The aging heart: changes in the pharmacodynamic electrophysiological response to verapamil in aged rabbit hearts.

The aim of this study was to investigate whether the L-type calcium current (I(Ca.L)) may be altered in aged hearts and whether the classical calcium antagonist verapamil may exhibit altered pharmacological profile in aged hearts. We examined male New Zealand rabbits aged either 6 months or 26 months. To examine I(Ca.L) whole-cell patch-clamp technique was performed on isolated cells. Moreover, activation-recovery intervals (ARI) of isolated hearts (Langendorff method) were assessed using an epicardial 256 channel mapping system. We found that the I(Ca.L) density, normalised to the cell volume was significantly reduced (p<0.001). Maximum conductance was also significantly decreased (p=0.01) and steady state inactivation was shifted to more positive potentials in aged hearts (p<0.001). A slightly reduced effect of beta-adrenergic modulation of the I(Ca.L) in aged hearts, and a significantly reduced effect of carbachol on isoprenaline-stimulated I(Ca.L) in aged hearts was observed. L-type alpha 1c subunit, SERCA2-ATPase and the Na(+)/Ca(2+)-exchanger expression were neither significantly different in atrial and ventricular tissues nor between young and old animals. Using the mapping system, isolated hearts were exposed to verapamil (0.005, 0.01, 0.02, 0.05 microM/L). While verapamil did not affect ARI in young hearts, in aged hearts ARI was concentration-dependently reduced and the negative inotropic effect of verapamil was significantly attenuated in aged hearts (p<0.05). From these results we conclude that there are distinct alterations in the electrophysiology of I(Ca.L) (reduced maximum conductance, a shift of the steady state inactivation) in the aged heart which may influence the response to verapamil.