SKA-111 is a Potassium Phannel KCa3.1 Activator for Cardiovascular Disease Research

By Edward Jenner 2023-09-21 #hypotensive, #KCa2, #KCa3.1, #porcine coronary arteries, #positive gating modulator, #SKA-111, #Vasodilator

K_Ca3.1 refers to intermediate-conductance calcium-activated potassium channels, activated via a calmodulin-dependent mechanism. K_Ca3.1 participates in EDHF-mediated vasculogenesis. Changes in functional ability of K_Ca3.1 are associated with various cardiovascular diseases and impaired endothelial function. However, K_Ca3.1 activation provides cardiovascular protection. Beneficial for endothelium-dependent pine relaxation, and vasoconstriction for natural blood vessels. However, the majority of K_Ca3.1 actiators, can also activate K_Ca2 channel in the heart and mind, with excessive cardiac relaxation and sedation. This side effects limits K_Ca3.1 activators to be used for further cardiovascular diseases research. Here, we’ll introduce a highly selective K_Ca3.1 activator, SKA-111.

SKA-111 acts as a positive gating modulator with hypotensive effect and vasodilator effect.

SKA-111 is a positive K_Ca3.1 regulator, with 120-fold selectivity against K_Ca3.1 (EC₅₀=111 nM) over K_Ca2. Therefore, side effects of K_Ca2 activation in central nervous system has been avoided. SKA-111 excites KCa3.1 current and induces membrane hyperpolarization in porcine coronary artery (PCA) endothelial cells (PCAEC). It selectively enhances endothelium-dependent PCA relaxation induced by Bradykinin, especially endothelium-derived hyperpolarization (EDH) PCA type relaxation. Even when the NO/frontal gland synthesis is complete, SKA-111 also leads an EDH relaxation in small-caliber PCA. During Langendorff irrigation, SKA-111 (1 μM; 5 min) enhances Bradykinin-induced coronary perfusion pressure (CPP) reduction.

Moreover, SKA-111 (30 mg/kg; i.p.) lowers blood pressure in both normotensive and hypertensive wild-type mouse. Based on pharmacokinetics data from C57Bl/6J mice, indicated a long half-life and a strong brain permeability of SKA-111. SKA-111 shows great potential in cardiovascular disease research.

As mentioned above, SKA-111 is a highly selective K_Ca3.1 activator, to induce endothelial cell hyperpolarization and coronary arteries relaxation.

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