Inhibition of cardiac Na+ current by primaquine.
The electrophysiological effects of the anti-malarial drug primaquine on cardiac Na(+) channels were examined in isolated rat ventricular muscle and myocytes. In isolated ventricular muscle, primaquine produced a dose-dependent and reversible depression of dV/dt during the upstroke of the action potential. In ventricular myocytes, primaquine blocked I(Na)(+) in a dose-dependent manner, with a K(d) of 8.2 microM. Primaquine (i) increased the time to peak current, (ii) depressed the slow time constant of I(Na)(+) inactivation, and (iii) slowed the fast component for recovery of I(Na)(+) from inactivation. Primaquine had no effect on: (i) the shape of the I - V curve, (ii) the reversal potential for Na(+), (iii) the steady-state inactivation and g(Na)(+) curves, (iv) the fast time constant of inactivation of I(Na)(+), and (v) the slow component of recovery from inactivation. Block of I(Na)(+) by primaquine was use-dependent. Data obtained using a post-rest stimulation protocol suggested that there was no closed channel block of Na(+) channels by primaquine. These results suggest that primaquine blocks cardiac Na(+) channels by binding to open channels and unbinding either when channels move between inactivated states or from an inactivated state to a closed state. Cardiotoxicity observed in patients undergoing malaria therapy with aminoquinolines may therefore be due to block of Na(+) channels, with subsequent disturbances of impulse conductance and contractility.
Orta-Salazar
Gerardo
G
Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Av. 14 Sur 6301, C.U. Puebla, México.
Bouchard
Ron A
RA
Morales-Salgado
Fernando
F
Salinas-Stefanon
Eduardo M
EM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010210:Papillary Muscles / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D011319:Primaquine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000502:physiology; D016276:Ventricular Function
D000962:Antimalarials; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D011319:Primaquine