Activation of β3-adrenergic receptor inhibits ventricular arrhythmia in heart failure through calcium handling.
Ventricular arrhythmia in chronic heart failure (CHF) is considered to be associated with stimulation of β-adrenergic receptors (β-ARs). Three classes of β-ARs have been identified; importantly, distinct from β1 and β2 subtypes, β3-AR could inhibit arrhythmia. Intracellular Ca2+ is considered as a predominant effecter of arrhythmia during heart failure. However, the exact role of β3-AR in arrhythmia and Ca2+ regulation in CHF is not clear yet. Therefore, we studied the effect of BRL37344, a specific β3-AR activator, on CHF-related ventricular arrhythmia and cellular Ca2+ transport. Rabbits with CHF induced by combined aortic insufficiency and aortic constriction were treated with BRL37344 in the presence or absence of β1-AR and β2-AR stimulation. We then evaluated the current produced by sodium calcium exchanger (INCX), an electrical marker of abnormal Ca2+ removal through ion transporter protein sodium calcium exchanger (NCX), Ca2+ transient, a sign of Ca2+ entering the cell, concentration of Ca2+ in sarcoplasmic reticulum (SR) (SR Ca2+ load) and its abnormal release (SR Ca2+ leak). After treatment with BRL37344, the incidence of ventricular arrhythmias induced by infusion of a β1-AR or β2-AR activator decreased significantly. Similarly, β3-AR stimulation remarkably inhibited increase of INCX, Ca2+ transient, SR Ca2+ load and leak induced by activation of β1-AR or β2-AR. SR59230A, a specific β3-AR blocker, abolished the inhibitory effects of BRL37344. These results suggest that β3-AR activation could inhibit ventricular arrhythmia through regulating intracellular Ca2+. Thus, β3-AR is a feasible therapeutic target that holds promise in the treatment of ventricular arrhythmias in CHF.
Department of Cardiology, Renmin Hospital of Wuhan Universityand Cardiovascular Research Institute, Wuhan University, Wuhan, PR China.
Haitao
H
Li
Yu
Y
Liu
He
H
Huang
Yanhong
Y
Tang
Bo
B
Yang
Congxin
C
Huang
D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004594:Electrophysiology; D004983:Ethanolamines / Q000494:pharmacology; D006333:Heart Failure; D008856:Microscopy, Fluorescence; D011412:Propanolamines / Q000494:pharmacology; D011817:Rabbits; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D004983:Ethanolamines; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D019831:Sodium-Calcium Exchanger; C057368:BRL 37344; D002118:Calcium