Amiodarone blocks calcium current in single guinea pig ventricular myocytes.
Ca++ current (lca) block by amiodarone and the underlying mechanisms thereof were investigated in guinea pig single ventricular myocytes using the single suction pipette whole cell voltage clamp method. The dose-response curve revealed a 1:1 stoichiometry for binding of amiodarone to its receptor with an apparent dissociation constant of 5.8 microM in the resting state. Amiodarone, 5 microM did not significantly alter the time course of ICa decay, but did shift the steady-state inactivation curve for lca in the hyperpolarizing direction by 9.2 +/- 3.1 mV. Development of block at depolarized potentials was voltage-dependent between -20 and 10 mV with time constants of 112 +/- 33 and 755 +/- 212 msec at 10 mV. In the presence of 0.2 microM amiodarone, recovery from inactivation was fitted by a double exponential most likely indicating rapid recovery of the drug-free Ca++ channels and slow recovery of the drug-associated Ca++ channels with time constants of 44 +/- 12 and 108 +/- 403 msec, respectively, at -80 mV. The proportion of the current recovering via the slow phase was 36 +/- 7%. By using this value, we estimated the dissociation constant in the inactivated state to be 0.36 microM. Amiodarone's marked use-dependent block of lca is explicable in terms of its high affinity for, and slow dissociation from, Ca++ channels in the inactivated state. These results suggest that amiodarone blocks lca in both the resting and inactivated states.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishimura
M
M
Reingold ECG Center Northwestern University Medical School, Chicago, Illinois.
Follmer
C H
CH
Singer
D H
DH
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology
D015220:Calcium Channels; D015222:Sodium Channels; D013779:Tetrodotoxin; D000638:Amiodarone