Cardiovascular and Renal Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Br J Pharmacol. 2012 Jan;165(1):223-34. doi: 10.1111/j.1476-5381.2011.01546.x.
In rodents, the endothelial KCa channels, KCa3.1 and KCa2.3, have been shown to play a crucial role in initiating endothelium-derived hyperpolarizing factor (EDHF) vasodilator responses. However, it is not known to what extent these channels are involved in blood pressure regulation in large mammals, which would also allow us to address safety issues. We therefore characterized canine endothelial KCa3.1 and KCa2.3 functions and evaluated the effect of the KCa3.1/KCa2.3 activator SKA-31 on blood pressure and heart rate in dogs.
Canine endothelial KCa3.1/KCa2.3 functions were studied by patch-clamp electrophysiology and wire myography in mesenteric arteries. Systemic cardiovascular actions of acute SKA-31 administration were monitored in conscious, unstressed beagle dogs.
Mesenteric endothelial cells expressed functional KCa3.1 and KCa2.3 channels that were strongly activated by SKA-31. SKA-31 hyperpolarized the endothelial membrane and doubled endothelial hyperpolarization-dependent vasodilator responses in mesenteric arteries. SKA-31 (2 mg·kg(-1), i.v.) rapidly decreased the MAP by 28 ± 6 mmHg; this response was transient (8 ± 1 s), and the initial drop was followed by a fast and pronounced increase in HR (+109 ± 7 beats min(-1)) reflecting baroreceptor activation. SKA-31 significantly augmented similar transient depressor responses elicited by ACh (20 ng·kg(-1)) and doubled the magnitude of the response over time.
Activation of endothelial KCa3.1 and KCa2.3 lowers arterial blood pressure in dogs by an immediate electrical vasodilator mechanism. The results support the concept that pharmacological activation of these channels may represent a potential unique endothelium-specific antihypertensive therapy.
在啮齿动物中，内皮细胞 KCa 通道 KCa3.1 和 KCa2.3 已被证明在启动内皮衍生超极化因子（EDHF）血管舒张反应中发挥关键作用。然而，这些通道在大型哺乳动物的血压调节中参与的程度尚不清楚，这也将使我们能够解决安全性问题。因此，我们对犬内皮细胞 KCa3.1 和 KCa2.3 的功能进行了表征，并评估了 KCa3.1/KCa2.3 激活剂 SKA-31 对犬血压和心率的影响。
通过在肠系膜动脉上进行膜片钳电生理学和线描描记法研究犬内皮细胞 KCa3.1/KCa2.3 的功能。在清醒、无应激的比格犬中监测急性 SKA-31 给药的全身心血管作用。
肠系膜内皮细胞表达功能性 KCa3.1 和 KCa2.3 通道，SKA-31 强烈激活这些通道。SKA-31 使内皮细胞膜超极化，并使肠系膜动脉内皮依赖性超极化的血管舒张反应增加一倍。SKA-31（2mg·kg(-1)，静脉注射）可使 MAP 迅速下降 28±6mmHg；这种反应是短暂的（8±1s），初始下降后 HR 迅速而明显增加（+109±7 次/min），反映出压力感受器的激活。SKA-31 显著增强了 ACh（20ng·kg(-1)）引起的类似短暂降压反应，并使反应随时间增加一倍。
内皮细胞 KCa3.1 和 KCa2.3 的激活通过即时的电血管舒张机制降低犬的动脉血压。结果支持这样一种概念，即这些通道的药理学激活可能代表一种潜在的独特的内皮特异性抗高血压治疗方法。
