Restoration of Endothelium‐dependent Vasodilatory Responses in T2D Resistance Arteries by a Pharmacologic Activator of Endothelial K Ca Channels

Abstract

Endothelial dysfunction is a common early pathogenic event in patients with type 2 diabetes (T2D). In isolated hearts from diabetic Goto-Kakizaki (GK) rats, we have reported that SKA-31, a positive modulator of endothelial Ca2+-activated K+ (KCa) channels, enhances total coronary flow. In the current study, we examined the effects of SKA-31 on cannulated, myogenically active cremaster arteries from 24 week old wild-type (WT) and T2D GK rats, along with small intra-thoracic arteries from patients. At 70 mmHg intraluminal pressure, inhibition of myogenic tone by 0.3 μM acetylcholine (ACh) or 0.1 μM bradykinin (BK) (39.5±3.5% and 30.3±5.4%, respectively) was weaker in GK arteries than that observed in WT arteries (ACh = 59.2±3.9%, BK = 50.5±4.1%). In contrast, inhibition of tone by 10 μM SNP, a smooth muscle relaxant, was comparable in both arteries (GK = 56.2±3.3%, WT = 51.5±5.9%). Following exposure to a threshold concentration of SKA-31 (0.3 μM), vasodilatory responses to ACh (55.2±4.3%) and BK (49.2±5.5%) were significantly augmented in GK arteries, whereas only modest effects were observed in WT arteries. SKA-31 exposure also enhanced vasodilatory responses to ACh (0.3 μM) and BK (0.1 μM) in human arteries, but did not alter responses to either SNP or pinacidil. Electrophysiologically, KCa current densities were similar in isolated endothelial cells from WT and GK vessels. In summary, these data demonstrate that SKA-31 is able to restore endothelium-dependent vasodilatory responses in a rat model of T2D exhibiting endothelial dysfunction and metabolic syndrome, and has similar effects in resistance arteries from T2D patients. Supported in part by research funding to APB from the CIHR.