachyarrhythmias.