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 Ca channel current (I) 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 to inhibition, by three classes of structurally different L-type Ca channel antagonists.ResultsVerapamil, nifedipine, and diltiazem concentration-dependently blocked the ventricular I in all six age groups. However, although nifedipine and diltiazem blocked ventricular I with a similar potency in all age groups, verapamil more potently blocked ventricular I 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 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.

Nifedipine disturbs fetal cardiac function during hypoxemia in a chronic sheep model at near term gestation

“…5 In addition, electrophysiological studies using a mouse heart have shown a higher sensitivity of ventricular L-type Ca 2þ channel current to verapamil in neonatal and infant stages than in child and adult stages. 7 These results suggest that myocardial responsiveness to calcium channel blockers changes with maturation and age. In addition, the evidence concerning fetal myocardial responses to calcium channel blockers in hypoxemic environment is limited.…”

An improved procedure for isolating adult mouse cardiomyocytes for epicardial activation mapping

“…Patch pipettes (tip resistance was 2–3MΩ) were filled with the following solutions. The components of the pipette and bath solutions of the action potential, INa, Ito and ICa, L were described previously 6‐8 . All products were purchased from Sigma (Madison, WI, USA).…”

“…Junction potential, capacitance and series resistance were automatically compensated in the whole‐cell configuration. The holding potential and the voltage clamp were operated as described 6‐8 …”

“…The components of the pipette and bath solutions of the action potential, INa, Ito and ICa, L were described previously. 6 , 7 , 8 All products were purchased from Sigma (Madison, WI, USA). Junction potential, capacitance and series resistance were automatically compensated in the whole‐cell configuration.…”

“…The holding potential and the voltage clamp were operated as described. 6 , 7 , 8 The currents were filtered at 5 kHz, sampled at 50 kHz and stored on a desktop computer equipped with an AD converter (Digidata 1550B, Molecular Devices). All current measurements were normalized using the cell capacitance.…”