The acronym ‘EDHF’ (endothelium-derived hyperpolarizing factor) was coined by inter alia one of the senior authors (AHW) of the current paper by Weston et al. (2010) (Taylor and Weston, 1988; Chen et al., 1998). The term described endothelium-dependent smooth muscle hyperpolarization and relaxation independent of nitric oxide and was assumed to reflect the action of a diffusible factor (as per EDRF). The intervening years have witnessed quite considerable efforts expended in an attempt to identify this ‘EDHF’. At times differing data from groups around the world provided a quite confusing picture, but by and large it seems now this reflected the complexity of a hyperpolarizing pathway that cannot be explained simply on the basis of a single diffusible factor, and in addition that can also involve spread of hyperpolarization through heterocellular, myoendothelial gap junctions. Despite some variability in the actual EDHFs that operate in specific vessels, the endothelium-dependent hyperpolarizing pathway, or EDH, does display some key unifying characteristics. Initiation of EDH requires an increase in endothelial cell cytoplasmic calcium concentration. Of fundamental importance was the discovery (Edwards et al., 1998) that that this [Ca2+]i increase then activates two distinct types of KCa, the small and intermediate subtypes (SKCa and IKCa), both shown directly to reside on endothelial not smooth muscle cells (Edwards et al., 1998). These channels then together generate the EDH that leads to smooth muscle hyperpolarization and relaxation, and explains the requirement for a combination of selective channel blockers (apamin and TRAM-34) in order to block EDH-generated vascular relaxation. As a consequence, sensitivity to block with both apamin and TRAM-34, but not apamin and iberiotoxin is regarded as a defining ‘fingerprint’ for the EDH pathway (see Busse et al., 2002 for a review). But although both SKCa and IKCa operate in parallel to generate EDH and vasorelaxation, they can be activated independently. So in quiescent arteries, EDH is preferentially associated with SKCa activation, as it is blocked by apamin. But under more depolarizing conditions, EDH is generated by activation of both SKCa and IKCa. As both channel subtypes are activated by increased cytoplasmic calcium concentration, it was suggested that each subtype might be located in discrete regions of the endothelial cell membrane (Crane et al., 2003). This has indeed proved to be the case. In the rat mesenteric artery, a resistance-size vessel widely utilized in EDH studies and the subject of the current Weston et al. paper (Weston et al. 2010), SKCa channels distribute throughout the endothelial cell membrane, but cluster in the proximity of the large gap junctions between endothelial cells. In contrast, IKCa channels are only found in detectable amounts upon endothelial cell projections towards adjacent smooth muscle, where they can form myoendothelial gap junctions (Dora et al., 2008). Furthermore, the SKCa but not the IKCa channels are localized in caveolae (Absi et al., 2007), a relationship it is now suggested may be disrupted in the endothelium of spontaneously hypertensive rat (SHR) arteries (Weston et al., 2010). So apart from this very interesting observation, what is the importance of the current work? There are three key aspects. First, intracellular microelectrode recordings are used to provide a functional readout of the consequence of a c. 40% reduction in SKCa protein (detected by Western blots) in mesenteric arteries from SHRs; and second, related to and significantly enhancing these electrophysiological experiments is the use, for the first time in vascular tissue, of CyPPA, a positive modulator of SKCa channels. Previous studies have reported that EDH is reduced in SHR mesenteric arteries, but although this was associated with attenuated relaxation no mechanistic explanation was provided (Fujii et al., 1992). What is a very striking observation now is that although SKCa protein was reduced by 40%, SKCa hyperpolarization evoked by ACh was effectively abolished (compare figure 1A with B, in the latter apamin does not further reduce the ACh hyperpolarization in SHR vessels). However, (see figure 2) significant hyperpolarization could still be evoked from the SHR arteries by applying the trisubstituted pyrimidine, CyPPA, which appears to be completely selective in its ability to activate SKCa channels (as hyperpolarization was abolished by apamin). So by directly activating a reduced population of SKCa channels, it was still possible to evoke a greater hyperpolarization in SHR mesenteric arteries than that generated by ACh acting through these channels in control Wistar-Kyoto rat arteries. So does this mean it is the disruption of the membrane localization of SKCa relative to other components of the EDH pathway, inferred from the change in caveolin-1 monomer/dimer ratio, that is responsible for the depressed EDH, rather than the reduced channel protein per se? This is clearly an important aspect that merits further investigation. A third observation of note relates to the reduction in KIR protein that was also discovered in the SHR arteries (approximately 50% and similar in magnitude to the reduction in SKCa), and direct correlation of this reduction to attenuated smooth muscle hyperpolarization in response to exogenous K+. In the mesenteric artery, EDH invades the adjacent smooth muscle layers by passing through myoendothelial gap junctions and as a result of K+ efflux through endothelial KCa channels. The latter acts as an intercellular EDHF, activating KIR channels and Na+/K+ ATPase to cause smooth muscle hyperpolarization (Edwards et al., 1998; Mather et al., 2005). It has been suggested recently that K+ efflux although IKCa is closely coupled solely to Na+/K+ ATPase, and clustering of this pump close to these channels on endothelial cell projections supports this contention (Dora et al., 2008; Harno et al., 2008). A close link between SKCa and KIR would in this context make sense: K+ passing out through SKCa serving to relieve the rectifying block of KIR on the smooth muscle and also on the endothelium (exogenous K+ caused greater hyperpolarization in arteries with an extant endothelium); the latter perhaps serving to amplify endothelial cell hyperpolarization and thus the current available to pass through myoendothelial gap junctions. So by combining technically challenging electrophysiological experiments with molecular studies and the use of a novel pharmacological modulator of SKCa channels, the work of Weston et al. (2010) provides us with some important new insights into the vascular mechanisms that may underlie hypertension. Inevitably, the novelty of this work means it raises more questions than answers! Of course one is what comes first in SHR arteries, an increase in pressure or disrupted signalling through endothelial cell SKCa channels? As reducing SK3 protein in vivo leads to a significant increase in blood pressure, perhaps the latter is the more likely explanation (Taylor et al., 2003). Also important will be probing whether disrupted signalling correlates with morphological changes in channel distribution, and if there are any alterations in the IKCa-Na+/K+ ATPase signalling axis. Certainly, there is evidence from angiotensin-induced hypertensive rats to suggest IKCa channel protein, normally not present in caveolae, may also be decreased (Hilgers and Webb, 2007). Time will provide answers to these questions, but SKCa and its associated signalling pathways may represent promising novel therapeutic targets for blood pressure modulation.