Background

Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K⁺ channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D.

Methodology

Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca²⁺ in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging.

Main findings

Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 μM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca²⁺ elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca²⁺ release by the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitor cyclopiazonic acid.

Conclusions

Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca²⁺ mobilization.

中文翻译：

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KCa 通道激活通过改善细胞内 Ca2+ 动员使 2 型糖尿病阻力动脉的内皮功能正常化

背景

内皮功能障碍是 2 型糖尿病 (T2D) 患者心血管疾病进展的早期致病事件。内皮 KCa2.3 和 KCa3.1 K ⁺通道是动脉直径的重要调节器，因此我们假设 KCa2.3 和 KCa3.1 的小分子激活剂 SKA-31 将对激动剂诱发的肌源性扩张产生积极影响T2D 中的阻力动脉。

方法

动脉压肌图用于研究 22 至 24 周龄 T2D Goto-Kakizaki 大鼠、年龄匹配的 Wistar 对照和来自 T2D 受试者的小人胸腔内阻力动脉的离体提睾骨骼肌阻力动脉的内皮依赖性血管舒张。使用 Fura-2 荧光成像检查来自 Wistar 和 T2D Goto-Kakizaki 提睾管和脑动脉的急性分离的单个内皮细胞中的激动剂刺激的细胞溶质游离 Ca ^{2+ 的}变化。

主要发现

与 Wistar 对照相比，T2D Goto-Kakizaki 大鼠的离体提睾动脉对乙酰胆碱 (ACh) 或缓激肽 (BK) 的内皮依赖性血管舒张反应显着受损，并且在人胸内动脉中观察到类似的结果。相比之下，硝普钠（一种直接平滑肌松弛剂）对生肌张力的抑制在大鼠和人类 T2D 动脉中均未改变。用阈值浓度的 SKA-31 (0.3 μM) 处理显着增强了 T2D Goto-Kakizaki 大鼠和人类受试者动脉中对 ACh 和 BK 的血管舒张反应，而在两种物种的非糖尿病动脉中仅观察到适度的影响。从机制上讲，诱发扩张的 SKA-31 增强与血管 NO 合酶和 COX 活性无关。值得注意的是，来自 T2D Goto-Kakizaki 提睾管和脑动脉的急性分离内皮细胞的²⁺升高，但来自 Wistar 对照血管的未升高。相比之下，SKA-31 处理不影响肌/内质网 Ca ²⁺ -ATPase (SERCA) 抑制剂环吡酮酸释放的细胞内 Ca ²⁺。

结论

总的来说，我们的数据表明 KCa 通道调节可以迅速恢复大鼠和人类 T2D 阻力动脉的内皮依赖性血管舒张反应，这似乎涉及改善内皮 Ca ²⁺动员。