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


CONCLUSIONS
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.
Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Xue
X
Cao
Zhijun
Z
Sun
Boya
B
Zhang
Xueqi
X
Li
Hongyuan
H
Xia
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000601:surgery; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006334:Heart Function Tests; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000077550:Ivabradine; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin
D001552:Benzazepines; D002317:Cardiovascular Agents; D009419:Nerve Tissue Proteins; C073021:brain natriuretic peptide-45; D000077550:Ivabradine; D013311:Streptozocin; D009638:Norepinephrine