Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
Am J Physiol Heart Circ Physiol. 2014 Apr 1;306(7):H989-H1000. doi: 10.1152/ajpheart.00636.2013. Epub 2014 Jan 24.
Recent studies have indicated that the myogenic response (MR) in cerebral arteries is impaired in Fawn Hooded Hypertensive (FHH) rats and that transfer of a 2.4 megabase pair region of chromosome 1 (RNO1) containing 15 genes from the Brown Norway rat into the FHH genetic background restores MR in a FHH.1(BN) congenic strain. However, the mechanisms involved remain to be determined. The present study examined the role of the large conductance calcium-activated potassium (BK) channel in impairing the MR in FHH rats. Whole-cell patch-clamp studies of cerebral vascular smooth muscle cells (VSMCs) revealed that iberiotoxin (IBTX; BK inhibitor)-sensitive outward potassium (K+) channel current densities are four- to fivefold greater in FHH than in FHH.1(BN) congenic strain. Inside-out patches indicated that the BK channel open probability (NPo) is 10-fold higher and IBTX reduced NPo to a greater extent in VSMCs isolated from FHH than in FHH.1(BN) rats. Voltage sensitivity of the BK channel is enhanced in FHH as compared with FHH.1(BN) rats. The frequency and amplitude of spontaneous transient outward currents are significantly greater in VSMCs isolated from FHH than in FHH.1(BN) rats. However, the expression of the BK-α and -β-subunit proteins in cerebral vessels as determined by Western blot is similar between the two groups. Middle cerebral arteries (MCAs) isolated from FHH rats exhibited an impaired MR, and administration of IBTX restored this response. These results indicate that there is a gene on RNO1 that impairs MR in the MCAs of FHH rats by enhancing BK channel activity.
最近的研究表明，在 Fawn Hooded 高血压（FHH）大鼠中，脑动脉的肌源性反应（MR）受损，而将包含 15 个基因的 1 号染色体（RNO1）的 240 万个碱基对区域从褐鼠转移到 FHH 的遗传背景中，可恢复 FHH.1（BN）近交系大鼠的 MR。然而，所涉及的机制仍有待确定。本研究探讨了大电导钙激活钾（BK）通道在损害 FHH 大鼠 MR 中的作用。脑血管平滑肌细胞（VSMCs）的全细胞膜片钳研究显示，在 FHH 大鼠中，IBTX（BK 抑制剂）敏感的外向钾（K+）通道电流密度比 FHH.1（BN）近交系大鼠高 4 至 5 倍。内面向外贴片表明，BK 通道开放概率（NPo）在 FHH 大鼠 VSMCs 中高 10 倍，IBTX 降低 NPo 的程度比 FHH.1（BN）大鼠大。与 FHH.1（BN）大鼠相比，FHH 大鼠的 BK 通道电压敏感性增强。与 FHH.1（BN）大鼠相比，FHH 大鼠分离的 VSMCs 中的自发性瞬态外向电流的频率和幅度显著增大。然而，通过 Western blot 测定，两组大脑血管中 BK-α和-β亚基蛋白的表达相似。从 FHH 大鼠分离的大脑中动脉（MCA）表现出受损的 MR，而 IBTX 的给药恢复了这种反应。这些结果表明，RNO1 上存在一个基因，通过增强 BK 通道活性，损害 FHH 大鼠 MCA 的 MR。
