Inhibition of cardiac Na+ current by primaquine.

Abstract

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.

• Authors: Gerardo Orta-Salazar, Ron A Bouchard, Fernando Morales-Salgado, Eduardo M Salinas-Stefanon
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 135 Issue 3 Pg. 751-63 (Feb 2002) ISSN: 0007-1188 [Print] England
• PMID: 11834623 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Potassium Channel Blockers
• Potassium Channels
• Sodium Channel Blockers
• Sodium Channels
• Primaquine

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Antimalarials (pharmacology)
• Dose-Response Relationship, Drug
• Heart Ventricles (cytology, drug effects)
• Myocardium (cytology, metabolism)
• Papillary Muscles (cytology, drug effects, physiology)
• Potassium Channel Blockers
• Potassium Channels (physiology)
• Primaquine (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sodium Channel Blockers
• Sodium Channels (physiology)
• Ventricular Function