Effect of verapamil on tachycardia-induced early cellular electrical remodeling in rabbit atrium.

We investigated the effects of a 7-day verapamil pretreatment (VPT, 7.5 mg/kg bodyweight subcutaneously every 12 h) on ionic currents and molecular mechanisms underlying tachycardia-induced early electrical remodeling after 24-h rapid atrial pacing (RAP, 600 bpm) in rabbit atrium. Animals were divided into four groups (n = 6 each group): control (not paced, no verapamil), paced only, verapamil only and verapamil and paced, respectively. VPT doubled ICa,L [7.0 +/- 0.7 pA/pF (control) vs 14.2 +/- 0.6 pA/pF (verapamil only)]. RAP reduced ICa,L by 48% to 3.6 +/- 0.7 pA/pF (paced only). RAP did not affect ICa,L in verapamil-treated animals and averaged 15.3 +/- 0.2 pA/pF (paced and verapamil). RAP resulted in a significant decrease of the expression of the alpha1c subunit (-24.7%) and the beta2A subunit (-13.3%), respectively. VPT led to a similar alteration of subunit expression as RAP ["control" vs "verapamil only", decrease of alpha1c subunit (-25.4%), but no significant change in beta2A subunit expression]. However, after VPT, further diminishment of alpha1c and beta2A subunit expression after rapid atrial pacing was absent. ("verapamil" vs "verapamil and paced", n = 6 both groups). RAP decreased Ito [-45%, 51.5 +/- 3.9 pA/pF (control) vs 26.8 +/- 1.5 pA/pF (paced only)] and was not influenceable by VPT. IK1 was neither affected by RAP nor verapamil pretreatment. Downregulation of alpha1c and beta2A subunit expression and the resulting decay of ICa,L current densities were prevented by verapamil. However, these effects are abolished by multiple other adverse effects of verapamil on atrial electrophysiology.

Influence of verapamil on tachycardia-induced alterations of PP1 and PP2A in rabbit atrium.

BACKGROUND: Long-term atrial fibrillation changes in many regulatory and structural processes may result in stabilization of the arrhythmia. There is evidence that decreased amplitude of L-type Ca(2+) current - probably a key mechanism of atrial remodelling -resulting from changes in expression of regulatory proteins is at least jointly responsible. OBJECTIVES: To assess the expressions of protein phosphatases PP1 and PP2A, as well as the effect of verapamil pretreatment (VPT), in the early phases of atrial fibrillation in a rabbit model. METHODS: FOUR GROUPS, EACH CONSISTING OF SIX ANIMALS, WERE STUDIED: 'not paced, no drug' group; 'paced, no drug' group (rapid atrial pacing [RAP] 600 beats/min for 24 h); 'not paced, verapamil' (NPV) group (duration of VPT was seven days, verapamil 7.5 mg/kg was administered every 12 h); and 'paced, verapamil' (PV) group (pacemaker stimulation after VPT). Protein expression was evaluated by Western blot analysis. RESULTS: RAP resulted in an augmented (32%) PP1 expression (not paced, no drug group versus paced, no drug group). The increase in PP1 expression was prevented with VPT (NPV group versus PV group). Expression of PP2A was not influenced by RAP. However, VPT led to an increase of PP2A expression (16%) after RAP (NPV group versus PV group). CONCLUSIONS: Fortified expression of protein phosphatases might be - besides transcriptional downregulation of channel subunits - another important cause of reduced L-type Ca(2+) current after RAP. Blocking L-type Ca(2+) channels with verapamil to prevent tachycardia-induced changes of PP1 expression might be expedient.