The Intermediate Conductance Ca -Activated K Channel (KCa3.1) and the Regulation of Blood Pressure

Local vascular tone is generally determined by a variety of factors such as neurotransmitters released from autonomic nerves, circulating vasoactive compounds, tissue metabolites, and endothelium-derived autacoids. The best characterized autacoids are the potent vasodilators nitric oxide (NO) and prostacyclin (PGI2) and the vasoconstrictor peptide endothelin-1. Several studies have, however, convincingly demonstrated the existence of an NO/PGI2independent component of endothelium-dependent relaxation in various arterial beds, most notably in mesenteric, carotid, cerebral, coronary, and renal arteries. Because the NO/PGI2independent vasodilatation originally described was coincident with vascular smooth muscle hyperpolarization and was abolished by depolarizing concentrations of potassium, it was proposed to be mediated by an endothelium-derived hyperpolarizing factor or “EDHF. ”1 When the term EDHF was initially coined, researchers expected to be able to identify a specific chemical entity synthesized in, and released from, the endothelium which hyperpolarizes vascular smooth muscle cells and elicits relaxation. However, there does not seem to be a specific EDHF, as at least 3 principal mechanisms have been linked to the EDHF phenomenon: (1) an increase in endothelial [Ca ]i after cell stimulation triggers the synthesis of a cytochrome P450 metabolite which is essential for the subsequent EDHFmediated responses; (2) K , released from endothelial cells via Ca -dependent K (K Ca) channels induces smooth muscle hyperpolarization by activating inwardly rectifying K channels or the Na -K -ATPase on vascular smooth muscle cells; and (3) endothelial cell hyperpolarization is transmitted to the vascular smooth muscle via gap junctions. The strengths and weaknesses of the arguments for each of these specific types of EDHF have been reviewed recently.2,3 The resting membrane potential of smooth muscle cells in normal pressurized arteries and arterioles is mainly determined by the open probability of K and, to a lesser extent, Cl channels and ranges in vivo between 55 and 35 mV, reflecting the fact that arteries are usually partially contracted, a state from which they can constrict or dilate. The mechanism by which hyperpolarization elicits relaxation is controversial, but the most direct and obvious explanation is that the opening of K channels hyperpolarizes the smooth muscle cell membrane, reducing the open probability of voltagedependent Ca channels and activating Ca sequestration and extrusion mechanisms, so that [Ca ]i is lowered and relaxation can take place. However although the literature relating to EDHF seems confusing, there is widespread agreement that the initial step in all of the EDHF-mediated responses studied to date is activation of small (SKCa) and intermediate conductance K Ca (IKCa) channels in the endothelium.2 This explains why NO/PGI2-independent hyperpolarization and relaxation are exquisitely sensitive to the combination of charybdotoxin and apamin,4–7 or the more specific inhibitors TRAM-348 and UCL1684,9 and insensitive to iberiotoxin, an inhibitor of large conductance (BKCa) K Ca channels. However, the lack of selectivity of the available tools has made it difficult to determine whether the activation of the endothelial IKCa or SKCa or the release of a hyperpolarizing factor such as the cytochrome P450 epoxygenasederived epoxyeicosatrienoic acids underlies the NO/PGI2independent responses.10,11 For example, clotrimazole, an inhibitor of cytochrome P450 epoxygenases, also blocks IKCa, whereas charybdotoxin blocks IKCa as well as BKCa. Thus it seems that a genetic approach is the only way to elucidate the relative importance of the two channels in EDHFas well as NOand PGI2-dependent responses. In this issue of Circulation Research, Si et al13 report that the targeted deletion of KCa3.1 (to give the IKCa its proper name14) attenuates the acetylcholine (ACh)-induced hyperpolarization of endothelial and vascular smooth muscle cells. These effects were associated with an attenuated EDHFdependent relaxation of the isolated carotid artery as well as resistance-sized vessels in the cremaster microcirculation indicating that a significant portion of the NO and PGI2independent relaxation in the arteries studied was related to the opening of KCa3.1 (Figure). With the type of genetic approach used there is a risk that compensation occurs and that the relative importance of remaining KCa channels, in this case the SKCa (or KCa2.3), increases after specific deletion of the KCa3.1. Although resting membrane potential was not different in aortic and carotid artery endothelial cells from wild-type and KCa3.1 / mice, the response to the application of ACh was significantly smaller in cells from animals lacking KCa3.1 and completely reversed by the UCL1684, a specific KCa2.3 blocker. In wild-type mice, UCL1684 had a minimal effect on the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. Correspondence to Ingrid Fleming, PhD, Vascular Signalling Group, Institut für Kardiovaskuläre Physiologie, Johann Wolfgang GoetheUniversität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail fleming@em.uni-frankfurt.de (Circ Res. 2006;99:462-464.) © 2006 American Heart Association, Inc.