Ranolazine's sweet side--improvement of glycaemic control by the novel mechanism of skeletal muscle microvascular recruitment.

Type II diabetes mellitus is a major public health problem afflicting in excess of 250 million individuals worldwide. The presence of this condition in patients with coronary artery disease more than doubles their risk for cardiovascular events. Among the most critical factors are the attendant development of endothelial dysfunction and insulin resistance, which contribute to impaired glycaemic control and acceleration of atherosclerosis. Contemporary therapies have important limitations and safety concerns, as treatment with agents in extensive clinical use, including β-adrenergic receptor blocking agents, thiazide diuretics, and calcium channel antagonists, is associated with increased rates of newly diagnosed diabetes as a result of pro-diabetic effects. These limitations have prompted a search for alternative modalities of drug action. In the current issue of The Journal of Physiology, Fu and colleagues (2013) explored whether ranolazine can improve blood flow and distribution of insulin through α-adrenergic receptor-mediated vasodilatation. Ranolazine is a weak competitive antagonist of α-adrenergic receptors (Allely et al. 1993) and in the conscious dog this antagonism is unmasked by activation of the autonomic nervous system (Zhao et al. 2011). Fu and colleagues (2013) reported that in the therapeutic range of doses ranolazine recruited muscle microvasculature, resulting in a significant >2-fold increase in skeletal muscle blood flow and volume and a substantial enhancement of insulin-mediated whole-body disposal in the range of 30%. In addition, ranolazine improved delivery of insulin into skeletal muscle. Ranolazine increased endothelial nitric oxide synthase (eNOS) phosphorylation and cyclic adenosine monophosphate (cAMP) production without affecting endothelial insulin uptake. Isolated phenylephrine pre-constricted arterial rings were relaxed in the presence of ranolazine, indicating an α-adrenergic receptor-mediated effect. This observation is consistent with evidence obtained in vivo in which the vasoconstrictor effect of intracoronary phenylephrine was abolished by ranolazine (Nieminen et al. 2011) and the vasopressor response to methoxamine was blunted by ranolazine in a dose-dependent manner (Wang et al. 2008). Fu and colleagues (2013) also found that the vasodilatory effects on the pre-capillary arterioles occurred via actions on both the endothelium and smooth muscle cells. Overall, their observations indicate that at therapeutic concentrations ranolazine acutely recruits skeletal muscle microvasculature, increasing microvascular exchange surface area and perfusion. This effect, in combination with the drug's α-adrenergically mediated vasodilatation of pre-capillary arterioles, improves insulin delivery to skeletal muscle and glucose use. This intriguing study by Fu and coworkers (2013) raises important questions relevant to potential clinical applications. As the present studies were performed on an acute basis in normal rats, it remains to be determined whether microvascular recruitment persists following chronic administration in a diabetic animal model. Also, is there evidence that this action of ranolazine on muscle microvasculature operates in patients with various degrees of insulin resistance and early and late stage type 2 diabetes? Clinical trials have demonstrated that ranolazine significantly improves glycaemic control as suggested by reduced levels of glycated haemoglobin (HbA1c) in diabetic as well as non-diabetic subjects (Timmis et al. 2006; Morrow et al. 2009; Chisholm et al. 2010; Kosiborod et al. 2013). Use of ranolazine is also attractive in light of the excellent safety profile shown in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in NonST-Elevation Acute Coronary Syndromes Thrombolysis in Myocardial Infarction 36) trial, which enrolled 6560 patients with cardiovascular disease, 2028 (31%) of whom had pre-existing diabetes (Morrow et al. 2009). However, the mechanisms whereby ranolazine reduces HbA1c remain unknown. The clinical implications of this study are multifold and significant. Essentially, the authors have identified mechanisms that may underlie ranolazine's unique salutary effects, which can potentially improve the cardiovascular health of diabetic patients while reducing myocardial ischaemic events and risk for atrial and ventricular arrhythmias. Although considerable further work will be required to assess fully the clinical applicability of Fu and coworkers’ novel findings (2013), available clinical evidence suggests that the basic concept presented in the current study is promising and worthy of vigorous pursuit.