Endothelium-dependent hyperpolarization: out of the dish and into the brain.

Certain agonists are known to dilate cerebral arteries and/or arterioles by hyperpolarizing the endothelium through activation of endothelial intermediate-conductance calcium-activated K channels (IKCa or KCa3.1) alone or in combination with small-conductance calcium-activated K channels (SKCa or KCa2.X, most likely KCa2.3) (Faraci et al, 2004; Marrelli et al, 2003; McNeish et al, 2006; You et al, 1999). A major component of this dilatory mechanism involves spread of the endothelial hyperpolarization to the vascular smooth muscle (VSM) through myo-endothelial gap junctions (Bryan et al, 2005). This hyperpolarization relaxes VSM by reducing cytoplasmic Ca2+ through closing voltage-operated calcium channels that reside in the plasmalemma of VSM but not endothelium. Although traditionally known as endothelium-derived hyperpolarizing factor, a more appropriate term for this mechanism of dilation is endothelium-dependent hyperpolarization (EDH), as no ‘factor', per se, is transferred between cells (Bryan et al, 2005). Utilizing techniques that covered a spectrum from single-cell K+ currents to isolated pressurized parenchymal arterioles (PAs) to laser Doppler perfusion, a measure of cerebral blood flow (CBF), Hannah et al (this issue) now demonstrate that this EDH mechanism does not require receptor stimulation but is active in the basal state and is responsible for helping to maintain a resting CBF. Although it has been known that IKCa and SKCa are expressed by endothelium, this is the first time that K+ currents from these channels have been measured in freshly isolated endothelial cells from cerebral vessels and the first for any arteriole. Given the difficulty in obtaining single-cell currents in freshly isolated endothelium in general, the fact that these were from arterioles is impressive. More importantly, Hannah et al demonstrated that IKCa and SKCa contribute to the resting tone of PA and contribute significantly to resting CBF. Combined blockade of IKCa and SKCa decreased CBF by ∼15%, a response similar to that produced by the inhibition of NO. Whereas previous studies have demonstrated EDH as an important mechanism in isolated vessels, Hannah et al now show that it is an important mechanism in vivo during resting conditions. Several observations point to the fact that EDH is a major regulator of CBF: (1) EDH is more important than NO as a dilator mechanism in isolated PA upon activation of P2Y2 receptors (You et al, 1999); (2) EDH contributes to resting CBF and the resting tone of arterioles (Hannah et al, this issue) (Cipolla and Bullinger, 2008; Cipolla et al, 2009); (3) EDH is as important as NO in controlling resting CBF (Hannah et al, this issue); and (4) EDH dilations persist or are even upregulated in cerebral vessels, following a number of pathological states, when NO bioavailability is diminished (Cipolla and Bullinger, 2008; Cipolla et al, 2009; Golding et al, 2001; Marrelli et al, 1999; Prisby et al, 2006). Thus, EDH must be considered as a significant mechanism for the regulation of CBF and as a potential target for increasing CBF in pathological states where flow has been compromised. Certainly, more in vivo studies, similar to the one highlighted by this editorial, are needed to fully understand the role of EDH in the cerebral circulation.