Berberine alleviates the cerebrovascular contractility in streptozotocin-induced diabetic rats through modulation of intracellular Ca 2+ handling in smooth muscle cells

摘要

Background Vascular 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. Methods Sprague–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 (Ca_L) currents, assessing the protein expressions of Ca_L 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 Ca_L channel current densities, reduced the α_1C-subunit expressions of Ca_L 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 Ca_L currents and suppress the hyperglycemia-induced Ca2+ releases from RyRs in cerebral VSMCs isolated from normal control rats. Conclusions Our 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.