Electrophysiology of cerebral blood vessels.

Pharmac. Ther.Vol. 56, pp. 341-358, 1992 Printed in Great Britain.All rightsreserved

0163-7258/92 $15.00 © 1993PergamonPress Ltd

Specialist Subject Editor: R. M. WADSWORTH

ELECTROPHYSIOLOGY OF CEREBRAL BLOOD VESSELS FRANCES PLANE a n d CHRISTOPHER J. GARLAND

Department of Physiology and Pharmacology, University of Southampton, Southampton, S09 3TU, U.K. Abstract--In spite of the relatively large amount of in vitro and in vivo data indicating that, in a number of ways, cerebral arteries are pharmacologically different from peripheral arteries, the mechanisms responsible for these differences are far from clear. An understanding of these mechanisms is particularly important for a rational approach to the treatment of disorders of the cerebral circulation including migraine, hypertension and the responses of cerebral vessels to subarachnoid haemorrhage. This review outlines electrophysiological data which are available from cerebrovascular smooth muscle cells, including the possibility that inwardlyrectifying potassium channels, active at potentials close to the resting membrane potential, are intimately involved in the changes in smooth muscle tone which couple blood flow to regional changes in nerve cell activity. The membrane potential changes in response to perivascular nerve stimulation, noradrenaline, 5-hydroxytryptamine and endothelium-derived hyperpolarizing factor are also described, together with the underlying membrane mechanisms and their relationship to smooth muscle contraction and relaxation.

CONTENTS 1. Introduction 2. Membrane Properties of Smooth Muscle Cells from Cerebral Arteries 2.1. General membrane properties 2.2. Smooth muscle potassium handling 3. Responses of Isolated Cerebral Arteries to Electrical Stimulation 4. Effects of Noradrenaline on Membrane Potential 5. Effects of 5-Hydroxytryptamine on Membrane Potential 6. Endothelium-Mediated Responses 7. Hypertension 8. Cerebral Vasospasm Acknowledgements References

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1. I N T R O D U C T I O N The regulation of smooth muscle tone underlies the very close coupling which exists in the brain between neuronal activity and local alterations in blood flow required to meet the consequent changes in metabolic demand. In spite of this fact, the number of studies specifically investigating the mechanisms responsible for the control of contraction and relaxation in cerebral blood vessels is somewhat limited. This is surprising considering the importance of these mechanisms and that some workers have suggested that cerebrovascular smooth muscle cells may have properties which are different from similar cells in peripheral blood vessels. For example, cerebrovascular smooth muscle is generally relatively insensitive to vasoconstrictor agents like noradrenaline, compared to

Abbreviations--ATP, adenosine triphosphate; cAMP, adenosine-3',5'-cyclic monophosphate; cGMP, guanosine-3',5'-cyclic monophosphate; CGRP, calcitonin gene-related peptide; EDHF, endothelium-derived hyperpolarizing factor; EDRF, endothelium-derived relaxing factor; ejp, excitatory junction potential; 5-HT, 5-hydroxytryptamine; KAVp,ATP-sensitive potassium channels; NPY, neuropeptide Y; SAH, sub-arachnoid haemorrhage; TTX, tetrodotoxin. 341

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the equivalent cells in peripheral arteries. This review focuses on the membrane properties of cerebrovascular smooth muscle cells and the electrophysiological mechanisms which underlie their responses to perivascular nerve stimulation and to various agonists, together with the influence exerted on these responses by the vascular endothelium.

2. M E M B R A N E P R O P E R T I E S OF S M O O T H M U S C L E CELLS FROM CEREBRAL ARTERIES 2.1. GENERALMEMBRANEPROPERTIES

The resting membrane potential of vascular smooth muscle cells, assessed by intracellular microelectrodes, has been reported to vary between values as low as - 30 mV to around - 70 mV. Generally, larger values for the resting membrane potential have become more usual, as the techniques for pulling and filling microelectrodes and for both impaling and recording from the very small smooth muscle cells (diameter ca. 4 /~m) have become more refined. Data relating specifically to the electrophysiological characteristics of cerebrovascular smooth muscle are somewhat limited, although the passive membrane properties of smooth muscle cells from the rabbit basilar artery have been measured (Surprenant et al., 1987). In this artery, space and time constants were calculated as 1.54 + 0.14 mm and 350 + 53 msec, respectively, which are of a similar order to those reported for the smooth muscle of a variety of peripheral arteries from different species (e.g. Haeusler and Thorens, 1980; Mekata, 1971, 1974, 1980). Input resistances and time constants for decay of electrotonic potentials in the rabbit basilar artery varied between 5 and 40 Mf~ and 5-30 msec, respectively. Brief, depolarizing current injection gave rise to transients of up to 50 mV, but failed to induce spike potentials, whereas long duration pulses ( > 50 msec) of lower intensity did initiate spike potentials of a similar form to the regenerative action potentials which occur in other excitable cells. These spike potentials were not 'all or none' as they varied in amplitude and also did not attain a positive potential. However, they were unusual in that similar events are normally not induced in peripheral blood vessels, except in the presence of potassium channel blockers (Casteels et al., 1977; Hara et al., 1980). The spike potentials were associated with smooth muscle contraction, and were followed by a slower, maintained depolarization, the amplitude and time course of which also depended on the size of the initial stimulus. An after-hyperpolarization occurred when electrical stimulation ceased (Surprenant et al., 1987). Patch-clamp studies on dispersed cerebrovascular smooth muscle cells are limited, but voltage-sensitive calcium channels and large conductance calcium-acivated potassium channels have been described recently in cells from rabbit and rat basilar arteries (Worley et al., 1991; Stockbridge et al., 1992). Earlier experiments by Hirst et al. (1986) described two separate calcium currents and two outward currents, using single-electrode voltage clamp in cells of the rat middle cerebral artery. It has been suggested that the membrane properties of the smooth muscle cells in cerebral arteries differ significantly from those in systemic arteries, and that as a consequence, the resting membrane potential of the cells in these vessels is more negative than in peripheral arteries (Harder, 1980, 1983). However, there have been few studies directly comparing the membrane properties of smooth muscle in cerebral and systemic arteries in the same species and under the same experimental conditions, which would allow this assertion to be made with any confidence. In fact, the studies which are available, have provided apparently conflicting observations. In a comparison of feline middle cerebral arteries with mesenteric and coronary arteries, the former were reported to contain cells with a membrane potential close to - 7 0 mV, while lower values of - 4 9 mV and - 5 8 mV were reported for cells in the respective peripheral vessels (Harder, 1980, 1983). This difference was ascribed to a greater contribution to the resting potential in the cerebral arteries from the electrogenic sodium-pump, assessed by the magnitude of smooth muscle depolarization induced by ouabain, and to a higher potassium conductance derived from the relative input resistances. These differences were suggested to underlie the steeper slope for plots of Em vs log [K]0 in cerebral compared to peripheral arteries. This may render the contractile state of cerebrovascular smooth muscle cells more sensitive to small changes in the extracellular concentration of potassium ion, so that any changes reflecting neural activity are coupled to blood flow (Harder, 1980, 1983).

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However, these results may also be explained by the presence of inwardly rectifying potassium channels in cerebrovascular smooth muscle, a point which is dealt with in detail below. A further difference between feline cerebral and peripheral vessels, was the ability of cells in the former to develop rhythmic spike activity, on a background of slow depolarization, in the presence of either 5-hydroxytryptamine (5-HT) or raised extracellular potassium. This spike activity was blocked by the calcium antagonist verapamil and presumably reflected voltage-sensitive calcium entry. In contrast, cells in mesenteric vessels from the cat simply displayed smooth, concentration-dependent depolarization in response to these stimulants. The latter electrical events were not related to changes in smooth muscle tone (Harder, 1980). In contrast to the cat, studies with guinea-pig arteries revealed a resting membrane potential of only - 5 0 mV in the basilar artery (Fujiwara and Kuriyama, 1983a), which was less negative than the potential of cells in mesenteric arteries from the same species, which was close to - 7 0 mV (Kuriyama and Suzuki, 1981; Karashima, 1981). The low membrane potential in the guinea-pig basilar artery may reflect the absence of a particular type of potassium channel in these cells as, in contrast to the cells in peripheral arteries, it was not altered by either 2-nicotinamidoethyl nitrate or 4-aminopyridine (Fujiwara and Kuriyama, 1983b). In the guinea-pig mesenteric artery, 2-nicotinamidoethyl nitrate increased potassium conductance and induced hyperpolarization (Itoh et al., 1981; Fujiwara and Kuriyama, 1983b), while in the pulmonary artery 4-aminopyridine increased membrane resistance and depolarized the smooth muscle cells (Hara et al., 1980). 2.2. SMOOTH MUSCLE POTASSIUMHANDLING

The smooth muscle handling of potassium is of particular interest in the cerebral circulation, where it has been implicated in the control of cerebral blood flow. In vivo, a moderate increase in the local extracellular concentration of potassium is followed by vasodilatation (Kuschinsky et aL, 1972). As the extracellular potassium concentration rises very rapidly during periods of increased neuronal activity, these changes may serve to couple blood flow to metabolic demand (Lubbers and Leniger-Follert, 1978). In small pial arterioles from the cat, increasing the extracellular potassium concentration in stages up to 20 mM was followed by concentration-dependent vasodilatation, consistent with this idea (Kuschinsky et al., 1972). This response to potassium seems somewhat paradoxical, because at rest the membrane potential of vascular smooth muscle cells is determined predominately by the membrane permeability to potassium, with an equilibrium potential around - 9 0 mV (Keatinge and Harman, 1980; Hirst and Van Helden, 1982). Increasing the potassium concentration will therefore cause depolarization (Hirst and Van Helden, 1982), a response normally associated with contraction in most vessels, including large cerebral arteries (Garland, 1987). This apparent paradox can be explained by the presence of potassium-selective channels which display inward rectification. Similar channels have been demonstrated in isolated submucosal arterioles from the guinea-pig (Edwards and Hirst, 1988) and in rat cerebral arterioles (Edwards et aL, 1988). Like the potassium-selective inward rectification recorded in other cell types (Standen and Stanfield, 1978; Hagiwara et aL, 1978), the current-voltage relationship for these channels was non-linear, with the membrane resistance falling at more negative membrane potentials. In common with other inwardly rectifying potassium channels, these channels were also sensitive to blockade with barium ions. In contrast to the channels in other tissues, the activation voltage for the potassium-selective inward rectifier in arterioles was changed by altering the extracellular potassium concentration (Hagiwara and Takashi, 1974; Standen and Stanfield, 1978; Hille, 1984; Hirst and Edwards, 1989). A reduction in extracellular potassium concentration caused the activation curve to move to more negative potentials, so that inward rectification no longer contributed to the resting conductance of the membrane and depolarization occurred (Edwards et al., 1988). These channels also differed from the inward rectifier in other cells, as they were active at potentials positive to EK. Consequently, in arterioles arising from the middle cerebral artery, virtually all the potassium conductance at rest resulted from activated inwardly-rectifying potassium channels, which could be demonstrated by the depolarization stimulated in the presence of barium (Edwards et al., 1988). In cerebral arterioles, both the activation curve for inward rectification and the resting membrane potential were also reported to vary in different regions. Smooth muscle cells in arterioles arising

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directly from the middle-cerebral artery, had a stable membrane potential of - 6 9 mV and showed inward rectification at this potential. However, distal arterioles had a lower membrane potential and displayed less pronounced rectification at rest. In these latter vessels, raising the extracellular potassium concentration resulted in hyperpolarization, whereas cells in the more proximal vessels were depolarized. These data can be explained by a regional variation in the external potassium concentration required, at a given membrane potential, to activate inwardly rectifying potassium channels. Raising the extracellular potassium will result in a greater contribution from the inward rectifier, so that although EK is less negative, the increase in relative permeability to potassium ion will dominate the membrane potential and cause hyperpolarization, reducing the open-state probability for voltage-sensitive calcium channels (Casteels et al., 1977; Hirst et al., 1986). Thus in normal potassium solutions, small distal vessels will generate myogenic activity which will be suppressed should the local potassium concentration increase, consequently inducing vasodilatation. Interestingly, the distal cerebral arterioles in the rat, in contrast to the more proximal vessels, had no significant sympathetic innervation (Hill et al., 1986). The variation in inward rectification may therefore indicate atrophic control exerted by the perivascular sympathetic nerves on the post-synaptic expression of membrane ion channels. A t r o p h i c regulation of membrane ion channels may also underlie the correlation which exists between the presence of nerves and the ability to support inward calcium movement in these vessels (Hill et al., 1986; Hirst et al., 1986). The observations relating to inward rectification do not prove that potassium ions are involved in cerebrovascular autoregulation in vivo, but they do show that an increase in potassium concentration can cause a decrease in distal arteriolar excitability and may underlie vasodilatation. Although a similar conductance has not, as yet, been described in other species, modification of the extracellular potassium concentration does cause changes in membrane potential which are consistent with this theory (Fujiwara and Kuriyama, 1983b; Garland, 1987). 3. RESPONSES OF ISOLATED CEREBRAL ARTERIES TO ELECTRICAL STIMULATION Although sympathetic nerve stimulation has little or no effect on overall cerebral vascular resistance under normal conditions, it does alter the resistance in individual segments of the circulation (Aim and Bill, 1973; Heistad et al., 1977, 1978). The resistance to blood flow which is presented by large arteries is normally around 40% of the total and can be significantly increased by nerve stimulation. At this time, the resistance presented by small vessels actually decreases (Baumbach and Heisted, 1983). In hypertension, vasoconstriction due to sympathetic nerve stimulation appears to extend the upper limit for autoregulation and thereby reduces the possibility of damage to the blood-brain barrier (Bill and Linder, 1976; Heistad et al., 1978; Tamaki and Heistad, 1986). In vitro, cerebral arteries show considerable heterogeneity in response to nerve stimulation, not only between species (Duckies et al., 1977; Chiba and Tsuji, 1985; Hamel et al., 1985) but also between and within specific vessels (Toda, 1977; Duckies et al., 1977; Duckies, 1979; Hamel et al., 1988). In addition, the perivascular nerves may also exert atrophic influence on cerebrovascular smooth muscle, as discussed in the previous section. There have been relatively few comparative studies of the membrane electrical events which underlie nerve-stimulated tension changes in cerebral and peripheral arteries, and an even smaller number of studies in which electrical and mechanical events have been recorded simultaneously. Spontaneous and induced transient depolarizations, resembling excitatory junction potentials (ejps), have been recorded in a variety of cerebral vessels from different species (Holman and Surprenant, 1979; Hirst et al., 1982; Fujiwara et al., 1982; Yamamoto and Hotta, 1986; Nagao and Suzuki, 1987). The time course of the ejps was similar to comparable responses in peripheral arteries (see for example, Bell, 1969; Hirst, 1977) and were not normally associated with smooth muscle contraction. With high levels of stimulation, rapid spike potentials, which resembled regenerative action potentials, could be induced. These fast depolarizations were followed by contraction of the isolated tissue (Hirst et al., 1982) and as in peripheral vessels failed to overshoot zero potential (Holman and Surprenant, 1979; Hirst, 1977). In both cerebral and peripheral vessels, the fast component of the ejp was followed by a prolonged depolarization, lasting up to 2 min, which became more prominent during long trains of stimulation (Holman and Surprenant, 1979;

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Cheung, 1982; Hirst et al., 1982; Suzuki and Kou, 1983; Yamamoto and Hotta, 1986). Most of these responses were unaffected by the presence of tetrodotoxin (TTX) and also in some cases guanethidine (Holman and Surprenant, 1979; Suzuki, 1981; Hirst et al., 1986; Yamamoto and Hotta, 1986; Nagao and Suzuki, 1987; Surprenant et al., 1987). However, the current intensity used in these studies may have been sufficient to cause direct entry of calcium into the perivascular nerves and so stimulate transmitter release independently of nerve action potentials (Katz, 1969). These responses may also reflect, at least in part, the release of factors from other regions of the vessel wall, such as the endothelium. For example, in the rabbit basilar artery, ejps were apparently abolished by removal of the endothelium (Nagao and Suzuki, 1987). Some workers have, however, reported that the responses of cerebral arteries to nerve stimulation can be blocked with TTX (Fujiwara et al., 1982; Karashima and Kuriyama, 1981). A slow, TTX-sensitive hyperpolarization, with a variable amplitude of up to l0 mV and an associated increase in membrane conductance, followed ejps in guinea-pig and canine arteries (Karashima and Kuriyama, 1981; Fujiwara et al., 1982; Suzuki and Fujiwara, 1982). Guanethidine, noradrenaline, adenosine triphosphate (ATP) and 6-hydroxydopamine all depressed the amplitude of the ejps, but did not alter this after-hyperpolarization. However, unlike the ejps, the after-hyperpolarization was depressed by repetitive nerve stimulation. The hyperpolarization may reflect the release of an inhibitory neurotransmitter, consistent with the idea of a functional, dual innervation to cerebral arteries, an idea derived from in vitro studies (Duckies, 1979). Furthermore, persistence of the hyperpolarization in the presence of atropine, suggests that it may make a contribution to the atropine-insensitive neurogenic dilatation which has been observed in the feline cerebral circulation (Bevan et al., 1982; Lee, 1982). However, the possibility that factors derived from the endothelium contribute to these responses remains to be discounted. The relative importance of noradrenaline and other putative co-transmitters, such as ATP and neuropeptide Y (NPY), in the cerebral circulation is not at all clear. Exogenous noradrenaline depolarizes cerebrovascular smooth muscle (see below) and in canine basilar and middle cerebral arteries the amplitude of nerve-evoked ejps could be reduced by noradrenaline and by ct-adrenoreceptor antagonists (Fujiwara et al., 1982). In contrast, in the rat basilar artery, ejps were unaffected by exogenous noradrenaline and ct-adrenoreceptor antagonists (Hirst et al., 1982). It was therefore suggested that the post-junctional responses to noradrenaline in this vessel may be mediated by specialized adrenoreceptors, termed ~-receptors which were originally described in sub-mucosal arterioles of the guinea-pig (Hirst and Neild, 1982). These receptors, although not directly coupled to smooth muscle contraction, were suggested to mediate the initiation of action potentials, which caused contraction. The presence of receptors distinct from classical ~- and fl-adrenoreceptors was used to explain the observation that even miltimolar concentrations of noradrenaline failed to stimulate contraction in this artery (Hirst et al., 1982). However, the rat basilar artery may be somewhat unusual, because in rabbit cerebral arteries, both ejps and the contraction and depolarization evoked by high concentrations of noradrenaline were abolished by the irreversible and relatively selective s-antagonist, benextramine (Garland, 1989; Rand and Garland, 1990). The electrical events underlying the action of putative co-transmitters such as ATP and NPY have received little attention and although depolarization to both ATP and NPY has been reported, there are no data directly relating membrane responses to smooth muscle contraction (Karashima and Kuriyama, 1981; Fujiwara et al., 1982; Abel and Han, 1989; Fallgren et al., 1990). For example, in the canine basilar artery, ATP release was enhanced by transmural stimulation and exogenously applied ATP induced tension responses similar to those evoked by nerve stimulation, although the membrane events which occurred under these conditions were not recorded (Murumatsu et al., 1981). In a separate study, ATP was shown to depolarize smooth muscle and to reduce the amplitude of nerve-evoked ejps in the same vessel by decreasing membrane resistance (Fujiwara et al., 1982). The sensitivity to ATP, like that to noradrenaline (Duckles and Bevan, 1976) and acetylcholine (Karashima and Kuriyama, 1981), may be lower in cerebral compared with peripheral arteries. In the guinea-pig basilar artery, the minimum concentration of ATP required to produce a depolarization was higher and the maximum response was smaller, than in other vascular preparations (Karashima and Takata, 1979; Karashima and Kuriyama, 1981). In many arterial preparations, including the rabbit basilar artery (Edvinsson et al., 1984a), NPY has only a small direct constrictor action, whereas in other vessels such as the guinea-pig basilar

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(Fallgren et al., 1990) and feline pial arteries (Edvinsson et al., 1984b) dose-dependent contractions can be induced, which have a similar maximal response to noradrenaline. This indicates that there may be both regional and species differences in the contractile responses of cerebrovascular smooth muscle cells to this peptide. In addition to a direct action, NPY may also have a synergistic interaction with other transmitter agents, e.g. in the rabbit ear artery, NPY markedly increases the rate of contraction to both exogenous noradrenaline and nerve stimulation (Edvinsson et al., 1984a; Saville et al., 1990), while in rat pial arterioles NPY acts via Yl receptors to potentiate the constrictor action of the thromboxane-mimetic, U46619 (Xia et al., 1992). The susceptibility of ejps in the rabbit middle cerebral artery to the c~-antagonist, benextramine, may possibly in part reflect an action of NPY (Rand and Garland, 1990), as binding studies have indicated that benextramine has an appreciable affinity for NPY receptors (Doughty et al., 1990). In addition, the role of membrane depolarization, or other mechanisms, in mediating the potentiation of noradrenalineevoked contractions by NPY and other possible interactions between putative co-transmitters, have yet to be investigated in detail. Another peptide of interest in the cerebral circulation is calcitonin gene-related peptide (CGRP), which is present in cerebrovascular nerves where it co-localizes with substance P. CGRP is a potent dilator agent on cerebral blood vessels both in vivo and in vitro (McCulloch et al., 1986). Vasodilatation induced by CGRP released from sensory, trigeminovascular nerve fibres may be involved in the pathogenesis of migraine (Humphrey and Feniuk, 1991; Wei et al., 1992). Extensive studies on the mechanisms which underlie smooth muscle relaxation to CGRP in cerebral arteries are lacking. In peripheral vessels, increases in adenosine-Y,5'-cyclic monophosphate (cAMP) have been reported and CGRP has also been found to induce significant smooth muscle hyperpolarization (Kubota et al., 1985; Nelson et al., 1990). The hyperpolarization to CGRP, which was demonstrated in the rabbit mesenteric artery, was sensitive to glibenclamide, as, in separate experiments, was the smooth muscle relaxation. This led to the suggestion that both responses were mediated by ATP-sensitive potassium channels (Nelson et al., 1990). However, this may not be a general phenomenon, because CGRP-induced relaxation in rat isolated coronary arteries was not blocked by glibenclamide (Prieto et al., 1991). In cerebral arteries, increases in both cAMP and guanosine-3',5'-cyclic monophosphate (cGMP) have been reported, which may account for the relaxation to CGRP (Edwards et al., 1991; Wei et al., 1992). CGRP has been shown to stimulate hyperpolarization in large cerebral arteries from the cat (around 6 mV with 10 nM CGRP), cells which also display capsaicin-sensitive inhibitory junction potentials and relaxation (Saito et al., 1989). However, in the rabbit basilar artery CGRP did not induce marked changes in smooth muscle membrane potential, 30 ng CGRP was sufficient to induce maximal relaxation, but only hyperpolarized the smooth muscle cells by around 3 mV (Trezise and Weston, 1992). It was not clear whether this hyperpolarization was glibenclamide-sensitive, because glibenclamide directly depolarized the smooth muscle cells (Trezise and Weston, 1992). 4. EFFECTS OF NORADRENALINE ON MEMBRANE POTENTIAL Cerebral arteries from a number of species display a low responsiveness to the contractile action of noradrenaline, both in vitro (Toda and Fujita, 1973; Duckles and Bevan, 1976; Duckles, 1979; Bevan et al., 1987) and in vivo (Wahl et al., 1972). In cerebral arteries, the predominant effect of noradrenaline is to stimulate smooth muscle depolarization and contraction. It has been suggested that these effects are mediated by a class of adrenoreceptor distinct from the classical e-receptor (Hirst et al., 1982; Laher et al., 1986). However, both the depolarization and contraction of smooth muscle cells in the rabbit basilar artery to noradrenaline could be mimicked by the selective cq-agonist, phenylephrine. In addition, they were reduced by the competitive eL-antagonist, prazosin and blocked by the non-competitive c~-antagonist benextramine, indicating that the responses are mediated by classical c~-adrenoreceptors (Garland, 1989). These data are supported by experiments with feline cerebral arteries, where both the depolarization and contraction to noradrenaline could be satisfactorily explained by an action on c~-adrenorecepors (Harder et al., 1981). The mechanisms which underlie the contraction to noradrenaline in cerebrovascular smooth muscle cells are not clear, but are, at least in part, the consequence of voltage-dependent processes.


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~-Agonists stimulate concentration-dependent smooth muscle depolarization and contraction in isolated cerebral arteries (Garland, 1989; Harder et al., 1981; Surprenant et al., 1987). In the rabbit basilar artery, the onset of depolarization preceded smooth muscle contraction by around 8 sec, indicating a possible causal role. High concentrations of noradrenaline induced additional, active spike potentials, which were followed by rhythmic smooth muscle contraction (Garland, 1989; Fig. 1). These active membrane responses were superimposed on a relatively slow depolarization and may be mediated by calcium channels (Surprenant et al., 1987). The cause of the primary depolarization is not clear, but may in part reflect a change in chloride conductance. In isolated smooth muscle from the rabbit ear artery, noradrenaline has been shown to stimulate a calcium-dependent increase in chloride conductance, as well as a non-selective cation conductance (Amedee et al., 1990). It remains to be shown whether or not a similar mechanism operates in cerebral arteries. It is also highly likely that non-electrical events contribute to the noradrenaline-induced contraction ofcerebrovascular smooth muscle. In peripheral arteries, cq-adrenoreceptors link to the activation of phospholipase C, stimulation of the receptors leading to increased levels of both IP 3 and diacylglycerol and the subsequent release of internal calcium stores and sensitization of the contractile machinery (Hashimoto et al., 1986; Himpens et al., 1990). If similar mechanisms operate in cerebral vessels, they may underlie the contraction which can be recorded in the basilar artery at membrane potentials greater than - 4 0 to - 5 0 mV, when the open-state probability for voltage-sensitive calcium channels is low (Garland, 1989; Hirst et al., 1986). 5. EFFECTS OF 5-HYDROXYTRYPTAMINE ON MEMBRANE POTENTIAL 5-HT has been implicated in a variety of disorders which at some stage involve dysfunction of the cerebral circulation e.g. migraine and stroke. The main sources of 5-HT in the cerebral circulation are release from activated blood platelets and perivascular nerve fibres. Specific serotonergic, perivascular nerve fibres have been reported in some regions of the brain and in addition, sympathetic perivascular nerves are able to take up and possibly then release 5-HT (Edvinsson et al., 1983; Levitt and Duckies, 1986). In isolated feline cerebral arteries, a positive correlation between smooth muscle depolarization and contraction to 5-HT, led to the suggestion that the contraction was closely coupled to changes in membrane potential (Harder and Waters, 1983). This suggestion is supported by the occurrence of fast, rhythmic depolarizations in cerebrovascular smooth muscle, in response to high concentrations of 5-HT (>1 #M; Fujiwara and Kuriyama, 1983a; Garland, 1987). An interesting possibility is that similar rhythmic depolarizations may be induced in vivo, by the focal release of

0.1 mM-noradrenaline

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FIG. 1. Responses of the rabbit basilar artery to 100 #M noradrenaline. Upper trace shows intracellular recording, lower trace simultaneous record of smooth muscle tension. The resting membrane potential before application of noradrenaline was -72 mV and the threshold for the first action potential -46 mV. Synchronized changes in tension followed the depolarizations. Reprinted from Garland (1989), with permission of the copyright holder, Cambridge University Press, Cambridge.

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high concentrations of 5-HT. Active events of this type might then propagate round the artery wall and serve to amplify the focal constrictor action of 5-HT. The resulting contraction might then occlude an artery already partially narrowed by atheroma. Although voltage-dependent mechanisms do play some role in the contraction to 5-HT, as with most agonists acting on smooth muscle, non-electrical mechanisms are also important. In the rabbit basilar artery, the primary events stimulated by 5-HT appear to be non-electrical (Garland, 1987). Although simultaneous measurements of membrane potential and tension showed that 5-HT could depolarize and contract smooth muscle cells, this depolarization did not precede the onset of contraction. In addition, for a given change in smooth muscle membrane potential in the rabbit basilar artery, the increase in tension to 5-HT was greater than that to raised extracellular potassium. Depolarization to potassium, like the depolarization to noradrenaline, preceded the onset of smooth muscle contraction (Garland, 1987, 1989). Under certain conditions, smooth muscle contraction and depolarization could be induced independently of each other, supporting the involvement of voltage-independent mechanisms (Garland, 1987; Clark, 1990). With high concentrations of 5-HT, additional, fast depolarizations were superimposed on the background depolarization and these were followed by additional, rhythmic contractions, presumably initiated by voltage-dependent means. Voltage-independent contraction stimulated by 5-HT appears to involve the activation of protein kinase C. Contraction to all but the highest concentration of 5-HT was blocked by inhibitors of this enzyme, and was associated with a concentration-dependent increase in membrane levels of diacylglycerol (Clark and Garland, 1991). Interestingly, the cytoplasmic concentration of inositol phosphates was not increased at this time, suggesting that a novel secondary messenger system may operate in cerebrovascular smooth muscle (Clark and Garland, 1991). For example, the activation of 5-HT receptors may lead to the formation of diacylglycerol from phosphatidylcholine rather than phosphatidylinositol. This possibility requires further investigation, but a novel signalling system for 5-HT in the cerebral circulation would obviously be of potential interest, particularly as 5-HT-induced contraction in cerebral arteries is coupled to a 5-HTt-like receptor, unlike peripheral arteries where contraction is generally mediated via 5-HT2 receptors (Feniuk and Humphrey, 1989). Voltage-dependent mechanisms do appear to predominate in the sustained contraction of cerebral arteries to 5-HT. This idea can be inferred from the observation that established contractions to 5-HT are reversed by calcium antagonists, although depolarization is sustained, and that during the wash-out of 5-HT, smooth muscle repolarization always precedes relaxation (A. Clark and C. J. Garland, unpublished observations; Garland, 1987). A direct demonstration that 5-HT can open voltage-sensitive calcium channels in the rabbit basilar artery has been provided in a recent patch-clamp study (Worley et al., 1991). In these experiments, two distinct voltage-sensitive conductance levels for calcium were described. 5-HT increased the open probability of both levels and its effect was consistent with a shift in the activation curve for calcium channels and an increase in Pmax. 6. ENDOTHELIUM-MEDIATED RESPONSES By releasing inhibitory and excitatory factors, vascular endothelial cells exert a powerful influence on smooth muscle tone. In cerebral arteries from a variety of species, endotheliumdependent contraction has been demonstrated in response to stimuli such as noradrenaline, 5-HT, acetylcholine, arachidonic acid, stretch, hypoxia and increased transmural pressure (Usui et al., 1987; Seager et al., 1992; Shirahase et al., 1987; Katusic et al., 1987; Klaas and Wadsworth, 1989; Harder, 1987) which, in the case of hypoxia and increased transmural pressure, was shown to reflect the release of a diffusible factor(s) from the endothelium (Rubanyi and Vanhoutte, 1985; Harder et al., 1989). In the majority of studies, endothelium-dependent contraction appears to involve a metabolite of arachidonic acid, possibly thromboxane A:, although the electrophysiological aspects of this phenomenon have not been investigated in any detail. However, in contrast to cells from guinea-pig small ear arteries, graded depolarization in response to increasing intraluminal pressure has been demonstrated in cerebrovascular smooth muscle cells from cats and rabbits (Keef and Neild, 1982; Harder, 1984; Harder et al., 1989; Brayden and Nelson, 1992). In cat cerebral arteries,


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this depolarization was endothelium-dependent and reduced the resting membrane potential from close to - 7 0 mV at 0 mmHg to nearly - 5 0 mV at 100 mmHg (Harder et al., 1989). In rabbit cerebral arteries, increased intraluminal pressure led to the activation of Ca2+-activated potassium channels, which may play an intimate role in the control of myogenic tone, so that in vivo they may contribute to the autoregulation of blood flow. The effect of changes in transmural pressure on smooth muscle tone did not appear to be influenced by the endothelium in this study (Brayden and Nelson, 1992). Endothelium-dependent smooth muscle relaxation has been much more extensively studied. Relaxation, which follows the generation of endothelium-derived relaxing factor (EDRF), is now thought to be largely explained by the release of nitric oxide, or a very closely related compound (Palmer et al., 1987). EDRF can be released from endothelial cells by a variety of vasoactive agents including, cholinomimetics, 5-HT, substance P, thrombin and adenosine nucleotides, and it evokes relaxation via the activation of soluble guanylyl cyclase and subsequent increases in the cytoplasmic levels of cGMP (Rapoport and Murad, 1983). Endothelium-dependent relaxation is usually associated with smooth muscle hyperpolarization. This was first demonstrated with cholinomimetics and has subsequently been reported with a number of agonists which can control tone via the endothelium, such as bradykinin and substance P (Bolton et al., 1984; Chen et al., 1988; Feletou and Vanhoutte, 1988; McPherson and Angus, 1991; Garland and McPherson, 1992; Rand and Garland, 1992; Nagao and Vanhoutte, 1992). The hyperpolarization appears to be independent of the EDRF-stimulated rise in intracellular cGMP (Martin et al., 1985; Taylor et al., 1988; Chen and Suzuki, 1989) and persists in the presence of either oxyhaemoglobin or methylene blue, which block the action of nitric oxide (Chen et al., 1988; Taylor and Weston, 1988). These observations led to the suggestion that a separate endotheliumdependent hyperpolarizing factor (EDHF) was released, together with nitric oxide (Taylor and Weston, 1988). This concept is supported by a number of studies, some with cerebral arteries, which have failed to show significant hyperpolarization in response to concentrations of exogenous nitric oxide which are capable of stimulating maximal smooth muscle relaxation (Komori et al., 1988; Huang et al., 1988; Brayden, 1990; Rand and Garland, 1992). The persistence of endotheliumdependent hyperpolarization and the associated relaxation, in the presence of competitive substrate inhibitors for nitric oxide synthase, also implies a role for an additional factor (Chen et al., 1991; Garland and McPherson, 1992; Nagao and Vanhoutte, 1992). By causing hyperpolarization, EDHF will close voltage-operated CaZ+-channels and hence induce smooth muscle relaxation (Feletou and Vanhoutte, 1988; Komori and Suzuki, 1987; Taylor et al., 1988). The hyperpolarizing action of EDHF is associated with an increase in membrane permeability to potassium (Bolton et al., 1984) and a rise in the rate of86Rb efflux (Taylor et al., 1988), events which reflect the opening of smooth muscle potassium channels (Hamilton et al., 1986; Taylor et al., 1988). Endothelium-dependent hyperpolarization has been reported in isolated cerebral arteries (Brayden and Wellman, 1989; Brayden, 1990; Rand and Garland, 1992) where, as in systemic vessels, the mediator of the response and the extent to which hyperpolarization contributes to smooth muscle relaxation is not entirely clear. In fact, the available evidence suggests that there may well be significant variation in the relative contribution made by EDHF/EDRF, even within the cerebrovascular circulation. In isolated rabbit (Brayden, 1990) and feline (Brayden and Wellman, 1989) middle cerebral arteries, the relaxation to acetylcholine is accompanied by sustained endotheliumdependent smooth muscle hyperpolarization. Blockade of this hyperpolarization inhibits the associated dilator response, indicating an important functional role for the increase in membrane potential (Brayden and Wellman, 1989; Brayden, 1990). These data are supported by experiments with methylene blue in the rabbit middle cerebral artery, where the hyperpolarization and a component of the relaxation remained after the inhibition of soluble guanylyl cyclase (Brayden, 1990). In contrast to the middle cerebral artery, hyperpolarization appeared to have a negligible role in relaxation of the rabbit basilar artery to cholinomimetics. In this artery, higher concentrations of acetylcholine and carbachol were required for hyperpolarization than for relaxation (Fig. 2). In addition, the hyperpolarization was transient and desensitized rapidly, whereas relaxation was both sustained and reproducible (Fig. 3). Furthermore, in this artery both the hyperpolarization and the relaxation were sensitive to nitric oxide synthase inhibitors (Rand and Garland, 1992). Therefore, the hyperpolarization in this artery might reflect the release of a high, JPT 5 6 / 3 ~

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FIG. 2. Mean concentration response curves to acetylcholine (ACh) in the rabbit basilar artery. Responses show the mean hyperpolarization (A) and relaxation (11) of arteries precontracted with noradrenaline. Points are the mean + SE of at least five separate experiments. Lower concentrations of acetylcholine are required for relaxation in this artery than for endothelium-dependent hyperpolarization. Reprinted from Rand and Garland (1992), with permission of the copyright holder, MacMillan Press Ltd, U.K. localized concentration of nitric oxide, as high concentrations of exogenous nitric oxide has been shown to stimulate smooth muscle hyerpolarization in some vessels, namely rat small mesenteric and guinea-pig uterine arteries (Garland and McPherson, 1992; Tare et al., 1990). One possible explanation for these apparently contrasting observations with acetylcholine in the basilar and middle cerebral arteries, is that the relative contribution which is made to muscle relaxation by nitric oxide and E D H F varies between separate branches of a particular vascular bed. The type of potassium channel which mediates the action of EDHF is not clear. It has been suggested that the hyperpolarization to acetylcholine in smooth muscle cells of the rabbit middle cerebral artery follows the opening of ATP-sensitive potassium channels (Km~) (Standen et al., 1989; Brayden, 1990). This idea was based on two separate sets of observations. First, that the potassium-channel blockers glibenclamide and barium inhibited both the hyperpolarization and the relaxation to acetylcholine in the middle cerebral artery and second, that glibenclamide blocked the potassium channels which were activated by cromakalim in smooth muscle membrane patches from rabbit and rat mesenteric arteries (Standen et al., 1989). In the mesenteric artery, the glibenclamide-sensitive channels which were activated by cromakalim, were apparently ATPsensitive. Some caution is required, however, in using glibenclamide sensitivity as the only evidence for the involvement of Kmp-channels. Although the ATP and cromakalim-sensitive channels which were described in mesenteric arteries by Standen et al. (1989) did not appear to be dissimilar, more extensive data are required to show that they are in fact identical. Certainly they are not identical to KATPchannels in other cell types, such as cardiac muscle and pancreatic fl-cells, as they have a higher unitary conductance (135pS) and, if they are the channels activated by cromakalim, a lower sensitivity to glibenclamide (Sturgess et al., 1988; Zunkler et al., 1988; Weston and Edwards, 1991). In addition, potassium channel activators do not only activate KATPchannels. These agents have been shown to activate several different types of potassium channel in smooth muscle cells, which have different conductances and sensitivities to ATP, GDP and Ca 2+ (Beech and Bolton, 1989; Inoue et al., 1989; Hu et al., 1990; Kajioka et al., 1990, 1991; Nakao and Bolton, 1991; Stockbridge et al., 1991; Noack et al., 1992). For example, in a rigorous study on cells from the rat portal vein, levcromakalim was clearly shown to activate a glibenclamide-sensitive potassium channel with a unitary conductance around 17pS, a similar order to the conductance of KAVp channels in other cell types. The activation of these channels caused a pronounced smooth muscle hyperpolarization (Noack et al., 1992). In contrast, in cells from the rat basilar artery both cromakalim and levcromakalim increased the open probability of large-conductance potassium channels which appeared to be both voltage and calcium-dependent (Stockbridge et al., 1991). Based on patch-clamp studies with single cells from mesenteric arteries, and separate measure-


351

ments of changes in smooth muscle tension and membrane potential, also mainly in mesenteric arteries, hyperpolarization resulting from the activation of KATp-channels has been suggested as a common mechanism for the action of many endogenous and pharmacological dilators (Brayden et al., 1991). This generalization certainly does not apply to the action of EDHF in all arteries, as endothelium-dependent hyperpolarization and relaxation to acetylcholine in the rat small mesenteric artery and the guinea-pig coronary artery are both resistant to the blocking action of glibenclamide (McPerson and Angus, 1991; Chen et al., 1991; Garland and McPherson, 1992; Eckman et al., 1992). Nor does it apply to the action of CGRP in the rabbit basilar artery, where relaxation appears largely independent of membrane potential (Trezise and Weston, 1992; see above). It is of interest to note that, in contrast to the study by Brayden (1990), glibenclamide failed to block endothelium-dependent relaxation in the rabbit middle cerebral artery (Parsons et al., 1991a,b). An explanation for this apparent discrepancy is not clear at present. Glibenclamide did, however, block the relaxation to cromakalim and both the hyperpolarization and relaxation to levcromakalim in the rabbit basilar artery (Parsons et al., 1991b; F. Plane and C. J. Garland, unpublished observations). Therefore, in common with peripheral vessels, cerebral arteries show endothelium-dependent hyperpolarization which contributes to smooth muscle relaxation. In general, the type and density of potassium channels which underlie these responses may vary in different regions, possibly explaining variation in the action of potassium channel activators and inhibitors, both within the cerebral and peripheral circulation in vivo and in vitro (Buckingham et al., 1986; Cain and Nicholson, 1989; Grant and O'Hara, 1989; McCarron et al., 1991; McPherson and Stork, 1992; Masuzawa et al., 1990; Parsons et al., 1991b). In the cerebral circulation, this apparent variability has largely been investigated by non-electrophysiological means. As these mechanisms have a

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FIG. 3. Responses of the basilar artery to acetylcholine (ACh). Acetylcholine (-log M) hyperpolarized and relaxed smooth muscle in the basilar artery (a), when reapplied to the same artery 60 min later, the hyperpolarization but not the relaxation was markedly depressed (b). Reprinted from Rand and Garland (1992), with permission of the copyright holder, MacMillan Press Ltd, U.K.

352


considerable potential for the future development of selective drug treatment for cerebrovascular dysfunctions, further detailed investigations are needed. 7. HYPERTENSION Animal models have been used to investigate the changes which occur in hypertension, and it is now well established that vascular smooth muscle cells from hypertensive rats show modified membrane ion handling, typified by an increase in the steady-state turnover of K +, Na +, CI ÷ and Ca 2÷ ions (Jones, 1981). Generally, this alteration is associated with spontaneous contractile activity and an increased responsiveness to vasoactive agents. Normally quiescent arterial preparations, which give graded and maintained contractions to agonists, showed spontaneous and agonist-induced rhythmic contractions. Simultaneous recording of tension and membrane potential changes showed these oscillations in tone to be associated with the expression of pacemaker activity (Hermsmyer, 1976; Haeusler and Finch, 1972; Holloway and Bohr, 1973; Lamb et al., 1985; Lamb and Webb, 1989; Myers et al., 1985). In the presence of elevated potassium concentrations or of potassium channel blockers, the oscillations in tone were converted to a sustained contraction (Myers et al., 1985; Lamb et al., 1985). Studies on cerebral arteries are extremely limited, but the involvement of potassium channels in the reactivity changes which occur in hypertension, together with the importance of potassium in the local regulation of cerebral blood flow (see above), underscores the importance of future research. Potassium-induced dilatation of blood vessels has been widely used as an indirect measure of Na ÷, K+-ATPase activity (Rinaldi and Bohr, 1989). Potassium-induced dilatation has been reported to be augmented (Hermsmyer and Harder, 1986) or attenuated (Overbeck et al., 1974; Lombard et al., 1987) in various forms of hypertension, which has been interpreted to indicate an alteration in sodium pump activity. However, in a recent study, altered sodium pump activity was found to account for only part of the potassium-induced inhibition of spontaneous tone in isolated, pressurized rat cerebral arteries (McCarron and Halpern, 1990a). This component of the response was transient. A second, sustained component was predominately barium-sensitive and might, therefore, reflect a contribution from the potassium-selective inward rectifier (see Edwards and Hirst, 1988). In isolated cerebral arteries from hypertensive rats, the sustained response was selectively reduced (McCarron and Halpern, 1990b). The potassium-selective inward rectifier negatively correlates with the density of sympathetic nerves in the rat cerebral circulation, such that channel activity predominates in regions with low innervation density (Edwards et al., 1988). McCarron and Halpern (1990b) suggested that, because the density of sympathetic nerves in cerebral vessels is actually increased in hypertensive rats (Lee and Saito, 1984) this may in some way reduce the contribution from the inward rectifier and thereby explain the loss of sustained dilatation to potassium. 8. CEREBRAL VASOSPASM The pathophysiological responses of cerebral vessels to subarachnoid haemorrhage (SAH) and the consequent ischaemia and cerebral dysfunction, are not understood. However, they may in part be due to changes in smooth muscle membrane conductance. In a canine model of SAH, in which autologous blood was injected cisternally, spasm of the basilar artery developed in vivo. This was associated with marked smooth muscle depolarization and enhanced electrical spike activity in isolated arteries, suggesting a decreased potassium conductance (Waters and Harder, 1985; Harder et al., 1987). The potassium channel opener nicorandil partially reversed the vasospasm in vivo and repolarized the smooth muscle in vitro, abolishing the spike activity (Harder et al., 1987). As potassium conductance effectively determines the membrane potential of vascular smooth muscle cells, any reduction in the resting potassium conductance will potentially alter tone, particularly in cerebral vessels where the inward rectifier is thought to be active at voltages close to the resting membrane potential. Changes in potassium conductance may then contribute to the altered reactivity of cerebrovascular smooth muscle following SAH (Harder et al., 1987). Further studies are again called for, to clarify the contribution which potassium channels make in this arterial form of spasm.


353

Acknowledgements--Work in the authors' laboratory was supported by the Wellcome Trust, Nuffield Foundation and the Wessex Medical Trust.

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