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(Circulation Research. 1996;78:148-153.)
© 1996 American Heart Association, Inc.

Articles

Electrical Activity Underlying Rhythmic Contraction in Human Pial Arteries

Natalia I. Gokina, Rosemary D. Bevan, Carrie L. Walters, John A. Bevan

From the A.A. Bogomoletz Institute of Physiology (N.I.G.), Ukrainian Academy of Sciences, Kiev, Ukraine, the Totman Laboratory for Human Cerebrovascular Research (R.D.B., J.A.B.), Department of Pharmacology, University of Vermont, College of Medicine, Burlington, and Neurological Surgeons (C.L.W.), Phoenix, Ariz.

Correspondence to John A. Bevan, Department of Pharmacology, University of Vermont, College of Medicine, Burlington, VT 05405.

	Abstract

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Abstract Human pial arteries obtained during surgery frequently exhibit spontaneous periodic contractions. Simultaneous measurements of membrane potential and vessel wall force were used to examine whether these contractions are associated with electrical activity of smooth muscle cells (SMCs). A total of 53 segments from 38 patients were studied, and of these, 26 showed spontaneous contractions related to periodic depolarization and generation of action potentials (APs). The resting membrane potential during the silent periods was -44.0±0.5 mV. APs without "overshoot" were observed when spontaneous depolarization reached levels of -40 to -35 mV. Just over half of the arterial segments failed to exhibit spontaneous activity; however, APs could be generated during K⁺-induced depolarization. The mean SMC resting membrane potential of these vessels was -53.5±1.5 mV, and this value differed significantly from that of SMCs in spontaneously active arteries. Application of tetrodotoxin did not change the amplitude and duration of APs. Removal of Ca²⁺ from the bathing solution and addition of nifedipine completely inhibited the spontaneous APs and associated contractions. K⁺ depolarization failed to induce APs and contraction in the presence of nifedipine. We conclude that periodic spontaneous depolarization and AP generation underlie the periodic spontaneous contractions of human pial arteries. Both the APs and associated contractions are related to the activation of dihydropyridine-sensitive voltage-dependent Ca²⁺ channels. It is suggested that AP generation can be responsible for vasomotion of human pial arteries in vivo.

Key Words: human cerebral arteries • vasomotion • membrane potential • action potential • Ca²⁺ channel

	Introduction

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Rhythmic spontaneous contractions of the vessel wall (vasomotion) have been described in most microvascular beds, including that of the brain.^{1 2 3 4 5 6} Periodic fluctuations of blood flow (flow motion), which are believed to be due to spontaneous constriction and dilation of small arteries, have been observed in the rat cerebral microcirculation by use of the laser Doppler flowmeter.^{7 8} Meyerson et al⁹ described flow motion from intraoperative as well as postoperative recordings of the regional cortical blood flow in the human brain. Oscillations in cerebral blood flow velocity have also been reported in the normal human.¹⁰ Spontaneous rhythmic variation in the diameter of small arteries has been observed through closed cranial windows in the pial microcirculation in vivo.^{2 3} Isolated pressurized cerebral arteries can also display rhythmic contraction.^{4 5} In vitro spiral or circular muscle strips or rings prepared from major cerebral arteries rarely exhibit spontaneous activity,¹¹ but rhythmic contractions can be induced by the application of excitatory agonists or the moderate elevation of extracellular concentration of K⁺ ions.^{11 12 13 14 15} There have been very few publications on the properties of small pial arteries in vitro. It has been demonstrated that distal arterioles originating from the rat middle cerebral artery can display spontaneous rhythmic constriction.⁶

Mechanisms underlying spontaneous vasomotion remain unclear. Surgical or chemical denervation of arteries, pretreatment with blockers of excitatory neurotransmission, application of tetrodotoxin (TTX), or removal of vascular endothelium did not attenuate vasomotion, indicating its myogenic origin.^{1 2 3 4 5 16} Electrophysiological studies in vivo and in vitro have shown that smooth muscle cells (SMCs) in the wall of rhythmically constricting vessels often display an unstable membrane potential and can generate spontaneous action potentials (APs) of different configurations and slow waves of depolarization. Simultaneous recordings of membrane potential and muscle tension demonstrate a close correlation between spontaneous depolarization and contraction in most vascular preparations.^{16 17 18 19} An influx of Ca²⁺ into the cells through Ca²⁺ channels during the generation of APs or slow waves of depolarization would lead to cyclic elevation of cytoplasmic Ca²⁺ concentration and periodic muscle contraction. These data suggest the possibility that spontaneous electrical activity of SMCs might be responsible for rhythmic contractions in some arteries in vitro and in vivo. It has been shown that spontaneous oscillations in cytoplasmic Ca²⁺ concentration can arise from the periodic discharge of Ca²⁺ from intracellular stores, presumably the sarcoplasmic reticulum. The function of these Ca²⁺ transients is unclear, but they could be involved in the activation of the spontaneous contractions in some blood vessels.²⁰

Human cerebral arteries can exhibit spontaneous contractions in vitro.¹¹ The main purposes of the present study were (1) to evaluate whether these spontaneous contractions are associated with spontaneous electrical activity of SMCs, (2) to characterize the APs generated by SMCs in the arteries during this activity, and (3) to determine whether TTX-sensitive Na⁺ channels and voltage-dependent Ca²⁺ channels are involved in AP production.

	Materials and Methods

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Human pial arteries were obtained from 38 patients (14 to 73 years of age) during neurosurgical resection of brain tumors. Modes of anesthesia differed among patients. Only normal (nonfeeding tumor) arteries were used. After removal they were placed in cold PSS containing streptomycin (50 µg/mL), penicillin (50 U/mL), and heparin (100 USP U/mL) and transported to the laboratory. Arteries were studied on the day of surgery or were kept in PSS at 4°C for 24 hours and used on the second day. Each arterial segment was placed in a tissue bath perfused with gassed PSS at room temperature. Two tungsten wires (20-µm diameter) were gently inserted through the lumen of the artery. One wire was attached to a micrometer displacement device and the other to a force transducer. The lumen diameter of the arteries was measured before stretching the vessels. After an equilibration period of 15 to 20 minutes and heating to 37°C, each arterial segment was stretched to a resting tension close to the optimum preload determined for pial arteries of different calibers in a preliminary set of experiments.

For measurement of SMC membrane potential, we used microelectrodes filled with 0.5 mol/L KCl that had tip resistances of 110 to 150 M. SMCs were impaled from the adventitial surface of the arterial segment. Electrical signals were displayed and recorded on a desktop computer using CODAS and AXOTAPE-2 data acquisition programs. We used the following criteria for acceptance of membrane potential recordings: (1) abrupt change in voltage upon impalement of the cells, (2) sharp return to zero voltage after withdrawal of microelectrode tip, (3) tip potential of less than 7 mV, and (4) unchanged resistance of microelectrodes after impalement. The resting potential in spontaneously active SMCs was considered to be the most negative potential recorded during the silent period. For description of fast regenerative depolarizations of large amplitude (20 to 30 mV), we will use the term action potentials, which is commonly applied to this type of electrical event in most vascular tissues, including cerebral arteries.^{14 16 17 18 19}

In our experiments we used a PSS of the following composition (mmol/L): 130 NaCl, 4.7 KCl, 1.18 KH₂PO₄, 1.17 MgSO₄, 14.9 NaHCO₃, 0.026 EDTA, 11.1 glucose, and 1.6 CaCl₂. Ca²⁺-free solution was made from regular PSS with MgCl₂ substitution for CaCl₂. EGTA (0.5 to 1 mmol/L) was added to Ca²⁺-free solution. To prepare K⁺-rich solutions, equimolar amounts of NaCl were replaced with KCl. Superfusion solutions were equilibrated with a mixture of 95% O₂ and 5% CO_2. The pH in the experimental chamber was 7.4. The drugs used were TTX, nifedipine hydrochloride, penicillin-streptomycin solution, EGTA (Sigma), and heparin sodium (Lyphomed).

Results are expressed as mean±SEM. Student's t test was used to determine the significance of differences between sets of data. Differences were considered significant at P<.05.

	Results

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A total of 53 arterial segments from 38 patients were studied; of these, 26 showed spontaneous activity. This activity usually appeared within 30 to 60 minutes after the arterial segments had been mounted in the organ bath and stretched to their resting tension. In some vessels (5 of 26) spontaneous contractions were induced by application and then washout of high-K⁺ solution (66 mmol/L). The majority of the arterial segments displayed long-lasting, periodic contractions that were separated by silent periods. The duration of these contractions was relatively constant for each arterial segment and was 7.2±0.6 minutes (n=13). The amplitude of periodic contractions varied from 25% to 70% of the force produced by high-K⁺ solution (66 mmol/L). Fig 1 shows the distribution of the arterial segments in which periodic contractions occurred and those in which they did not occur, in relation to their inner diameter and age of patient. The incidence of spontaneous activity was 75% in arteries with inner diameters <200 µm. In contrast, only 34.3% of arteries having inner diameters >200 µm exhibited spontaneous contractions. The incidence of periodic spontaneous contractions in larger arteries was higher in patients >40 years of age (43.5%) compared with arteries from younger patients (16.7%).

View larger version (21K): [in this window] [in a new window]   Figure 1. Distribution of human pial arteries with () and without () spontaneous activity in relation to their inner diameter and age of patients.

Electrophysiology of Spontaneously Active Arteries
Intracellular recording of the membrane potential showed that SMCs in the wall of spontaneously active vessels displayed complex electrical activity. Slow long-lasting waves of depolarization with bursts of APs were separated by silent periods of up to several minutes (Fig 2A). The mean membrane potential of 57 cells from 26 arterial segments, measured during those silent periods and referred to here as resting potential, was -44.0±0.5 mV. The maximum amplitude of the slow long-lasting waves of depolarization varied considerably among the different vessels and was in the range of 5 to 15 mV. When the slow depolarization exceeded a level of -40 mV, generation of APs occurred. SMCs from 17 vessels generated APs that consisted of an upstroke and a slow wave of depolarization. The peak amplitude of the upstroke of the APs varied between SMCs of different vessels and was 23.0±1.4 mV. The upstroke of the APs attained levels ranging between -5 and -15 mV and never showed an "overshoot." Duration of the APs varied significantly during a single periodic contraction. It was shortest at the beginning of the spontaneous depolarization (2.5±0.2 seconds) and increased as the depolarization developed. Prolongation of the APs was associated with the appearance of superimposed secondary spikes or slow oscillations of membrane potential (Fig 2B, tracings b and c). The frequency of the APs increased at the beginning of spontaneous depolarization up to 10.1±0.8/min and then often decreased during the one periodic cycle that occurred in association with the increase of duration of the APs. Generation of the APs was associated with rhythmic (phasic) contractions. The amplitude of these contractions increased with prolongation of the APs (compare contractions in tracings a and b of Fig 2B). As evident from simultaneous recording of electrical and contractile activity, the long-lasting periodic spontaneous contractions were mainly composed of partially fused rhythmic contractions that followed each AP.

View larger version (27K): [in this window] [in a new window]   Figure 2. Simultaneous recordings of membrane potential (upper trace) and force (lower trace) during spontaneous activity of a human pial artery segment (inner diameter, 562.5 µm) from a 62-year-old patient. A, One cycle of spontaneous activity. B, Fragments of the recording shown in A at greater time resolution. Ba, Action potential and phasic contraction in the beginning of spontaneous activity. Bb, An increase in the AP duration is associated with an increase in contractile force. Bc, The prolongation of the action potential leads to the appearance of additional spikes.

SMCs from nine human pial arteries (having inner diameter <200 µm) generated fast spontaneous APs without a slow wave of depolarization. Fig 3 illustrates the changes in the membrane potential during two sequential periodic contractions in one of these arteries. Repolarization of the membrane and cessation of AP generation at the end of the first contraction was followed by a short silent period. Then depolarization started again, bringing the membrane potential to the level for AP generation. The frequency of these APs increased with an increase of the level of spontaneous depolarization. APs did not display overshoot, and the peak amplitude of the upstroke was 24.8±1.0 mV. The duration of APs (329.1±41.0 milliseconds) did not change during spontaneous activity and was constant for all APs recorded from the cells of the same artery. Before the appearance of the APs the slowly developing spontaneous depolarization was associated with tonic contraction of the vessel wall (Fig 3A). The APs were followed by phasic contractions superimposed on a tonic background. However, the frequency of the APs on top of the spontaneous depolarization in most cases was very high (29.8±4.5/min). When this situation occurred it was impossible to distinguish separate phasic contractions that followed each AP.

View larger version (22K): [in this window] [in a new window]   Figure 3. Example of a simultaneous recording of spontaneous electrical (upper trace) and contractile (lower trace) activity of a human pial artery from a 53-year-old patient, showing a fast action potential (inner diameter, 175 µm). A, Membrane potential and force at the end of one cycle of contraction and the beginning of the second. B, Expanded fragments of recordings shown in A. Ba, AP generation is associated with phasic contraction. Bb, Duration of the action potentials did not change during development of spontaneous depolarization.

Electrophysiology of Arteries Without Spontaneous Activity
Periodic spontaneous contractions were not seen in 27 of 53 arterial segments. The mean SMC resting membrane potential of these vessels was -53.5±1.5 mV (115 cells), and this value differed significantly from the mean of the resting potential in spontaneously active arteries. There was no correlation between the level of SMC resting membrane potential and the age of the patient (P=.6150; r=.0894). The effects of different concentrations of K⁺ ions were tested in 14 arteries. Fig 4 illustrates the electrical and contractile responses induced by a moderate elevation of K⁺ ions (20 mmol/L). The application of a high-K⁺ solution induced a slowly developing depolarization followed by tonic contraction of the vessel wall. At the level of -40 mV, rhythmic discharges of the cell membrane were observed. Each AP was associated with a phasic contraction. Application of K⁺ in a concentration higher than 40 mmol/L produced strong depolarization, with generation of APs only initially. No APs occurred with depolarization exceeding -20 mV (not shown). In three arteries (inner diameter, 275.0, 400, and 612.5 µm), SMCs did not generate APs or membrane oscillations during K⁺-induced depolarization.

View larger version (15K): [in this window] [in a new window]   Figure 4. Changes in the membrane potential (upper trace) and tension (lower trace) of a human pial artery segment from a 25-year-old patient (inner diameter, 287.5 µm) produced by moderate elevation of K+ ions (concentration 20 mmol/L in the bath solution). Slowly developing depolarization is associated with tonic contraction, and action potential generation with rhythmic contractions. Note different time scales in parts A and B of the figure.

Ionic Basis of Action Potentials
Our data showed that SMCs of human pial arteries can generate APs during spontaneous depolarization or depolarization induced by high-K⁺ solution. Experiments were designed to investigate the ionic nature of the APs. It is known that Na⁺ and Ca²⁺ channels may be involved in the production of the AP upstroke in excitable cells. The presence of fast Na⁺ channels in some vascular SMCs has been reported.¹⁸ To examine an involvement of Na⁺ channels in the production of the APs in SMCs of human pial arteries, we studied the effect of TTX, a specific blocker of the fast Na⁺ channel, on the amplitude and duration of the spontaneous APs. TTX was used in a concentration sufficient to completely block fast Na⁺ channels in vascular SMCs.²¹ Treatment of the pial arteries with TTX (1 µmol/L) did not influence the amplitude and duration of the APs (n=4). In one artery TTX in the concentration of 5 µmol/L was also without effect.

To investigate the participation of Ca²⁺ channels in AP generation, we studied the influence of a Ca²⁺-free EGTA-containing solution and the Ca²⁺ channel blocker nifedipine on spontaneous activity. In six arteries removal of Ca²⁺ ions from the superfusion solution was followed by rapid and complete inhibition of spontaneous APs and contractions, leading to relaxation of the vessel wall (Fig 5A). Readdition of the Ca²⁺ ions to the superfusion solution restored spontaneous activity. The effect of nifedipine, a specific blocker of L-type voltage-dependent Ca²⁺ channels, was tested in eight arteries. Nifedipine (1 to 2 µmol/L) invariably blocked periodic spontaneous activity (Fig 5B). Fifteen to 20 minutes after the application of nifedipine, high-K⁺ solution produced depolarization without generation of APs. Depolarization was not followed by significant contraction of the vessel wall (Fig 5C). Nifedipine (1 to 2 µmol/L) produced irreversible inhibition of spontaneous electrical and contractile activity.

View larger version (22K): [in this window] [in a new window]   Figure 5. Inhibition of spontaneous action potentials and contraction of human pial arteries in Ca2+-free solution and by nifedipine. Upper trace in A, B, and C represents changes in membrane potential, and lower trace, force. A, Effect of Ca2+ ion removal from bath solution on spontaneous action potentials and force development of artery (inner diameter, 112.5 µm, 51-year-old patient). B, Inhibition of the spontaneous action potentials and relaxation produced by nifedipine (2 µmol/L). C, Effect of K+ ions 15 minutes after superfusion of the arterial segment with nifedipine. Recordings on B and C were obtained from the same cell (inner diameter, 225.0 µm, 41-year-old patient).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We have reported for the first time some characteristics of the membrane potential of SMCs of human pial arteries. The main finding of this study was that in these vessels rhythmic contractions were associated with generation of APs during spontaneous or K⁺-induced depolarization. The resting membrane potential of human pial arteries in vitro varied between -40 and -70 mV. The membrane potential of SMCs in rhythmically constricting arteries was significantly less negative than that of the silent ones. This finding indicates that spontaneous activity may be the result of a depolarized state of SMCs. The incidence of spontaneous activity was higher in those arteries that were obtained from patients >40 years old. Therefore, we cannot exclude an influence of age-related vascular changes or of disease on the determined properties of human pial arteries. Periodic spontaneous activity has been demonstrated in human coronary arteries^{22 23 24} and was most frequent in vessels taken from older patients or those with cardiovascular diseases²³ and atherosclerotic changes.²⁴

It is well documented that SMCs of major cerebral arteries from a number of species can generate APs when they are depolarized by electrical current, high-K⁺solution, or application of excitatory agonists.^{12 13 14 15 16 25} In the present experiments it was found that SMCs in the wall of human pial arteries can generate APs spontaneously or during K⁺-evoked depolarization. TTX failed to produce any significant changes in APs in human pial arteries, suggesting that fast Na⁺ channels are not important for their generation. There is strong evidence that Ca²⁺ ions are the major inward current carriers in the generation of APs in human pial arteries, since spontaneous APs were completely blocked in Ca²⁺-free solution and by nifedipine. In the presence of nifedipine, a high-K⁺ solution produced depolarization with no superimposed APs (Fig 5). These data indicate that the APs generated by SMCs in human pial arteries are the result of Ca²⁺ influx through dihydropiridine-sensitive voltage-dependent Ca²⁺ channels.

Generation of APs in human pial arteries was invariably associated with activation of contraction. Simultaneous recordings of electrical and contractile activity in our experiments showed that spontaneous long-lasting periodic contractions mainly consisted of partially fused rhythmic contractions activated by each AP (so-called tetanus). In silent arterial segments where APs can be induced by moderate K⁺ depolarization, the tetanic component of the contraction can be easily recognized (Fig 4). As can be seen in Fig 2B, the force of the rhythmic contraction increased with prolongation of APs. The existence of a correlation between duration of APs and the force of the associated contraction suggests that modulation of the AP parameters would have significant influence on the tone of human pial arteries. We also found that slowly developing spontaneous or K⁺-evoked depolarization was followed by tonic contraction before AP generation (Figs 3 and 4). In the presence of nifedipine, elevation of K⁺ ions in the bathing solution induced depolarization but not contraction, indicating that this contraction is a result of Ca²⁺ influx through voltage-dependent Ca²⁺ channels. Thus, there are two mechanisms involved in the electromechanical coupling in human pial arteries: Contraction can be activated by Ca²⁺ entering the cells through voltage-dependent Ca²⁺ channels during slow depolarization and also during the generation of APs.

The ability of SMCs in the wall of human pial arteries to generate APs spontaneously or in response to depolarization leads us to speculate that APs can be involved in the production of vasomotion in the human cerebral circulation. It has been shown that arterial SMCs are depolarized by an increase in intraluminal pressure, resulting in myogenic tone, and in some arteries such depolarization can evoke AP generation.^{26 27 28} In our experiments APs, as well as associated rhythmic contractions, can be generated only within a certain range of membrane potential (-40 to -20 mV). It has been demonstrated in vivo and in vitro that the appearance of cerebral vasomotion depends on the level of intraluminal pressure; it was inhibited by both pressure reduction and pressure increase.^{2 4 5 7 8} This phenomenon can be related at least in part to the level of pressure-induced depolarization, which in turn is critical for AP generation. Both APs and rhythmic contractions in our experiments and vasomotion in small cerebral arteries of a number of species were not influenced by TTX but can be inhibited by organic Ca²⁺ antagonists or in Ca²⁺-free solution.^{3 4 5} Thus, our observations are consistent with the hypothesis that vasomotion in human cerebral circulation might be induced by APs.

In conclusion, our data demonstrate that generation of APs underlies the rhythmic contractions in human pial arteries in vitro and may represent one of the mechanisms involved in the regulation of human cerebrovascular tone.

	Acknowledgments

 
This study was supported by Totman Medical Research Fund. We are indebted to Dr Joseph E. Brayden for his helpful advice, comments, and critical reading of the manuscript.

	Footnotes

 
Previously presented in part in abstract form (FASEB J. 1994;8:A34).

Received March 6, 1995; accepted August 30, 1995.

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