Faculty of Life Sciences, Core Technology Facility, The University of Manchester, Manchester, UK.
Br J Pharmacol. 2010 Jun;160(4):836-43. doi: 10.1111/j.1476-5381.2010.00657.x. Epub 2010 Mar 8.
Previous studies have shown that endothelium-dependent hyperpolarization of myocytes is reduced in resistance arteries from spontaneously hypertensive rats (SHRs). The aim of the present study was to determine whether this reflects down-regulation of endothelial K(+) channels or their associated pathways.
Changes in vascular K(+) channel responses and expression were determined by a combination of membrane potential recordings and Western blotting.
Endothelium-dependent myocyte hyperpolarizations induced by acetylcholine, 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309) (opens small- and intermediate-conductance calcium-sensitive K(+) channels, SK(Ca) and IK(Ca), respectively) or cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (SK(Ca) opener) were reduced in mesenteric arteries from SHRs. After blocking SK(Ca) channels with apamin, hyperpolarizations to acetylcholine and NS309 in SHR arteries were similar to those of controls. Hyperpolarization to 5 mM KCl was reduced in SHR arteries due to loss of the Ba(2+)-sensitive, inward-rectifier channel (K(IR)) component; the contribution of ouabain-sensitive, Na(+)/K(+)-ATPases was unaffected. Protein expression of both SK(Ca) and K(IR) channels was reduced in SHR arteries; the caveolin-1 monomer/dimer ratio was increased.
In SHRs, the distinct pathway that generates endothelium-dependent hyperpolarization in vascular myocyte by activation of IK(Ca) channels and Na(+)/K(+)-ATPases remains intact. The second pathway, initiated by endothelial SK(Ca) channel activation and amplified by K(IR) opening on both endothelial cells and myocytes is compromised in SHRs due to down-regulation of both SK(Ca) and K(IR) and to changes in caveolin-1 oligomers. These impairments in the SK(Ca)-K(IR) pathway shed new light on vascular control mechanisms and on the underlying vascular changes in hypertension.
先前的研究表明，自发性高血压大鼠（SHR）的阻力血管中层细胞的内皮依赖性超极化作用减弱。本研究旨在确定这是否反映了内皮 K(+)通道或其相关途径的下调。
通过膜电位记录和 Western blot 相结合的方法来确定血管 K(+)通道反应和表达的变化。
乙酰胆碱、6,7-二氯-1H-吲哚-2,3-二酮 3-肟（NS309）（分别打开小和中电导钙敏 K(+)通道，SK(Ca)和 IK(Ca)）或环己基-[2-(3,5-二甲基-吡唑-1-基）-6-甲基-嘧啶-4-基]-胺（SK(Ca) 开放剂）诱导的内皮依赖性肌细胞超极化作用在 SHR 的肠系膜动脉中减弱。用 apamin 阻断 SK(Ca)通道后，SHR 动脉对乙酰胆碱和 NS309 的超极化作用与对照相似。由于 Ba(2+)敏感内向整流通道（K(IR)）成分的丧失，SHR 动脉对 5 mM KCl 的超极化作用减弱；钠泵的作用不受影响。SHR 动脉中 SK(Ca)和 K(IR)通道的蛋白表达减少； caveolin-1 单体/二聚体比例增加。
在 SHR 中，通过激活 IK(Ca)通道和钠泵产生血管肌细胞内皮依赖性超极化的独特途径仍然完整。第二途径由内皮 SK(Ca)通道的激活引发，并通过内皮细胞和肌细胞上的 K(IR)开放放大，由于 SK(Ca)和 K(IR)的下调以及 caveolin-1 寡聚物的变化，在 SHR 中受到损害。SK(Ca)-K(IR)途径的这些损伤为血管控制机制和高血压中的潜在血管变化提供了新的见解。
