Endothelial hyperpolarisation is an important mechanism in the regulation of vascular tone. Herein, the Ca²⁺-dependent K⁺-channels SK3 (KCa2.3) and IK1 (KCa3.1) have been proposed to take center stage, however, their precise role in endothelium-dependent dilation in response to agonists or active hyperemia is not clearly understood. We studied microvascular dilations in mice deficient for only IK1 (IK-ko) or IK1 and SK3 (IKSK-ko) in response to agonist application as well as to skeletal muscle contraction by intravital microscopy.

After blockade of prostaglandins and NO, acetylcholine (ACh)-induced dilations were significantly reduced in IK-ko mice (at 10 mM from 67 to 49%) and further reduced to 25% in IKSK-ko. However, blockade of SK3 by UCL1684 in wildtype did not attenuate the ACh-response. Dilations elicited by adenosine or SNP remained mostly unaffected by deficiency or blockade of KCa. Skeletal muscle contraction initiated by stimulation of the motor nerve dilated arterioles gradually depending on time and frequency. The maximal dilation after 60 s stimulation was attenuated by blockade of SK3 in wt (UCL: from 74 to 37%). In contrast, dilation was fully intact in IK-KO (89%), but also reduced in IKSK-ko (50%).

We conclude that IK1 is mainly responsible for endothelial hyperpolarisation and dilation upon ACh, whereas SK3 only contributes in the absence of IK1. In contrast, exercise hyperemia relies heavily on SK3-activity and IK1 seems to be of minor importance.

These data suggest distinct roles of IK1 and SK3 in arteriolar dilation and may involve specific activation pathways which depend on the stimulus.