Ranolazine recruits muscle microvasculature and enhances insulin action in rats
Authors: Fu Zhuo , Zhao Lina , Chai Weidong , Dong Zhenhua , Cao Wenhong , Liu Zhenqi 
Published: June 2013

Key points
Ranolazine, an anti‐anginal compound, improves glycaemic control in clinical trials and increases myocardial perfusion via a direct vasodilatatory effect on coronary arteries.
Skeletal muscle microvasculature controls the delivery of nutrient and hormones into muscle and their exchanges between plasma and muscle interstitium by providing microvascular exchange surface area.
In this study we examined whether ranolazine improves glycaemic control via exerting vasodilatatory action on the pre‐capillary arterioles to recruit muscle microvasculature.
We demonstrate that ranolazine potently recruits muscle microvasculature, which expands microvascular endothelial surface area in muscle and results in increased muscle delivery and action of insulin.
The results help us better understand the physiological mechanism by which ranolazine improves glycaemic control and its potential as an insulin‐sensitizing agent.
Abstract  Ranolazine, an anti‐anginal compound, has been shown to significantly improve glycaemic control in large‐scale clinical trials, and short‐term ranolazine treatment is associated with an improvement in myocardial blood flow. As microvascular perfusion plays critical roles in insulin delivery and action, we aimed to determine if ranolazine could improve muscle microvascular blood flow, thereby increasing muscle insulin delivery and glucose use. Overnight‐fasted, anaesthetized Sprague‐Dawley rats were used to determine the effects of ranolazine on microvascular recruitment using contrast‐enhanced ultrasound, insulin action with euglycaemic hyperinsulinaemic clamp, and muscle insulin uptake using 125I‐insulin. Ranolazine's effects on endothelial nitric oxide synthase (eNOS) phosphorylation, cAMP generation and endothelial insulin uptake were determined in cultured endothelial cells. Ranolazine‐induced myographical changes in tension were determined in isolated distal saphenous artery. Ranolazine at therapeutically effective dose significantly recruited muscle microvasculature by increasing muscle microvascular blood volume (∼2‐fold, P < 0.05) and increased insulin‐mediated whole body glucose disposal (∼30%, P= 0.02). These were associated with an increased insulin delivery into the muscle (P < 0.04). In cultured endothelial cells, ranolazine increased eNOS phosphorylation and cAMP production without affecting endothelial insulin uptake. In ex vivo studies, ranolazine exerted a potent vasodilatatory effect on phenylephrine pre‐constricted arterial rings, which was partially abolished by endothelium denudement. In conclusion, ranolazine treatment vasodilatates pre‐capillary arterioles and increases microvascular perfusion, which are partially mediated by endothelium, leading to expanded microvascular endothelial surface area available for nutrient and hormone exchanges and resulting in increased muscle delivery and action of insulin. Whether these actions contribute to improved glycaemic control in patients with insulin resistance warrants further investigation.