Cao Xue, Sun Zhijun, Zhang Boya, Li Xueqi, Xia Hongyuan
Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Cell Physiol Biochem. 2016;39(5):2055-2064. doi: 10.1159/000447901. Epub 2016 Oct 31.
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.
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.
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.
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.
背景/目的：血浆去甲肾上腺素（NE）和脑钠肽（BNP，在大鼠中称为BNP - 45）被认为是指示心力衰竭进展的重要神经激素。本研究的目的是检查伊伐布雷定（IBD）对非糖尿病大鼠和糖尿病大鼠慢性缺血性心力衰竭（CHF）后心脏功能以及血浆NE和BNP - 45的影响。我们进一步确定交感神经NE摄取 - 1（代谢NE的主要途径）机制是否介导了IBD所起的作用。
我们结扎大鼠冠状动脉以诱导CHF；并注射链脲佐菌素（STZ）以诱导糖尿病性高血糖。采用超声心动图测定心脏功能。我们使用酶联免疫吸附测定法（ELISA）检测血浆NE和BNP - 45；并通过蛋白质免疫印迹分析检测交感神经中NE摄取 - 1的蛋白水平。
CHF使非STZ大鼠和STZ大鼠的NE和BNP - 45水平升高。全身注射IBD可显著减轻CHF诱导的这些大鼠中升高的NE和BNP - 45以及左心室功能受损。这种作用在STZ大鼠中似乎较小。给予IBD后，观察到NE/BNP - 45水平与左心室功能之间存在线性关系。此外，观察到IBD对CHF引起的下调的NE摄取 - 1有恢复作用，但在STZ大鼠中的程度较小。
我们的数据揭示了IBD改善心脏功能的特定信号传导机制，因为IBD减轻了受损的NE摄取 - 1，从而降低了CHF诱导的升高的NE和BNP - 45。我们的数据还表明，糖尿病性高血糖后IBD的作用减弱，可能是由于NE摄取 - 1途径恶化。因此，针对交感神经NE摄取 - 1信号分子对糖尿病性CHF的治疗和管理具有临床意义。我们的数据还为该药物的应用策略提供了线索，因为NE和BNP在CHF的进展和预后调节中起重要作用，特别是因为IBD在高血糖动物中对NE摄取 - 1途径的影响较小。
