Evidence for developmental changes in sodium channel inactivation gating and sodium channel block by phenytoin in rat cardiac myocytes.
The voltage-dependent properties of the voltage-activated sodium channel were studied in neonatal (1-2-day-old) and adult rat ventricular cardiac myocytes using the whole-cell variation of the patch-clamp technique (16 degrees C, [Na]i = 15 mM, [Na]o = 25 mM). The voltage dependence of the sodium conductance-membrane potential relation was similar in both neonatal and adult myocytes except for a difference in slope; the adult sodium conductance-membrane potential relation was slightly more steep. Neonatal cells also differed from adult cells by demonstrating a more negative voltage midpoint of their sodium availability curve, a slower rate of recovery from inactivation at hyperpolarized potentials, and a greater extent of slow inactivation development compared with adult cells. Phenytoin (40 microM) reduced the sodium current in a tonic and use-dependent manner in both adult and neonatal myocytes. However, phenytoin (40 microM) produced significantly more tonic block at negative holding potentials (e.g., -140 mV) in neonatal myocytes (22 +/- 5% [mean +/- SEM], n = 14) than in adult myocytes (10 +/- 2%, n = 11) (p less than 0.05). The amplitudes of use-dependent block obtained during trains of 1-second pulses to -20 mV were also significantly greater in neonatal myocytes than in adult myocytes when the diastolic interval was varied over a range of 0.1-1.5 seconds (p less than 0.05). Definition of the time courses of block development at -20 mV indicated that phenytoin had a slightly higher affinity for inactivated sodium channels in neonatal cells. In addition, the time constant of recovery from use-dependent block by phenytoin was found to be significantly longer in neonatal cells than in adult cells at membrane potentials between -160 and -100 mV (p less than 0.001). The marked differences in phenytoin effect on cardiac sodium channels in neonatal versus adult rat cardiac myocytes suggest that there may be significant developmental changes in the sodium channel blocking effects of class I antiarrhythmic drugs in cardiac tissue.
Xu
Y Q
YQ
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112.
Pickoff
A S
AS
Clarkson
C W
CW
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects*
D015222:Sodium Channels; D010672:Phenytoin; D012964:Sodium