Photoinduced removal of nifedipine reveals mechanisms of calcium antagonist action on single heart cells.
The currents through voltage-activated calcium channels in heart cell membranes are suppressed by dihydropyridine calcium antagonists such as nifedipine. Nifedipine is photolabile, and the reduction of current amplitude by this drug can be reversed within a few milliseconds after a 1-ms light flash. The blockade by nifedipine and its removal by flashes were studied in isolated myocytes from neonatal rat heart using the whole-cell clamp method. The results suggest that nifedipine interacts with closed, open, and inactivated calcium channels. It is likely that at the normal resting potential of cardiac cells, the suppression of current amplitude arises because nifedipine binds to and stabilizes channels in the resting, closed state. Inhibition is enhanced at depolarized membrane potentials, where interaction with inactivated channels may also become important. Additional block of open channels is suggested when currents are carried by Ba2+ but is not indicated with Ca2+ currents. Numerical simulations reproduce the experimental observations with molecular dissociation constants on the order of 10(-7) M for closed and open channels and 10(-8) M for inactivated channels.
Gurney
A M
AM
Nerbonne
J M
JM
Lester
H A
HA
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects; D008027:Light; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009543:Nifedipine / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D002121:Calcium Channel Blockers; D007473:Ion Channels; D009543:Nifedipine