Postnatal developmental changes in the sensitivity of L-type Ca2+ channel to inhibition by verapamil in a mouse heart model

Abstract

BackgroundIn the clinical setting, verapamil is contraindicated in neonates and infants, because of the perceived risk of hypotension or bradyarrhythmia. However, it remains unclear whether there is an age-dependent difference in the sensitivity of cardiac L-type Ca²⁺ channel current (I_Ca,L) to inhibition by verapamil.MethodsVentricular myocytes were enzymatically dissociated from the hearts of six different age groups (0, 7, 14, 21, 28 days, and 10-15 weeks) of mice, using a similar Langendorff-perfusion method. Whole-cell patch-clamp technique was applied to examine the sensitivity of I_Ca,L to inhibition, by three classes of structurally different L-type Ca²⁺ channel antagonists.ResultsVerapamil, nifedipine, and diltiazem concentration-dependently blocked the ventricular I_Ca,L in all six age groups. However, although nifedipine and diltiazem blocked ventricular I_Ca,L with a similar potency in all age groups, verapamil more potently blocked ventricular I_Ca,L in day 0, day 7, day 14, and day 21 mice, than in day 28, and 10-15-week mice.ConclusionIn a mouse heart model, ventricular I_Ca,L before the weaning age (~21 days of age) exhibited a higher sensitivity to inhibition by verapamil than that after the weaning age, which may explain one possible mechanism associated with the development of verapamil-induced hypotension in human neonates and infants.