Pleiotropic vascular effects of ivabradine in streptozotocin-induced diabetes

Ivabradine (IVA) reduces heart rate (HR) by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in sinoatrial node. Studies suggest that IVA has other beneficial effects on cardiovascular system that are not related to its effect on HR such as prevention of endothelial injury and the antioxidant effects. In addition to sinoatrial node, HCN channels exist in other tissues and their expression pattern differs in certain pathologies such as hypertension and hypertrophy. We investigated the mechanism of IVA effect in the setting of streptozotocin (STZ)-induced cardiovascular damage. Direct effects of IVA and their mechanism on thoracic aorta as well as possible prevention of vascular dysfunction in diabetes were investigated in this study. The effects of IVA on vascular function were investigated in control and STZ-diabetic rats. Some control and diabetic rats were treated with IVA. IVA treatment prevented diabetes-induced increase in plasma p-selectin and vascular cell adhesion molecule-1 levels and the decrease in nitric oxide content in the aortas of diabetic animals. When added to isolated organ bath, IVA induced concentration-dependent relaxations in thoracic aorta. Pre-incubation with Nω-Nitro- L -arginine methyl ester reduced IVA-induced relaxations. Expression patterns of all isoforms of HCN proteins were affected by both diabetes and IVA treatment. IVA improves vascular function in diabetes and HCN channels support vascular activity against damaging effects of diabetes. IVA may be added to prevent diabetic cardiovascular dysfunction with these beneficial effects that are unrelated to its primary mechanism of action. [Display omitted] •In isolated organ bath, ivabradine induced concentration-dependent relaxations in rat aorta.•L-NAME reduced ivabradine-induced vascular relaxations.•Ivabradine prevented diabetes-induced increase in plasma p-selectin and VCAM-1.•Ivabradine prevented diabetes-induced decrease in NO in diabetic rat aorta.•Both diabetes and ivabradine affected HCN proteins in the vasculature.