Increased sarcoplasmic/endoplasmic reticulum calcium ATPase 2a activity underlies the mechanism of the positive inotropic effect of ivabradine

New Findings What is the central question of this study? The therapeutic effect of ivabradine on patients with chronic heart failure and chronic stable angina pectoris is mediated through a reduction in heart rate: what are the haemodynamic characteristics and the mechanism of the inotropic effect? What is the main finding and its importance? Ivabradine has a positive inotropic effect and lowers the heart rate both in vivo and in vitro . These effects are likely mediated by ivabradine's significant increase of the fast component rate constant mediated by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and decrease of the slow component rate constant that is mediated by the Na + /Ca 2+ exchanger and sarcolemmal Ca 2+ ‐ATPase during the Ca 2+ transient decay phase. Abstract Ivabradine's therapeutic effect is mediated by a reduction of the heart rate; however, its haemodynamic characteristics and the mechanism of its inotropic effect are poorly understood. We aimed to investigate the positive inotropic effect of ivabradine and its underlying mechanism. The results demonstrated that ivabradine increased the positive inotropy of the rat heart in vivo by increasing the stroke work, cardiac output, stroke volume, end‐diastolic volume, end‐systolic pressure, ejection fraction, ±d P /d t max , left ventricular end‐systolic elastance and systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both non‐paced and paced rat isolated heart. Ivabradine increased the Ca 2+ transient amplitude and the reuptake rates of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), lowered the diastolic Ca 2+ level and suppressed the combined extrusion rate of the Na + /Ca 2+ exchanger and the sarcolemmal Ca 2+ ‐ATPase. In addition, ivabradine widened the action potential duration, hyperpolarized the resting membrane potential, increased sarcoplasmic reticulum Ca 2+ content and reduced Ca 2+ leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure.