Hydroxychloroquine reduces heart rate by modulating the hyperpolarisation-activated current 'If': Novel electrophysiological insights and therapeutic potential.

BACKGROUND: Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate (HR) is an important determinant of myocardial oxygen consumption.\n\nOBJECTIVES: To investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia.\n\nMETHODS: We assessed the effects of HCQ: i) on cardiac beating rate in vitro (mice); ii) on the If current in isolated guinea pig sino-atrial node (SAN) myocytes (1, 3, 10 µM); iii) On heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30mg/kg), iv) on blood pressure and ventricular function during feeding (mice, 100mg/kg/day for two weeks, tail cuff plethysmography, anaesthetised echocardiography).\n\nRESULTS: In mouse atria, spontaneous beating rate was significantly (P<0.05) reduced (by 9±3% and 15±2% at 3 and 10 µM HCQ, n=7). In guinea pig isolated SAN cells, HCQ conferred a significant reduction in spontaneous action potential firing rate (17±6%) and a dose-dependent reduction in If (13±3% at 1 µM; 19±2% at 3 µM). Effects were also observed on ICaL (12±4% reduction) and IKr (35±4%) at 3 µM. Intravenous HCQ decreased HR in anesthetised rats (14.3±1.1% at 15mg/kg; n=6) without significantly reducing mean arterial blood pressure. In vivo feeding studies in mice showed no significant change in systolic blood pressure nor left ventricular function.\n\nCONCLUSIONS: We have shown that HCQ acts as a bradycardic agent in SAN cells, atrial preparations and in vivo. HCQ slows the rate of spontaneous AP firing in the SAN through multi-channel inhibition, including If.