Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca²⁺ handling in smooth muscle cells.

Yu-Guang Ma,Hai-Tao Guan,Mei Liu,Zhi-Jun Dai,Yun-Gang Bai,Man-Jiang Xie,Liang Liang,Yin-Bin Zhang

doi:10.1186/s12933-016-0382-9

Abstract

BackgroundVascular dysfunction is a distinctive phenotype in diabetes mellitus. Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. As a classical natural medicine, berberine has been explored as a possible therapy for DM. In addition, it is reported that berberine has an extra-protective effect in diabetic vascular dysfunction. However, little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a functional endothelium under hyperglycemia. Furthermore, it remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca2+ handling in vascular smooth cells (VSMCs) under hyperglycemia.MethodsSprague–Dawley rats were used to establish the diabetic model with a high-fat diet plus injections of streptozotocin (STZ). Berberine (50, 100, and 200 mg/kg/day) were intragastrically administered to control and diabetic rats for 8 weeks since the injection of STZ. The intracellular Ca2+ handling of isolated cerebral VSMCs was investigated by recording the whole-cell L-type Ca2+ channel (CaL) currents, assessing the protein expressions of CaL channel, and measuring the intracellular Ca2+ in response to caffeine. Our results showed that chronic administration of 100 mg/kg/day berberine not only reduced glucose levels, but also inhibited the augmented contractile function of cerebral artery to KCl and 5-hydroxytryptamine (5-HT) in diabetic rats. Furthermore, chronic administration of 100 mg/kg/day berberine significantly inhibited the CaL channel current densities, reduced the α1C-subunit expressions of CaL channel, decreased the resting intracellular Ca2+ ([Ca2+]i) level, and suppressed the Ca2+ releases from RyRs in cerebral VSMCs isolated from diabetic rats. Correspondingly, acute application of 10 μM berberine could directly inhibit the hyperglycemia-induced CaL currents and suppress the hyperglycemia-induced Ca2+ releases from RyRs in cerebral VSMCs isolated from normal control rats.ConclusionsOur study indicated that berberine alleviated the cerebral arterial contractility in the rat model of streptozotocin-induced diabetes via regulating the intracellular Ca2+ handling of smooth muscle cells.

Highlights

Vascular dysfunction is a distinctive phenotype in diabetes mellitus
As compared with control rats, the levels of blood glucose significantly increased and the body weights significantly decreased in diabetic rats from 4 to 8 week after STZinjection, respectively, which indicated that diabetic rat model has been established successfully [13, 18]
In Experiment I, when the diabetic rats were treated with 100 mg/ kg/day berberine for 4 or 8 weeks, there were a marked decrease in the blood glucose and an obvious increase in the body weight of diabetic rats, respectively, which is well in accordance with earlier studies [13, 18]

Summary

Introduction

Current treatments mostly focus on the tight glycemic control and few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. Little is known whether the berberine treatment could ameliorate the smooth muscle contractility independent of a func‐ tional endothelium under hyperglycemia It remains unknown whether berberine affects the arterial contractility by regulating the intracellular Ca2+ handling in vascular smooth cells (VSMCs) under hyperglycemia. It is believed that hyperglycemia is the hallmark feature in the development of diabetic vascular dysfunction and so current treatments mostly focus on the tight glycemic control. Few of these treatments have been designed to directly recover the vascular dysfunction in diabetes. The intracellular Ca2+ handling with their related proteins could be an important therapeutic target in diabetic vascular complications [3]

Objectives

Methods

Results

Conclusion