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NEW FINDINGS What is the central question of this study? Although ivabradine therapeutic effect on patients with chronic heart failure and chronic stable angina pectoris, is mediated through the reduction in heart rate, the hemodynamic characteristics and the mechanism of inotropic effect are poorly understood. What is the main finding and its importance? We found that ivabradine had a positive inotropic effect and lowered 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 SERCA2a and decrease of the slow component rate constant which is mediated by the Na+ /Ca2+ exchanger (NCX) and sarcolemmal Ca2+ -ATPase (PMCA) during the Ca2+ transient decaying phase. ABSTRACT Ivabradine's therapeutic effect is mediated by the reduction of the heart rate, however, its hemodynamic characteristics and mechanism of 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, the cardiac output, the stroke volume, the end-diastolic volume, the end-systolic pressure, the ejection fraction, the ±dP/dtmax , the left ventricular end-systolic elastance, the systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both the non-paced and paced rat isolated heart. Ivabradine increased the Ca2+ transient amplitude and the reuptake rates of SERCA2a, lowered the diastolic Ca2+ level and suppressed the combined extrusion rate of the Na+ /Ca2+ exchanger and the sarcolemmal Ca2+ -ATPase. In addition, ivabradine widened the action potential duration, hyperpolarised the resting membrane potential, increased SR Ca2+ content and reduced Ca2+ 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. This article is protected by copyright. All rights reserved.