Electrophysiologic and antiarrhythmic effects of the new class III antiarrhythmic drug KCB-328 in experimental canine atrial flutter.

BACKGROUND: The electrophysiologic and antiarrhythmic effects of a new class III antiarrhythmic drug (KCB-328), a delayed rectifier potassium current (IKr) blocker with minimal reverse use-dependent effect on atrial repolarization, were evaluated in the canine night atrial crush-injury model of atrial flutter (AFL). METHODS: Ten anesthetized, open-chest dogs, were studied after right atrial crush-injury. Atrial effective refractory period (ERP), conduction velocity (CV), wavelength, and dispersion of refractoriness were determined during programmed stimulation (S1S2 at S1S1 = 200, 300, 400, and 500 msec) at four sites via a mapping plaque sutured on the right atrial free wall. Right and left ventricular ERP were similarly measured at single sites. Electrophysiological parameters were determined at baseline and following sequential cumulative doses of KCB-328 (10, 30, 100, and 300 microg/kg). RESULTS: Sustained AFL was inducible in 7/10 dogs by rapid pacing following baseline electrophysiologic measurements. KCB-328 significantly prolonged sinus cycle length, but had no effect on PR interval, and prolonged QTc only at the highest dose level. KCB-328 significantly prolonged atrial ERP and wavelength and ventricular ERP, and significantly reduced dispersion of atrial refractoriness. KCB-328 significantly prolonged AFL cycle length, and increasing doses progressively terminated sustained AFL and prevented its reinduction by pacing. No adverse hemodynamic or ventricular proarrhythmic effects were observed. CONCLUSIONS: The electrophysiologic profile of KCB-328 in this canine model of AFL, particularly its lack of reverse use-dependent effect on atrial refractoriness, suggests that it may have significant antiarrhythmic potential in treatment of atrial arrhythmias.

Persistence of Atrial Fibrillation After Its Induction-Importance of the Duration and Dispersion of Atrial Refractoriness and Electrical Remodeling.

BACKGROUND: The electrophysiologic mechanisms of the persistence of atrial fibrillation (AF) after its initiation are not well understood. Therefore, the electrophysiologic characteristics of the right atrium were evaluated in an acute, pacing-induced model of AF in the pig in order to identify parameters associated with persistence of AF. METHODS AND RESULTS: AF was induced by rapid atrial pacing in 30 anesthetized, open-chest, juvenile pigs. Sustained (S) AF was defined as that lasting >10 minutes, nonsustained (NS) AF <10 minutes but >30 seconds, and no (N) AF <30 seconds. Activation mapping and programmed stimulation (S1S1 = 200 ms) was performed at 56 electrodes on the right atrial free wall, to determine ERP (mean and minimum), dispersion of refractoriness (ERPdisp, ELEdisp), conduction velocity (CV), wavelength, AF cycle length (mean of 10 beats), and AF cycle length/time (electrical remodeling). SAF was induced in 10 pigs, NSAF in 9, and NAF in 11. AF cycle length was shorter in SAF and/vs NS vs NAF (P <.001). Mean ERP (107 +/- 9 and/vs 122 +/- 5 vs 142 +/- 9, p <.001) and wavelength (7 +/- 1 and/vs 9 +/- 1 vs 11 +/- 1, P <.001) were shorter in SAF and/vs NSAF vs NAF. Minimum ERP was shorter in SAF and NSAF vs NAF (P <.001). CV at cycle lengths of 200 and 150 msec was not different between groups. Dispersion of ERP was greater in SAF and/vs NSAF vs NAF (8 +/- 1 and/vs 11 +/- 1 vs 19 +/- 4, P <.001). CONCLUSIONS: Persistence of AF correlated with shorter ERP and wavelength, and greater dispersion of ERP and electrical remodeling. There was no correlation with CV.

Identification of functional angiotensin II receptors on rat cardiac fibroblasts.

BACKGROUND: Cardiac hypertrophy results in an increased deposition of the extracellular matrix (ECM) proteins fibronectin and collagen. Recent evidence indicates that angiotensin II (Ang II) might have an important role in the development of myocardial fibrosis accompanying cardiac hypertrophy. We sought to determine whether fibroblasts of cardiac origin (isolated from neonatal and adult animals) express receptors for Ang II and to examine the ability of this peptide to regulate fibronectin and collagen gene expression in a cultured adult cardiac fibroblast cell preparation. METHODS AND RESULTS: Binding of 125I-Ang II to both neonatal and adult cardiac fibroblasts in culture was specific, reversible, and saturable, with the receptor evenly distributed over the cell population. Competition binding experiments with receptor-specific antagonists indicate that Ang II receptors found on both fibroblast types were of the AT1 subtype. Analysis of mRNA levels for the AT1 receptor indicates that adult cardiac fibroblasts express higher levels of the message than neonatal fibroblasts or cardiac myocytes. Addition of 10(-9) mol/L Ang II to adult cardiac fibroblasts resulted in an induction of ECM proteins above control levels, as determined through Northern blots and total collagen assays. CONCLUSIONS: Results from this study indicate that neonatal and adult rat cardiac fibroblasts in culture express AT1 receptors for Ang II. Ang II stimulation of AT1 receptors results in an increased gene expression for ECM proteins. These data suggest that Ang II might have important regulatory roles over cardiac fibroblast function under normal and pathological conditions.