Programme Contents

Endothelium-dependent vasodilatation: Fundamental role of SK_Ca and IK_Ca potassium channels

Activation of vascular potassium (K) channels underlies both the radial and axial spread of dilatation within the artery wall. Radial spread, or an endothelium-dependent hyperpolarizing factor (EDHF) response, is initiated by agonist activation of endothelial cells, while axial, or spreading dilatation, can follow local hyperpolarization in either the endothelial or the smooth muscle cells.

EDHF describes the endothelium dependent smooth muscle hyperpolarization persisting in the presence of inhibitors of nitric oxide (NO) synthase and cyclooxygenase, and causes smooth muscle relaxation by closing voltage-operated calcium channels. Originally assumed to reflect the action of a diffusible factor or factors, with analogy to EDRF or NO, the term is now also taken to encompass the possibility of passive spread of hyperpolarization from the endothelium (Busse et al., 2002). Key to understanding this pathway is the observation that EDHF-evoked hyperpolarization and associated smooth muscle relaxation can be blocked with a combination of apamin (blocks small conductance calcium-activated K channels, SK_Ca) and charybdotoxin (blocks intermediate and large calcium-activated K channels, IK_Ca and BK_Ca, plus delayed rectifier channels, K_V). Alone, these toxins partially blocked EDHF responses, but in combination they totally abolished the response. Although initially taken to indicate that SK_Ca and BK_Ca on the smooth muscle were responsible for hyperpolarization (to a diffusible EDHF), iberiotoxin was unable to substitute for charybdotoxin (see Busse et al., 2002 for review). Furthermore, direct membrane potential measurements from endothelial cells in situ revealed that apamin and charybdotoxin are acting on K channels in these cells (Edwards et al., 1998). Pharmacological studies (using 1-EBIO and TRAM-34/39) then showed that the target for charybdotoxin is in fact the IK_Ca channel. Thus, agonist activation of the endothelium, leading to increases in [Ca²⁺]_i, activates both SK_Ca and IK_Ca (which may be spatially separated, Crane et al., 2003) causing hyperpolarization which is transfered by a diffusible factor or passive spread through myoendothelial gap junctions to the adjacent smooth muscle, where relaxation is evoked.

In addition to radial spread, axial spread of hyperpolarization is well described in the microcirculation (see Segal 2005). However, it seems to reflect an inherent property of resistance arteries as well (Takano et al., 2004). In small mesenteric arteries, selective activation of endothelial cell hyperpolarization, or of the K_ATP channels localized in the smooth muscle, results in hyperpolarization which spreads along the endothelium causing distant upstream dilatation. Interestingly, spread of hyperpoarization is not associated with an increase in endotheial cell [Ca²⁺] (Takano, 2004). It also may in part reflect K_IR activity (Goto et al., 2004).

Vascular potassium channels therefore play a crucial role in the spread of dilator signals through the artery wall, and disruption of this role may underlie alterations in vascular function in cardiovascular disease.

Busse, R., Edwards, G., Feletou, M., Fleming, I., Vanhoutte, P.M. & Weston, A.H. (2002) Trends in Pharmacological Sciences 23, 374-380.

Crane, G.J., Gallagher, N.T., Dora, K.A. & Garland C.J. (2003) Journal of Physiology 553, 183-189.

Edwards, G., Dora, K.A., Gardener, M.J., Garland, C.J. & Weston, A.H. (1998) Nature 396, 269-272.

Goto, G., Rummery, N.M., Grayson, T. & Hill, C.E. (2004) Journal of Physiology 561, 215-231.

Segal, S.S. (2005) Microcirculation 12, 33-45.

Takano, H., Dora, K.A., Spitaler, M.M. & Garland, C.J. (2004) Journal of Physiology 556, 887-903.