Department of Physiology and Pharmacology and Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Int J Mol Sci. 2019 Jul 16;20(14):3481. doi: 10.3390/ijms20143481.
Systemic hypertension is a major risk factor for the development of cardiovascular disease and is often associated with endothelial dysfunction. KCa2.3 and KCa3.1 channels are expressed in the vascular endothelium and contribute to stimulus-evoked vasodilation. We hypothesized that acute treatment with SKA-31, a selective activator of KCa2.x and KCa3.1 channels, would improve endothelium-dependent vasodilation and transiently lower mean arterial pressure (MAP) in male, spontaneously hypertensive rats (SHRs). Isolated vascular preparations exhibited impaired vasodilation in response to bradykinin (i.e., endothelial dysfunction) compared with Wistar controls, which was associated with decreased bradykinin receptor expression in mesenteric arteries. In contrast, similar levels of endothelial KCa channel expression were observed, and SKA-31 evoked vasodilation was comparable in vascular preparations from both strains. Addition of a low concentration of SKA-31 (i.e., 0.2-0.3 μM) failed to augment bradykinin-induced vasodilation in arteries from SHRs. However, responses to acetylcholine were enhanced. Surprisingly, acute bolus administration of SKA-31 in vivo (30 mg/kg, i.p. injection) modestly elevated MAP compared with vehicle injection. In summary, pharmacological targeting of endothelial KCa channels in SHRs did not readily reverse endothelial dysfunction in situ, or lower MAP in vivo. SHRs thus appear to be less responsive to endothelial KCa channel activators, which may be related to their vascular pathology.
系统性高血压是心血管疾病发展的一个主要危险因素，通常与内皮功能障碍有关。KCa2.3 和 KCa3.1 通道在血管内皮细胞中表达，并有助于刺激引起的血管舒张。我们假设，急性给予 SKA-31（一种选择性激活 KCa2.x 和 KCa3.1 通道的药物）治疗，可改善雄性自发性高血压大鼠（SHR）的内皮依赖性血管舒张，并短暂降低平均动脉压（MAP）。与 Wistar 对照组相比，分离的血管标本对缓激肽的血管舒张反应受损（即内皮功能障碍），这与肠系膜动脉中缓激肽受体表达减少有关。相比之下，在两种品系的血管标本中观察到相似水平的内皮 KCa 通道表达，并且 SKA-31 诱发的血管舒张作用相当。添加低浓度的 SKA-31（即 0.2-0.3μM）不能增强 SHR 动脉中缓激肽诱导的血管舒张。然而，对乙酰胆碱的反应增强。令人惊讶的是，体内急性给予 SKA-31（30mg/kg，腹腔注射）与给予载体相比，MAP 适度升高。总之，在 SHR 中对内皮 KCa 通道进行药理学靶向治疗，未能轻易逆转原位内皮功能障碍，或降低体内 MAP。因此，SHR 对内皮 KCa 通道激活剂的反应似乎较低，这可能与它们的血管病理学有关。
