The antiarrhythmic agent propafenone and its primary electropharmacologically active metabolite, 5-hydroxypropafenone, are known inhibitors of cardiac myocyte repolarizing currents. We recently documented potent propafenone inhibition of the transient outward potassium current (Ito) in human atrial myocytes from patients in the newborn and infant age range. In the current study we characterized ventricular Ito inhibition by propafenone and 5-hydroxypropafenone in neonatal myocytes enzymatically isolated from 2-day-old Sprague-Dawley rat pups. Using the whole-cell patch-clamp technique in ventricular myocytes kept in primary culture for 1-4 days, we observed comparably potent Ito inhibition by both agents, yielding 50% maximal inhibitory concentration (IC50) values of 2.1 +/- 0.5 and 1.5 +/- 0.2 microM for propafenone and 5-hydroxypropafenone, respectively. Ito blockade by both of these agents was time, concentration, and voltage dependent, but use independent. There was no drug effect on steady-state voltage dependence of Ito inactivation, or on the time course of Ito recovery from inactivation. These findings are consistent with an open channel-blocking mechanism as suggested by other models. We conclude that both propafenone and 5-hydroxypropafenone are potent Ito inhibitors in neonatal rat ventricular myocytes, with potencies exceeding those demonstrated for propafenone in adult rat ventricular myocytes or in human atrial myocytes from patients of all ages.
Gross. A novel rabbit model of variably compensated complete heart block. J Appl Physiol 92: 1199-1204, 2002; 10.1152/japplphysiol.00714.2001.-Complete heart block (CHB) provides a useful substrate for study of bradycardiadependent ventricular arrhythmias and cardiac function. Existing CHB animal models are limited by surgical recovery time and reliance on intrinsic escape rhythms. We describe a novel closed-chest rabbit model of CHB involving transcatheter radiofrequency (RF) atrioventricular (AV) node ablation and ventricular rate control with chronic transvenous pacing. Permanent CHB was achieved in 34 of 38 attempts overall. Procedural mortality due to cardiac tamponade (n ϭ 2), airway complications (n ϭ 2), and unknown causes (n ϭ 5) occurred in nine animals. Survivors with CHB (n ϭ 28) were maintained for Յ22 days, during which there were three late deaths related to infection (n ϭ 1) or respiratory distress (n ϭ 2). None of the survivors with CHB showed recovery of AV conduction or pacemaker capture loss during chronic ventricular pacing at about one-half normal sinus rates, and 25 animals surviving to death showed no overt signs of hemodynamic compromise such as lethargy, poor feeding, or respiratory distress. This approach provides a reproducible nonsurgical CHB model with adjustable ventricular rate control. atrioventricular node; ventricular pacing; radiofrequency ablation COMPLETE ATRIOVENTRICULAR (AV) conduction block [complete heart block (CHB)] is a useful model for investigation of hemodynamic and electrophysiological abnormalities arising from ventricular bradycardia, in general, and from loss of AV synchrony, in particular. Most previously described CHB models have been surgically created in large animals, such as pigs (4) and dogs (11,12), and rely primarily on intrinsic ventricular escape mechanisms for maintenance of heart rate and cardiac output. We have developed a closed-chest rabbit CHB model based on transcatheter radiofrequency (RF) AV node ablation and permanent transvenous ventricular pacemaker implantation. Our model is unique, because it minimizes surgical trauma and recovery time and enables chronic as well as acute ventricular rate control at reduced expense relative to large animal surgical CHB models.
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