Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and K 7 channels.

BACKGROUND AND PURPOSE

BK channels play important roles in various physiological and pathophysiological processes and thus have been the target of several drug development programmes focused on creating new efficacious BK channel openers, such as the GoSlo-SR compounds. However, the effect of GoSlo-SR compounds on vascular smooth muscle has not been studied. Therefore, we tested the hypothesis that GoSlo-SR compounds dilate arteries exclusively by activating BK channels.

EXPERIMENTAL APPROACH

Experiments were performed on rat Gracilis muscle, saphenous, mesenteric and tail arteries using isobaric and isometric myography, sharp microelectrodes, digital droplet PCR and the patch-clamp technique.

KEY RESULTS

GoSlo-SR compounds dilated isobaric and relaxed and hyperpolarised isometric vessel preparations and their effects were abolished after (a) functionally eliminating K channels by pre-constriction with 50 mM KCl or (b) blocking all K channels known to be expressed in vascular smooth muscle. However, these effects were not blocked when BK channels were inhibited. Surprisingly, the K 7 channel inhibitor XE991 reduced their effects considerably, but neither K 1 nor K 2 channel blockers altered the inhibitory effects of GoSlo-SR. However, the combined blockade of BK and K 7 channels abolished the GoSlo-SR-induced relaxation. GoSlo-SR compounds also activated K 7.4 and K 7.5 channels expressed in HEK 293 cells.

CONCLUSION AND IMPLICATIONS

This study shows that GoSlo-SR compounds are effective relaxants in vascular smooth muscle and mediate their effects by a combined activation of BK and K 7.4/K 7.5 channels. Activation of K 1, K 2 or K 7.1 channels or other vasodilator pathways seems not to be involved.