Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential
| Autor: | Keith M. Channon, Gillian Douglas, Rebecca A. Capel, Neil Herring, Derek A. Terrar, Gary R. Mirams, Manish Kalla, Gil Bub, Arash Yavari, David J. Paterson, Rebecca-Ann B. Burton |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Patch-Clamp Techniques SBA specific bradycardic agent Action Potentials 030204 cardiovascular system & hematology Rats Sprague-Dawley Mice 0302 clinical medicine Funny current Enzyme Inhibitors SAN sinoatrial node ANOVA analysis of variance Sinoatrial Node 0303 health sciences HR heart rate If funny current IKr rapid delayed rectifier potassium current Hyperpolarization (biology) 3. Good health Electrophysiology Pacemaker medicine.anatomical_structure PSS physiological saline solution Ion channels Cardiology ICaL L-type calcium ion current medicine.symptom Cardiology and Cardiovascular Medicine Arrhythmia Hydroxychloroquine Bradycardia medicine.medical_specialty I f If Guinea Pigs Heart rate Heart failure Article 03 medical and health sciences In vivo Internal medicine Physiology (medical) medicine Animals Plethysmograph Heart Atria SDD spontaneous diastolic depolarization 030304 developmental biology business.industry Sinoatrial node HCQ hydroxychloroquine V50 voltage of half-activation medicine.disease Electrophysiological Phenomena Rats Disease Models Animal LV left ventricle Blood pressure AP action potential business |
| Zdroj: | Heart Rhythm |
| Popis: | BACKGROUND: Bradycardic agents are of interest for the treatment of ischemic heart disease and heart failure, as heart rate is an important determinant of myocardial oxygen consumption. OBJECTIVES: The purpose of this study was to investigate the propensity of hydroxychloroquine (HCQ) to cause bradycardia. METHODS: We assessed the effects of HCQ on (1) cardiac beating rate in vitro (mice); (2) the "funny" current (If) in isolated guinea pig sinoatrial node (SAN) myocytes (1, 3, 10 µM); (3) heart rate and blood pressure in vivo by acute bolus injection (rat, dose range 1-30 mg/kg), (4) blood pressure and ventricular function during feeding (mouse, 100 mg/kg/d for 2 wk, tail cuff plethysmography, anesthetized echocardiography). RESULTS: In mouse atria, spontaneous beating rate was significantly (P < .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%, 1 μM dose) and a dose-dependent reduction in If (13% ± 3% at 1 µM; 19% ± 2% at 3 µM). Effects were also observed on L-type calcium ion current (ICaL) (12% ± 4% reduction) and rapid delayed rectifier potassium current (IKr) (35% ± 4%) at 3 µM. Intravenous HCQ decreased heart rate in anesthetized 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. CONCLUSIONS: We have shown that HCQ acts as a bradycardic agent in SAN cells, in atrial preparations, and in vivo. HCQ slows the rate of spontaneous action potential firing in the SAN through multichannel inhibition, including that of If. |
| Databáze: | OpenAIRE |
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