The Effects of Ivabradine on Cardiac Function after Myocardial Infarction are Weaker in Diabetic Rats

Abstract

Background/Aims: Plasma norepinephrine (NE) and brain natriuretic peptide (BNP, termed BNP-45 in rats) are considered as essential neurohormones indicating heart failure progression. The purposes of this study were to examine the effects of ivabradine (IBD) on cardiac function and plasma NE and BNP-45 after chronic ischemic heart failure (CHF) in non-diabetic rats and diabetic rats. We further determined if sympathetic NE uptake-1 (a major pathway to metabolize NE) mechanism is responsible for the role played by IBD. Methods: We ligated rat's coronary artery to induce CHF; and injected streptozotocin (STZ) to induce diabetic hyperglycemia. Echocardiography was employed to determine cardiac function. We used ELISA to examine plasma NE and BNP-45; and Western Blot analysis to examine the protein levels of NE uptake-1 in sympathetic nerves. Results: CHF increased the levels of NE and BNP-45 in non-STZ rats and STZ rats. Systemic injection of IBD significantly attenuated the augmented NE and BNP-45 and impaired left ventricular function induced by CHF in those rats. This effect appeared to be less in STZ rats. A liner relation was observed between the NE/BNP-45 levels and left ventricular function after administration of IBD. Also, IBD was observed to have a recovery effect on the downregulated NE uptake-1 evoked by CHF, but to a smaller degree in STZ rats. Conclusion: Our data revealed specific signaling mechanisms by which IBD improves the cardiac function as IBD alleviates impaired NE uptake-1and thereby decreases heightened NE and BNP-45 induced by CHF. Our data also demonstrated that the effects of IBD are weakened after diabetic hyperglycemia likely due to worsen NE uptake-1 pathway. Thus, targeting sympathetic NE uptake-1 signaling molecules has clinical implications for treatment and management of CHF in diabetes. Our data were also to shed light on strategies for application of this drug because NE and BNP play an important role in regulation of progression and prognosis of CHF, and in particular, because IBD affects NE uptake-1 pathway in hyperglycemic animals to a less degree.

H3 Relaxin Protects Against Myocardial Injury in Experimental Diabetic Cardiomyopathy by Inhibiting Myocardial Apoptosis, Fibrosis and Inflammation

“…The ejection fraction was used to investigate systolic function. The average time from the DM induction to the development of heart failure, defined by both systolic and diastolic dysfunction, was 4 months [35]. …”

Synergistic effects of ivabradine and metformin in the treatment of concomitant chronic heart failure and diabetes mellitus by regulating the activity of the H19/miR-423-5p/HCN4 axis

“…In fact, IBD was shown to exert a therapeutic effect in CHF patients by affecting the remodeling of left ventricle [14,15]. Moreover, it was revealed that IBD enhances cardiac functions by restoring the uptake-1 of norepinephrine (NE) via specific signaling pathways, thus decreasing the elevated levels of BNP-45 and NE in CHF [16]. Other findings suggested that the activity of IBD is inhibited in diabetic hyperglycemia, potentially caused by the impaired uptake-1 of NE [16].…”

“…Previous findings showed that the presence of diabetes mellitus (DM) may reduce the therapeutic effect of IBD in the treatment of CHF [16]. Meanwhile, it has also been shown that MET may reduce the expression of H19 by enhancing the methylation status of H19 promoter, which subsequently promotes the expression of miR-423-5p and suppresses the expression of HCN4, a target of miR-423-5p [17].…”

“…For example, it was shown that IBD can significantly restore impaired uptake-1 of NE in the sympathetic ganglion and subsequently normalize the plasma level of NE in CHF rats [45]. Similarly, the effect of IBD on enhancing the uptake-1 of NE is impaired in STZ animals [16].…”

Isolated downregulation of HCN2 in ventricles of rats with streptozotocin-induced diabetic cardiomyopathy

“…Furthermore, cardiac HCN channels blockade was shown to reduce lethal arrhythmias in dilated cardiomyopathy [12]. Interestingly, although clinical studies reported efficacy and safety of ivabradine in diabetic patients [21], cardiac effects of ivabradine have been reported to be weaker in rats with streptozotocin (STZ)-induced diabetic heart damage [22]. Recently, reduced expression of HCN channels in the sinoatrial node of streptozotocin (STZ)-induced diabetic rats was found [20].…”