Physiology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, 86159 Augsburg, Germany.
Institute of Experimental Cardiology, Cardiology Research Center, 121552 Moscow, Russia.
Int J Mol Sci. 2024 Jun 28;25(13):7140. doi: 10.3390/ijms25137140.
It has been reported that, in the spontaneously hypertensive rat (SHR) model of hypertension, different components of the G-protein/adenylate cyclase (AC)/Calcium-activated potassium channel of high conductance (BK) channel signaling pathway are altered differently. In the upstream part of the pathway (G-protein/AC), a comparatively low efficacy has been established, whereas downstream BK currents seem to be increased. Thus, the overall performance of this signaling pathway in SHR is elusive. For a better understanding, we focused on one aspect, the direct targeting of the BK channel by the G-protein/AC pathway and tested the hypothesis that the comparatively low AC pathway efficacy in SHR results in a reduced agonist-induced stimulation of BK currents. This hypothesis was investigated using freshly isolated smooth muscle cells from WKY and SHR rat tail artery and the patch-clamp technique. It was observed that: (1) single BK channels have similar current-voltage relationships, voltage-dependence and calcium sensitivity; (2) BK currents in cells with a strong buffering of the BK channel activator calcium have similar current-voltage relationships; (3) the iloprost-induced concentration-dependent increase of the BK current is larger in WKY compared to SHR; (4) the effects of activators of the PKA pathway, the catalytic subunit of PKA and the potent and selective cAMP-analogue Sp-5,6-DCl-cBIMPS on BK currents are similar. Thus, our data suggest that the lower iloprost-induced stimulation of the BK current in freshly isolated rat tail artery smooth muscle cells from SHR compared with WKY is due to the lower efficacy of upstream elements of the G-Protein/AC/BK channel pathway.
据报道，在自发性高血压大鼠（SHR）高血压模型中，G 蛋白/腺苷酸环化酶（AC）/钙激活的大电导钾通道（BK）通道信号通路的不同组成部分改变不同。在该通路的上游部分（G 蛋白/AC），已经建立了相对较低的效力，而下游 BK 电流似乎增加。因此，该信号通路在 SHR 中的整体表现难以捉摸。为了更好地理解，我们专注于该通路的一个方面，即 G 蛋白/AC 通路对 BK 通道的直接靶向，并测试了以下假设：即 SHR 中相对较低的 AC 通路效力导致激动剂诱导的 BK 电流刺激减少。该假设使用来自 WKY 和 SHR 大鼠尾动脉的新鲜分离平滑肌细胞和膜片钳技术进行了测试。结果观察到：（1）单个 BK 通道具有相似的电流-电压关系、电压依赖性和钙敏感性；（2）BK 通道激活剂钙缓冲能力强的细胞中的 BK 电流具有相似的电流-电压关系；（3）与 SHR 相比，WKY 中伊洛前列素诱导的 BK 电流浓度依赖性增加更大；（4）PKA 通路激活剂、PKA 的催化亚基和强效且选择性的 cAMP 类似物 Sp-5,6-DCl-cBIMPS 对 BK 电流的作用相似。因此，我们的数据表明，与 WKY 相比，来自 SHR 的新鲜分离大鼠尾动脉平滑肌细胞中伊洛前列素诱导的 BK 电流刺激较低，这是由于 G 蛋白/AC/BK 通道通路的上游元件效力较低所致。
