| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
CLASSICAL PERSPECTIVES |
1 Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 2601, Australia Email: caryl.hill{at}anu.edu.au
A perspective on the classic papers of Edwards & Hirst (1988) and Edwards et al. (1988)
Potassium channels are known to play an important role in the regulation of vascular tone through their ability to hyperpolarize smooth muscle cells and produce vasodilatation, primarily by causing the closure of voltage-dependent calcium channels. Of the four different classes of potassium channels found in blood vessels (ATP-sensitive potassium channels, inwardly rectifying potassium channels (KIR), voltage-activated potassium channels and calcium-activated potassium channels), KIR channels have been implicated in a range of vasomotor functions, from vasodilatation of cerebral, coronary and skeletal muscle vascular beds in response to local release of potassium ions (K+; for example, see Quayle et al. 1997; Armstrong et al. 2007) to augmentation and facilitation of the propagation of vasodilatory responses over distance along microcirculatory arterioles and feed arteries (Rivers et al. 2001; Goto et al. 2004; Jantzi et al. 2006). Finally, down-regulation or inactivation of these channels is increasingly seen as instrumental in the increased excitability of vascular smooth muscle found in pathological conditions such as hypertension, hypercholesterolaemia and diabetes (Chrissobolis & Sobey, 2003; Jackson, 2006; Matsushita & Puro, 2006).
KIR channels are activated by hyperpolarization and most readily pass inward currents, selective for K+, at potentials negative to the equilibrium potential for K+ (EK). However, at membrane potentials between the activation voltage and EK, KIR channels sustain small outward currents. Thus, although the channel name refers to the greater ability to pass inward than outward current, the involvement of KIR channels in vasomotor function centres on the smaller outward currents activated at membrane potentials between about –40 and –80 mV. KIR channels are blocked by low concentrations of barium ions (Ba2+) and most importantly, their activation potential is shifted to more positive potentials by increases in extracellular potassium concentration ([K+]o) and to more negative potentials by decreases in [K+]o (Quayle et al. 1997).
Over 60 years ago, it was known that small increases in [K+]o could initiate vasodilatation, although the effect depended on the vascular bed, the level of vascular tone and the concentration of KCl (Dawes, 1941). While the underlying mechanism was unknown at the time, Dawes suggested that this phenomenon could explain the increased blood flow seen in contracting muscle, particularly if sufficient K+ were released during muscular activity. Subsequent studies confirmed the link between small increases in perivascular [K+] and vascular tone in other vascular beds, including the cerebral circulation (Kuschinsky et al. 1972), underscoring the importance of activity-dependent alterations in [K+]o in tuning blood supply to organ activity.
As potassium channels make a significant contribution to resting membrane potential, an increase in [K+]o would be expected to shift EK to more positive potentials and thus lead to depolarization and constriction. The fact that small increases in [K+]o produced hyperpolarization and vasodilatation in certain arteries was seen as somewhat of a paradox. In 1988, although KIR channels had been described in skeletal muscle fibres, starfish eggs and neurones of the olfactory cortex (Katz, 1949; Hagiwara & Takahashi, 1974; Constanti & Galvan, 1983), they had not been described in arterioles, nor were they considered to be activated at membrane potentials more positive to EK. In earlier studies, Hirst & Neild (1978) had detected rectification in segments of guinea pig submucosal arterioles with resistances falling with membrane hyperpolarization, while Hirst & van Helden (1982) had observed that a reduction in [K+]o resulted in depolarization and an increase in membrane resistance of similar arteriolar segments. Thus the aim of the first study by Edwards & Hirst in 1988 was to determine whether this hyperpolarization-induced rectification and the paradoxical effects of changing [K+]o could be attributed to a K+-selective inward rectifier.
Experiments were carried out on short isopotential segments of arterioles in which it was possible to investigate the current–voltage relationships in either voltage or current clamp mode. In these short unpressurized segments the resting membrane potential was –70 mV. The results demonstrated membrane rectification, with the membrane resistance starting to fall at an activation voltage of around –50 mV and membrane conductance increasing with hyperpolarization. The rectifying current was blocked by Ba2+ and showed substantial changes in activation potential with only small changes in [K+]o, i.e. from 1.25 to 10 mM. More importantly, Edwards & Hirst (1988) showed that the activity of this channel could impact on arteriolar excitability, the very aspect now considered in pathological studies to be crucial. Thus, the time course of action potentials initiated from hyperpolarized potentials, at which KIR channels would be active, were briefer than those initiated from more depolarized potentials. Similar effects were observed when the membrane potential was held at –70 mV and [K+]o altered; time courses were shorter in 10 mM K+ (more active KIR) and longer in 2.5 mM K+ (less active KIR). The effect of the KIR current in attenuating the decay of excitatory junction potentials following nerve stimulation could also be seen with summed excitatory junction potentials (more depolarized, less active KIR) having larger time constants than single excitatory junction potentials (more hyperpolarized, more active KIR).
In a back-to-back paper, Hirst and colleagues investigated the role of KIR channels in cerebral arterioles (Edwards et al. 1988). Again current–voltage relationships in short arterial segments and the effect of alterations in [K+]o, from a control value of 5 mM, were tested. Both arteriolar segments located close to the middle cerebral as well as those located at some distance from this larger vessel were chosen, as previous studies had demonstrated loss of sympathetic fibres with increasing distance from the middle cerebral artery (Hill et al. 1986) and neuronal activity was considered to be capable of producing appropriate changes in [K+]o. Interestingly, the results showed that distal arterioles were more excitable than proximal arterioles, had more depolarized membrane potentials, often with superimposed oscillations, and little evidence of inward rectification. Moreover, regional differences in responses to increases in [K+]o were found; distal segments hyperpolarized and now demonstrated inward rectification, while proximal segments depolarized and showed inward rectification at more positive potentials. Since Ba2+ abolished inward rectification of proximal segments, and of distal segments exposed to elevated [K+]o, it was clear that KIR channels were expressed in both areas but that these channels differed in their sensitivity to [K+]o, i.e. higher concentrations were required to activate KIR channels in distal than in proximal segments.
In both studies, inhibition of the KIR channels with Ba2+ resulted in a large depolarization of submucous arterioles and proximal cerebral arterioles leading the authors to conclude that KIR channels constituted the predominant resting potassium conductance. However, the resting membrane potential detected in these early studies was around –70 mV, representing recordings from unpressurized vessels. This value is considerably more hyperpolarized than that measured subsequently in vivo in systemic vessels at around –30 to –40 mV (Welsh & Segal, 1998; Emerson & Segal, 2000; Siegl et al. 2005). Although KIR channels would be expected to be largely closed at these more physiological potentials, low concentrations of Ba2+ which selectively inhibit KIR channels (Quayle et al. 1997) have been reported to reduce the diameter of skeletal muscle arterioles (Loeb et al. 2000) and large cerebral arteries in vivo and of other vessels in vitro (Chrissobolis & Sobey, 2003), suggesting perhaps a minor contribution at rest. Such a contribution seems especially surprising in the cerebral vessels since the [K+]o of cerebrospinal fluid is around 3 mM and at this concentration the activation potential of the KIR channels would be expected to be shifted to more negative potentials.
Irrespective of whether KIR channels contribute to resting vascular tone, these two classical papers provided proof that these channels could influence vascular reactivity, especially in situations where [K+]o was increased. They were the first to describe the existence of a potassium-sensitive inward rectifier in both cerebral and systemic arterioles, demonstrate the activation of this current at potentials more positive than EK, show how the activation potential could be moved to more depolarized potentials by small increases in [K+]o and illustrate how this current could modify arteriolar excitability. However, the original studies failed to take into account the fact that the preparations contained both smooth muscle and endothelial cells and so the precise cellular location of the channels was not determined. Although subsequent studies confirmed the existence of KIR currents in smooth muscle cells isolated from cerebral arteries (Quayle et al. 1993), others have shown that KIR channels are also expressed in isolated endothelial cells (Nilius et al. 1997) and in intact rat mesenteric arteries, they may even be confined to this layer (Doughty et al. 2001; Crane et al. 2003; Goto et al. 2004).
Such differential cellular expression of KIR channels may be a characteristic of different vascular beds, with vessel size perhaps contributing to further variation. Given that heterocellular coupling has been reported to play a critical role in vasodilatation evoked by endothelial-derived hyperpolarization and that the incidence of myoendothelial gap junctions varies along and between vascular beds (Sandow & Hill, 2000; Sandow et al. 2002, 2003), the specific cellular location of KIR channels may differentially affect smooth muscle contractility. Indeed, a recent study has shown that KIR channels expressed in vascular smooth muscle cells of cerebral or coronary arteries act as electrical amplifiers of hyperpolarizing responses activated in either the endothelium or the smooth muscle (Smith et al. 2007). However, this was not the case in mesenteric arteries in which KIR channels were not highly expressed in the smooth muscle cells (Smith et al. 2007). If these vessels are analogous to those evaluated in previous studies of the mesenteric circulation, then one would expect the endothelium to express KIR channels. In this case, the physiological role of these endothelial channels warrants further investigation.
The pioneering studies of Hirst and colleagues on arteriolar KIR channels raised other questions which remain topics for future research. For example, what is the significance of the regional variation in the sensitivity of the KIR channels to [K+]o? Interestingly, pericytes surrounding microvessels in the rat retina have also been shown to display a topographical heterogeneity in KIR currents (Matsushita & Puro, 2006), while studies in the spiral modiolar artery of the ear have described a heterogeneously coupled population of smooth muscle cells with a bimodal distribution of membrane potentials resulting from the continuous activation or not of KIR channels (Jiang et al. 2001). In the latter study, the two cell populations clearly differed in their sensitivity to [K+]o in a manner analogous to that of the proximal and distal arteriolar cells. In the cerebral circulation, the distal arteriolar segments which demonstrated the less sensitive KIR channels lacked a sympathetic innervation (Hill et al. 1986) leading the authors to suggest a possible trophic influence of the nerves on muscle properties (Edwards et al. 1988). It is not known whether such correlations exist in other vascular beds. Nevertheless, the end result is that the proximal cerebral vessels will hyperpolarize and relax to smaller increases in [K+]o than will the distal vessels, a characteristic conducive to producing an effective increase in blood flow.
Future studies will need to address in more detail the differential regional and cellular expression of KIR channels throughout the vascular system and the contribution of these channels to arteriolar excitability in vivo. The factors which might regulate the expression and biophysical characteristics of KIR channels are also of great interest, particularly if these may vary with cell type or pathophysiological condition. In this respect it should be borne in mind that even a small change in the magnitude of fluctuations in perivascular [K+]o could a have profound effect on the ability of KIR channels to influence vascular excitability.
References
Armstrong ML, Dua AK & Murrant CL (2007). Potassium initiates vasodilatation induced by a single skeletal muscle contraction in hamster cremaster muscle. J Physiol 581, 841–852.
Chrissobolis S & Sobey CG (2003). Inwardly rectifying potassium channels in the regulation of vascular tone. Curr Drug Targets 4, 281–289.[CrossRef][Medline]
Constanti A & Galvan M (1983). Fast inward-rectifying current accounts for anomalous rectification in olfactory cortex neurones. J Physiol 335, 153–178.
Crane GJ, Walker SD, Dora KA & Garland CJ (2003). Evidence for a differential cellular distribution of inward rectifier K channels in the rat isolated mesenteric artery. J Vasc Res 40, 159–168.[CrossRef][Medline]
Dawes GS (1941). The vaso-dilator action of potassium. J Physiol 99, 224–238.
Doughty JM, Boyle JP & Langton PD (2001). Blockade of chloride channels reveals relaxations of rat small mesenteric arteries to raised potassium. Br J Pharmacol 132, 293–301.[CrossRef][Medline]
Edwards FR & Hirst GD (1988). Inward rectification in submucosal arterioles of guinea-pig ileum. J Physiol 404, 437–454.
Edwards FR, Hirst GD & Silverberg GD (1988). Inward rectification in rat cerebral arterioles; involvement of potassium ions in autoregulation. J Physiol 404, 455–466.
Emerson GG & Segal SS (2000). Electrical coupling between endothelial cells and smooth muscle cells in hamster feed arteries: role in vasomotor control. Circ Res 87, 474–479.
Goto K, Rummery NM, Grayson TH & Hill CE (2004). Attenuation of conducted vasodilatation in rat mesenteric arteries during hypertension: role of inwardly rectifying potassium channels. J Physiol 561, 215–231.
Hagiwara S & Takahashi K (1974). The anomalous rectification and cation selectivity of the membrane of a starfish egg cell. J Membr Biol 18, 61–80.[CrossRef][Medline]
Hill CE, Hirst GD, Silverberg GD & van Helden DF (1986). Sympathetic innervation and excitability of arterioles originating from the rat middle cerebral artery. J Physiol 371, 305–316.
Hirst GD & Neild TO (1978). An analysis of excitatory junctional potentials recorded from arterioles. J Physiol 280, 87–104.
Hirst GD & van Helden DF (1982). Ionic basis of the resting potential of submucosal arterioles in the ileum of the guinea-pig. J Physiol 333, 53–67.
Jackson WF (2006). Silent inward rectifier K+ channels in hypercholesterolemia. Circ Res 98, 982–984.
Jantzi MC, Brett SE, Jackson WF, Corteling R, Vigmond EJ & Welsh DG (2006). Inward rectifying potassium channels facilitate cell-to-cell communication in hamster retractor muscle feed arteries. Am J Physiol Heart Circ Physiol 291, H1319–H1328.
Jiang ZG, Si JQ, Lasarev MR & Nuttall AL (2001). Two resting potential levels regulated by the inward-rectifier potassium channel in the guinea-pig spiral modiolar artery. J Physiol 537, 829–842.
Katz B (1949). Les constants electriques de la membrane du muscle. Arch Sci Physiol (Paris) 2, 285–299.
Kuschinsky W, Wahl M, Bosse O & Thurau K (1972). Perivascular potassium and pH as determinants of local pial arterial diameter in cats. A microapplication study. Circ Res 31, 240–247.
Loeb AL, Godeny I & Longnecker DE (2000). Functional evidence for inward-rectifier potassium channels in rat cremaster muscle arterioles. Microvasc Res 59, 1–6.[CrossRef][Medline]
Matsushita K & Puro DG (2006). Topographical heterogeneity of KIR currents in pericyte-containing microvessels of the rat retina: effect of diabetes. J Physiol 573, 483–495.
Nilius B, Viana F & Droogmans G (1997). Ion channels in vascular endothelium. Annu Rev Physiol 59, 145–170.[CrossRef][Medline]
Quayle JM, McCarron JG, Brayden JE & Nelson MT (1993). Inward rectifier K+ currents in smooth muscle cells from rat resistance-sized cerebral arteries. Am J Physiol Cell Physiol 265, C1363–C1370.
Quayle JM, Nelson MT & Standen NB (1997). ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 77, 1165–1232.
Rivers RJ, Hein TW, Zhang C & Kuo L (2001). Activation of barium-sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles. Circulation 104, 1749–1753.
Sandow SL, Bramich NJ, Bandi HP, Rummery NM & Hill CE (2003). Structure, function, and endothelium-derived hyperpolarizing factor in the caudal artery of the SHR and WKY rat. Arterioscler Thromb Vasc Biol 23, 822–828.
Sandow SL & Hill CE (2000). Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. Circ Res 86, 341–346.
Sandow SL, Tare M, Coleman HA, Hill CE & Parkington HC (2002). Involvement of myoendothelial gap junctions in the actions of endothelium-derived hyperpolarizing factor. Circ Res 90, 1108–1113.
Siegl D, Koeppen M, Wolfle SE, Pohl U & de Wit C (2005). Myoendothelial coupling is not prominent in arterioles within the mouse cremaster microcirculation in vivo.Circ Res 97, 781–788.
Smith PD, Brett SE, Luykenaar KD, Sandow SL, Marrelli SP, Vigmond EJ & Welsh DG (2007). Kir channels function as electrical amplifiers in rat vascular smooth muscle. J Physiol; DOI: 10.1113/jphysiol.2007.145474.
Welsh DG & Segal SS (1998). Endothelial and smooth muscle cell conduction in arterioles controlling blood flow. Am J Physiol Heart Circ Physiol 274, H178–H186.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
