Endothelin-1 (ET-1) is a potent endogenously derived vasoconstrictor, which increases pulmonary hypertension via stimulation of [Ca²⁺]_i level in pulmonary artery smooth muscle cells (PASMCs). In this communication, we sought to investigate the mechanism by which ET-1 causes stimulation of Ca²⁺ concentration in caveolae vesicles of bovine PASMCs (BPASMCs). ET-1 activates PKC-α in the caveolae vesicles by O₂^.− derived from PKCζ–NADPH oxidase dependent pathway. PKC-α phosphorylates Kv1.5 channels leading to a marked stimulation of Na⁺ and Ca²⁺ concentration in the caveolae vesicles. The stimulation of Ca²⁺ concentration in the caveolae vesicles by ET-1 occurs predominantly via Cav1.2 channels. Additionally, an increase in Na⁺ concentration by ET-1 due to stimulation of Nav1.5 channels marginally increases Ca²⁺ level in the caveolae vesicles via reverse-mode Na⁺/Ca²⁺ exchanger (NCX-1) and also through “slip-mode conductance” Nav1.5 channels. 4-AP, a well-known inhibitor of Kv channels, also increases Ca²⁺ concentration in the caveolae vesicles via Cav1.2 channels, reverse-mode NCX-1 and Nav1.5 channels by phosphorylation independent modulation of Kv1.5 channels without the involvement of PKCζ–NADPH oxidase–PKCα signaling axis. Overall, PKCζ–NADPH oxidase–PKCα dependent phosphorylation of Kv1.5 by ET-1 modulates Nav1.5–NCX1–Cav1.2 axis for stimulation of Ca²⁺ concentration in caveolae vesicles of BPASMCs, which provides a crucial mechanism for better understanding of ET-1-mediated modulation of pulmonary vascular tone.

内皮素-1（ET-1）是一种有效的内源性血管收缩剂，可通过刺激肺动脉平滑肌细胞（PASMC）中的[Ca ²⁺ ] _i水平增加肺动脉高压。在此交流中，我们试图研究ET-1引起牛PASMCs（BPASMCs）海绵小泡中Ca ²⁺浓度刺激的机制。ET-1通过源自PKCζ–NADPH氧化酶依赖性途径的O ₂ ^.-激活小窝囊泡中的PKC-α 。PKC-α磷酸化Kv1.5通道，从而明显刺激小窝囊泡中的Na ⁺和Ca ²⁺浓度。Ca ²⁺的刺激ET-1在小窝囊泡中的浓缩主要通过Cav1.2通道发生。此外，增加的Na ⁺由于钠通道的通道的刺激浓度由ET-1或多或少地增加的Ca ²⁺在小窝的囊泡经由反向模电平的Na ⁺ /钙²⁺交换器（NCX-1）并且还通过“滑模电导” Nav1.5通道。4-AP，一种著名的Kv通道抑制剂，也会增加Ca ²⁺通过Cv1.2通道，反向模式NCX-1和Nav1.5通道通过磷酸化独立调节Kv1.5通道而不通过PKCζ-NADPH氧化酶-PKCα信号轴参与小窝囊泡中的浓度。总体而言，ET-1对PKCζ–NADPH氧化酶–PKvα依赖性Kv1.5的磷酸化调节Nav1.5–NCX1–Cav1.2轴，以刺激BPASMC海绵体囊泡中的Ca ²⁺浓度，这为进一步理解提供了关键机制介导的ET-1调节肺血管张力。