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

BACKGROUND: In 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,I-L) to inhibition by verapamil. METHODS: Ventricular 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,I-L to inhibition, by three classes of structurally different L-type Ca2+ channel antagonists. RESULTS: Verapamil, nifedipine, and diltiazem concentration-dependently blocked the ventricular I-Ca,I-L in all six age groups. However, although nifedipine and diltiazem blocked ventricular I-Ca,I-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. CONCLUSION: In a mouse heart model, ventricular I-Ca,I-L before the weaning age (similar to 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.