Vasodilation of rat skeletal muscle arteries by the novel BK channel opener GoSlo is mediated by the simultaneous activation of BK and Kv7 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 programs 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 hyperpolarized isometric vessel preparations and their effects were abolished after (i) functionally eliminating K channels by pre-constriction with 50 mM KCl or (ii) 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(V)7 channel inhibitor XE991 reduced their effects considerably, but neither K(V)1 nor K(V)2 channel blockers altered the inhibitory effects of GoSlo-SR. However, the combined blockade of BK and K(V)7 channels abolished the GoSlo-SR-induced relaxation. GoSlo-SR compounds also activated K(V)7.4 and K(V)7.5 channels expressed in HEK 293 cells. CONCLUSIONS 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(V)7.4/K(V)7.5 channels. Activation of K(V)1, K(V)2 or K(V)7.1 channels or other vasodilator pathways seem not to be involved

Gravitational Lensing by Black Holes

We review the theoretical aspects of gravitational lensing by black holes, and discuss the perspectives for realistic observations. We will first treat lensing by spherically symmetric black holes, in which the formation of infinite sequences of higher order images emerges in the clearest way. We will then consider the effects of the spin of the black hole, with the formation of giant higher order caustics and multiple images. Finally, we will consider the perspectives for observations of black hole lensing, from the detection of secondary images of stellar sources and spots on the accretion disk to the interpretation of iron K-lines and direct imaging of the shadow of the black hole.Comment: Invited article for the GRG special issue on lensing (P. Jetzer, Y. Mellier and V. Perlick Eds.). 31 pages, 12 figure

Innervation of sheep mesenteric lymphatics

SIGLEAvailable from British Library Document Supply Centre- DSC:DXN002084 / BLDSC - British Library Document Supply CentreGBUnited Kingdo