Diabetes mellitus is a pandemic metabolic disease characterized by chronically elevated blood glucose concentration due to insulin dysfunction. Diabetics are prone to limbs fungal infections and ulcers due to vascular injury and end-organ damage such as nephropathy, retinopathy and neuropathic pain all of which are associated with methylglyoxal elevation. Methylglyoxal is generated through carbohydrate, lipid and protein metabolism which are all found to be exacerbated in diabetes. Moreover, methylglyoxal is highly reactive with various cellular and interstitial molecules such as proteins and phospholipids to form stable adducts and advanced glycation end products. Methylglyoxal induces insulin resistance, pancreatic β-cells cytotoxicity, and induces endothelial dysfunction that accelerates retinopathy, another diabetes complication. Additionally, methylglyoxal induces hyperalgesia and neuronal inflammation associated with neuropathic pain. Therefore, methylglyoxal might represent a potential therapeutic target in diabetes and associated complications.2

The elevated serum Ox-LDL in hyperglycaemic STZ-diabetic rats may contribute to diabetic endothelial dysfunction, possibly through downregulation of endothelial CAV-1 and eNOS.

Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.

Endothelial dysfunction is a common complication in diabetes in which endotheliumdependent vasorelaxation is impaired. The aim of this study was to examine the involvement of the TRPV4 ion channel in type 1 diabetic endothelial dysfunction and the possible association of endothelial dysfunction with reduced expression of TRPV4, endothelial nitric oxide synthase (eNOS) and caveolin-1.Male Wistar rats (350-450 g) were injected with 65mg/kg i.p. streptozotocin (STZ) or vehicle. Endothelial function was investigated in aortic rings and mesenteric arteries using organ bath and myograph, respectively. TRPV4 function was studied with fura-2 calcium imaging in endothelial cells cultured from aortas from control and STZ treated rats. TRPV4, caveolin-1 and eNOS expression was investigated in these cells using immunohistochemistry. STZ-treated diabetic rats showed significant endothelial dysfunction characterised by impaired muscarinic-induced vasorelaxation (aortic rings: STZ-diabetics: Emax= 29.6±9.3%; control: Emax=77.2±2.5% P˂0.001), as well as significant impairment in TRPV4-induced vasorelaxation (aortic rings, 4αPDD STZ-diabetics: Emax= 56.0±5.5%; control: Emax= 81.1±2.1% P˂0.001). Furthermore, STZ-diabetic primary aortic endothelial cells showed a significant reduction in TRPV4-induced intracellular calcium elevation (P˂0.05) compared with the control group. This was associated with significantly lower expression of TRPV4, caveolin-1 and eNOS and this was reversed by insulin treatment of the endothelial cultures from STZ -diabetic rats. Taken together, these data are consistent with the hypothesis that signalling through TRPV4, caveolin-1, and eNOS is downregulated in STZdiabetic aortic endothelial cells and restored by insulin treatment.