Bing-Mei Zhu

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide.

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose-response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio-adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1, 3-dimethyl-6-2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]eth ylamino-2,4 (1H,3H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[N-(3, 4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (KCB-328) and E-1-[(5-(4-chlorophenyl)-2-furanyl)methylene]amino-3-[4-(4-methyl-1 -piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.

Na/H Exchange and Arrhythmia

The Na/H exchanger is a transporter protein embedded in the plasma membrane, extruding H in exchange for extracellular Na using a high concentration gradient of Na existing across the plasma membrane, which is high in the extracellular space. This transporter functions as a controller of intracellular pH in the face of continual production of H especially in the setting of cellular ischemia and anaerobic metabolism. Myocytes have isozyme 1 and during ischemia/reperfusion when the H suddenly accumulates, this is followed by Na increases intracellularly, inducing Ca overload via activation of Na/Ca exchangers. Recently selective Na/H exchange inhibitors such as cariporide have been developed. These drugs have been shown to protect against ischemic myocardial damage in various experimental models, including coronary ischemia/reperfusion ventricular arrhythmias. These drugs, unlike beta blockers, Ca antagonists, Na channel blockers etc, are effective even given after the start of ischemia, or given simultaneously with reperfusion, and large scale clinical trials have been presently undertaken.