Pharmacologic targeting of endothelial Ca2+-activated K+ channels: A strategy to improve cardiovascular function

Abstract

Endothelial small and intermediate-conductance, Ca²⁺-activated K⁺ channels (KCa2.3 and KCa3.1, respectively) play an important role in the regulation of vascular function and systemic blood pressure. Growing evidence indicates that they are intimately involved in agonist-evoked vasodilation of small resistance arteries throughout the circulation. Small molecule activators of KCa2.x and 3.1 channels, such as SKA-31, can acutely inhibit myogenic tone in isolated resistance arteries, induce effective vasodilation in intact vascular beds, such as the coronary circulation, and acutely decrease systemic blood pressure in vivo. The blood pressure-lowering effect of SKA-31, and early indications of improvement in endothelial dysfunction suggest that endothelial KCa channel activators could eventually be developed into a new class of endothelial targeted agents to combat hypertension or atherosclerosis. This review summarises recent insights into the activation of endothelial Ca²⁺ activated K⁺ channels in various vascular beds, and how tools, such as SKA-31, may be beneficial in disease-related conditions.

Keywords: SKA-31; blood pressure; calcium-activated K+ channels; endothelium; hyperpolarization; nitric oxide; vasodilation.

Figure 1.

Chemical structure of SKA-31 (naphtho [1,2-d] thiazol-2-ylamine).

Figure 2.

Cartoon depicting nitric oxide (NO) and hyperpolarization-dependent mechanisms contributing to agonist-induced vasodilation in resistance arteries. Stimulation of endothelial GPCR/Gαq complexes by Ca²⁺-mobilizing vasodilatory agonist promotes activation of PLC-β, the generation of IP₃ via phosphatidyl inositol 4,5-bisphosphate (PIP₂) hydrolysis and the opening IP3 receptors/Ca²⁺ release channels on the endoplasmic reticulum (ER). ER Ca²⁺ release is sensed by STIM1, an EF-hand protein localized in the ER membrane that migrates and couples with the Ca²⁺ influx channel Orai1, leading to Store-Operated Ca²⁺Entry (SOCE). The elevation of cytosolic Ca²⁺ by combined ER release and SOCE regulates the activity of endothelial NO synthase and Ca²⁺-activated K⁺ channels (KCa2.3 and KCa3.1); the latter effectors initiate endothelial-derived hyperpolarization (EDH) that can increase the electrical driving force for Ca²⁺ entry in endothelium and also transfer to the adjacent smooth muscle via myo-endothelial gap junctions (MEGJ) to reduce voltage-gated Ca²⁺ channel activity. The presence of SKA-31 or similar KCa channel positive modulators can pharmacologically “sensitize” KCa2.3 and KCa3.1 channel activation, thereby augmenting cell signaling mechanisms influenced by these channels. Key pathways that may be enhanced following KCa channel sensitization (i.e. generation and transfer of hyperpolarizing current, de novo NO generation) are highlighted with red shading.