van der Horst Jennifer, Rognant Salomé, Hellsten Ylva, Aalkjær Christian, Jepps Thomas A
Department of Biomedical Sciences (J.v.d.H., S.R., C.A., T.A.J.), University of Copenhagen, Denmark.
The August Krogh Section for Human Physiology, Department of Nutrition, Exercise and Sports (J.v.d.H., Y.H.), University of Copenhagen, Denmark.
Hypertension. 2022 Oct;79(10):2214-2227. doi: 10.1161/HYPERTENSIONAHA.122.19351. Epub 2022 Aug 5.
The voltage-gated potassium channel (Kv)7.4 and Kv7.5 channels contribute to the β-adrenoceptor-mediated vasodilatation. In arteries from hypertensive rodents, the Kv7.4 channel is downregulated and function attenuated, which contributes to the reduced β-adrenoceptor-mediated vasodilatation observed in these arteries. Recently, we showed that disruption of the microtubule network, with colchicine, or inhibition of the microtubule motor protein, dynein, with ciliobrevin D, enhanced the membrane abundance and function of Kv7.4 channels in rat mesenteric arteries. This study aimed to determine whether these pharmacological compounds can improve Kv7.4 function in third-order mesenteric arteries from the spontaneously hypertensive rat, thereby restoring the β-adrenoceptor-mediated vasodilatation.
Wire and intravital myography was performed on normotensive and hypertensive male rat mesenteric arteries and immunostaining was performed on isolated smooth muscle cells from the same arteries.
Using wire and intravital microscopy, we show that ciliobrevin D enhanced the β-adrenoceptor-mediated vasodilatation by isoprenaline. This effect was inhibited partially by the Kv7 channel blocker linopirdine and was dependent on an increased functional contribution of the β2-adrenoceptor to the isoprenaline-mediated relaxation. In mesenteric arteries from the spontaneously hypertensive rat, ciliobrevin D and colchicine both improved the isoprenaline-mediated vasorelaxation and relaxation to the Kv7.2 -7.5 activator, ML213. Immunostaining confirmed ciliobrevin D enhanced the membrane abundance of Kv7.4. As well as an increase in the function of Kv7.4, the functional changes were associated with an increase in the contribution of β2-adrenoceptor following isoprenaline treatment. Immunostaining experiments showed ciliobrevin D prevented isoprenaline-mediated internalizationof the β2-adrenoceptor.
Overall, these data show that colchicine and ciliobrevin D can induce a β2-adrenoceptor-mediated vasodilatation in arteries from the spontaneously hypertensive rat as well as reinstating Kv7.4 channel function.
电压门控钾通道（Kv）7.4和Kv7.5通道参与β-肾上腺素能受体介导的血管舒张。在高血压啮齿动物的动脉中，Kv7.4通道下调且功能减弱，这导致了在这些动脉中观察到的β-肾上腺素能受体介导的血管舒张减少。最近，我们发现用秋水仙碱破坏微管网络或用西洛比文D抑制微管运动蛋白动力蛋白，可增强大鼠肠系膜动脉中Kv7.4通道的膜丰度和功能。本研究旨在确定这些药理化合物是否能改善自发性高血压大鼠三级肠系膜动脉中Kv7.4的功能，从而恢复β-肾上腺素能受体介导的血管舒张。
对正常血压和高血压雄性大鼠肠系膜动脉进行线栓法和活体血管造影，并对来自相同动脉的分离平滑肌细胞进行免疫染色。
使用线栓法和活体显微镜，我们发现西洛比文D增强了异丙肾上腺素介导的β-肾上腺素能受体介导的血管舒张。这种作用被Kv7通道阻滞剂利诺吡啶部分抑制，并且依赖于β2-肾上腺素能受体对异丙肾上腺素介导的舒张作用的功能贡献增加。在自发性高血压大鼠的肠系膜动脉中，西洛比文D和秋水仙碱都改善了异丙肾上腺素介导的血管舒张以及对Kv7.2 -7.5激活剂ML213的舒张反应。免疫染色证实西洛比文D增加了Kv7.4的膜丰度。除了Kv7.4功能增加外，功能变化还与异丙肾上腺素处理后β2-肾上腺素能受体的贡献增加有关。免疫染色实验表明西洛比文D可防止异丙肾上腺素介导的β2-肾上腺素能受体内化。
总体而言，这些数据表明秋水仙碱和西洛比文D可在自发性高血压大鼠的动脉中诱导β2-肾上腺素能受体介导的血管舒张，并恢复Kv7.4通道功能。
