Z. Liu: Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, PO Box 801410, Charlottesville, VA 22908, USA.
J Physiol. 2013 Oct 15;591(20):5235-49. doi: 10.1113/jphysiol.2013.257246. Epub 2013 Jun 24.
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 (125)I-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.
雷诺嗪是一种抗心绞痛化合物，已被证明在大规模临床试验中能显著改善血糖控制，短期雷诺嗪治疗与改善心肌血流相关。由于微血管灌注在胰岛素传递和作用中起着关键作用，我们旨在确定雷诺嗪是否可以改善肌肉微血管血流，从而增加肌肉胰岛素传递和葡萄糖利用。我们使用 overnight-fasted、麻醉的 Sprague-Dawley 大鼠来确定使用对比增强超声确定雷诺嗪对微血管募集的影响，使用 euglycaemic hyperinsulinaemic clamp 确定胰岛素作用，使用 (125)I-insulin 确定肌肉胰岛素摄取。在培养的内皮细胞中，确定雷诺嗪对内皮一氧化氮合酶 (eNOS) 磷酸化、cAMP 生成和内皮胰岛素摄取的影响。在分离的远端隐静脉中，确定雷诺嗪引起的肌电图变化。雷诺嗪在治疗有效剂量下可通过增加肌肉微血管血液量（约 2 倍，P < 0.05）和增加胰岛素介导的全身葡萄糖处置（约 30%，P = 0.02）显著募集肌肉微血管。这与增加胰岛素进入肌肉（P < 0.04）有关。在培养的内皮细胞中，雷诺嗪增加了 eNOS 磷酸化和 cAMP 生成，而不影响内皮胰岛素摄取。在离体研究中，雷诺嗪对预先用苯肾上腺素收缩的动脉环具有强烈的血管扩张作用，内皮剥脱部分消除了这种作用。总之，雷诺嗪治疗可使毛细血管前小动脉扩张，增加微血管灌注，这部分通过内皮介导，导致用于营养和激素交换的微血管内皮表面积扩大，从而增加肌肉胰岛素的传递和作用。这些作用是否有助于改善胰岛素抵抗患者的血糖控制需要进一步研究。
