Effect of small and intermediate conductance calcium activated potassium channel modulation on cortical cerebral blood flow in vivo

Abstract

Pharmacological studies using selective inhibitors and activators of small and intermediate conductance calcium‐activated potassium channels (SKCa and IKCa) indicate that these channels participate in endothelium‐derived hyperpolarization responses and modulate vascular tone in isolated cerebral arteries. However, the relevance of SKCa and IKCa channel activity in the regulation of cerebral blood flow (CBF) in vivo has not been determined. The present study investigated the effect of SKCa and IKCa modulation on cortical CBF in vivo using laser Doppler flowmetry. Superfusion of inhibitors of SKCa and IKCa (apamin, 300 nM, and TRAM‐34, 10 μM, respectively) through a cranial window over the somatosensory cortex in mouse reduced resting cortical CBF by 17 ± 4 % (n=6, p<0.001). This was similar to the reduction in resting CBF with administration of the nonselective nitric oxide synthase inhibitor, N?‐nitro‐L‐arginine (L‐NNA, 1 mM), of 14 ± 6 % (n=6, p<0.01). Superfusion of the SKCa and IKCa activator, NS309, produced a rapid and robust increase in cortical CBF of 37 ± 9 %, which was largely blocked by apamin and TRAM‐34 (n=7, p<0.01). Inhibition of nitric oxide synthesis with L‐NNA had no effect on the increase in CBF in response to NS309. These results indicate that SKCa and IKCa channels are involved in the regulation of cortical CBF in vivo under resting conditions. The results suggest that SKCa and IKCa channels may also mediate in vivo cerebral vascular responses to metabolic and humoral stimuli, and may be potential therapeutic targets for maintenance of cerebral perfusion. This study was supported by National Heart, Lung, and Blood Institute grant HL‐44455.