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Am J Physiol Heart Circ Physiol 278: H2094-H2104, 2000;
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Vol. 278, Issue 6, H2094-H2104, June 2000

Histamine-induced depolarization: ionic mechanisms and role in sustained contraction of rabbit cerebral arteries

N. I. Gokina and J. A. Bevan

Department of Pharmacology, College of Medicine, The University of Vermont, Burlington, Vermont 05405


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The role of membrane depolarization in the histamine-induced contraction of the rabbit middle cerebral artery was examined by simultaneous measurements of membrane potential and isometric force. Histamine (1-100 µM) induced a concentration-dependent sustained contraction associated with sustained depolarization. Action potentials were observed during depolarization caused by histamine but not by high-K+ solution. K+-induced contraction was much smaller than sustained contraction associated with the same depolarization caused by histamine. Nifedipine attenuates histamine-induced sustained contraction by 80%, with no effect on depolarization. Inhibition of nonselective cation channels with Co2+ (100-200 µM) reversed the histamine-induced depolarization and relaxed the arteries but induced only a minor change in K+-induced contraction. In the presence of Co2+ and in low-Na+ solution, histamine-evoked depolarization and contraction were transient. We conclude that nonselective cation channels contribute to histamine-induced sustained depolarization, which stimulates Ca2+ influx through voltage-dependent Ca2+ channels participating in contraction. The histamine-induced depolarization, although an important and necessary mechanism, cannot fully account for sustained contraction, which may be due in part to augmentation of currents through voltage-dependent Ca2+ channels and Ca2+ sensitization of the contractile process.

cimetidine; nifedipine; low sodium; cobalt; voltage-dependent calcium channels; nonselective cation channels


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

HISTAMINE, A POTENT MODULATOR of cerebrovascular tone, can be released from nerve terminals and mast cells in the cerebral arterial wall and has been implicated in a number of physiological and pathophysiological processes (7, 15, 17, 42). Histamine can cause cerebral vasoconstrictor or dilator effects, depending on the level of arterial tone, anatomic location in the cerebrovascular tree, and animal species (1, 7, 8, 15, 17, 35, 39, 41, 43, 45). In subthreshold concentrations, histamine dramatically potentiates contractile responses of the rabbit cerebral artery to nerve stimulation, serotonin, and norepinephrine (1). The cellular mechanisms responsible for histamine-induced constriction and potentiation phenomena in the cerebral circulation remain largely unknown.

Various mechanisms have been shown to underlie the vasoconstrictor effect of histamine. It can depolarize vascular smooth muscle cells (SMCs), thereby increasing Ca2+ influx through voltage-dependent Ca2+ channels and causing contraction (3, 8, 22, 29, 41). In addition, stimulation of histamine receptors can directly augment the voltage-dependent Ca2+ current (21, 34). In some arteries, a major part of the sustained histamine-induced contraction was resistant to dihydropyridines, suggesting that influx of Ca2+ through pathways other than voltage-dependent Ca2+ channels was a major contributor (3, 23). Histamine can induce inositol phospholipid hydrolysis in smooth muscle, resulting in inositol trisphosphate-induced mobilization of Ca2+ from intracellular stores (17). This Ca2+ not only initiates contraction, but it also regulates the ionic permeabilities of the plasma membrane, affecting the membrane potential of SMCs (5, 20, 25). Exposure to histamine augmented Ca2+-induced contraction in smooth muscle permeabilized with alpha -toxin, suggesting that Ca2+ sensitization of the contractile mechanism might also contribute to histamine-induced contraction (11).

There is evidence that histamine can depolarize cerebrovascular smooth muscle (8, 22, 29, 41). The role of this depolarization in excitation-contraction coupling as well as underlying ionic mechanisms is not understood. We hypothesized that membrane depolarization plays an essential role in histamine-induced constriction. To verify this hypothesis, we 1) characterized the relationships between histamine-induced changes in the membrane potential and contractile force in rabbit middle cerebral artery (MCA), 2) evaluated the contribution of nonselective cation channels to histamine-induced depolarization, and 3) examined the role of membrane depolarization and voltage-dependent Ca2+ channels in the activation of the contraction. We have demonstrated that histamine-induced sustained contraction of rabbit MCA is associated with sustained membrane depolarization. This depolarization is unaffected by nifedipine but is inhibited by Co2+ and reduction in extracellular Na+, suggesting the involvement of nonselective cation channels. The primary role of histamine-induced depolarization is an activation of Ca2+ influx through voltage-dependent Ca2+ channels. Although the depolarization is a necessary mechanism, it cannot fully account for sustained histamine-induced contraction of rabbit MCA. Direct enhancement of Ca2+ channel activity and Ca2+ sensitization of the contractile process might operate as additional mechanisms.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Preparation of arterial segments and experimental procedure. All experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals [DHHS Publication No. (NIH) 85-23, revised 1985, Office of Science and Health Reports, Bethesda, MD 20892]. The experimental protocols were approved by the Institutional Animal Use and Care Committee of the University of Vermont.

Adult male New Zealand White rabbits (2-3 kg) were anesthetized with pentobarbital sodium (39 mg/kg), heparinized (1,000 U/kg), and killed by rapid exsanguination. The brain was removed and placed in physiological salt solution (PSS) at room temperature. The proximal part of the MCA was dissected from the surface of the brain and cleaned of connective tissue. Usually, one ring arterial segment (2 mm long) per animal was used for simultaneous recordings of membrane potential and isometric contractile force. Each arterial segment was placed in an experimental chamber (3-ml volume) continuously superfused with gassed PSS at 2-3 ml/min. Two tungsten wires (20 µm diameter) were gently inserted through the lumen of the artery. One wire was attached to a micromanipulator for stretching of the artery and the other to a force transducer. Before the vessel was stretched, the luminal diameter of the artery was measured and was in the range 220-250 µm. After an equilibration period of 15-20 min and heating to 37°C, each arterial segment was stretched to a resting tension of 100 mg, which was the optimal preload for force development (4). After 1 h, the arterial segment was constricted by a combination of histamine (3 µM) and serotonin (1 µM). ACh (3 µM) was then added to the superfusate to verify the functional integrity of vascular endothelium.

The responses of cerebral arteries to different concentrations of histamine were obtained in a cumulative fashion by applying each concentration until stabilization of the level of membrane potential and contraction, usually 5-10 min. Occasionally, we tested single doses of histamine, and application of each dose was separated by a washout period of 20-30 min.

In all other experiments, 3 µM histamine was used in the presence of cimetidine (3 µM).

Electrophysiology. All electrophysiological experiments were performed in current-clamp mode. For measurement of membrane potential, we used glass microelectrodes that were filled with 0.5 M KCl and had tip resistances of 110-150 MOmega . An Ag-AgCl pellet was used as an indifferent electrode. Microelectrode intracellular impalements of SMCs were made from the adventitial surface of arterial segments. A microelectrode was connected to a motorized micromanipulator (model DC-3K, Fine Science Tools). Membrane potential was recorded using a high-input impedance amplifier (Electro 705, World Precision Instruments). The changes in the membrane potential and isometric force were displayed and recorded on a desktop computer with use of the Axotape 2.0 (Axon Instruments) data acquisition program and on a chart recorder. We used the following criteria for acceptance of membrane potential recordings: 1) abrupt negative change in voltage on impalement of the cells, 2) sharp return to zero voltage after withdrawal of a microelectrode tip, 3) tip potential of <7 mV, and 4) unchanged resistance of microelectrode after its withdrawal. Experimental manipulations were started 2-5 min after stabilization of the membrane potential.

Removal of the vascular endothelium. In a separate set of experiments, we tested the effects of histamine and high-K+ solution in endothelium-denuded arteries. To minimize potential damage of SMCs, endothelium was removed by air perfusion (46). For this purpose, a small glass cannula was placed into the lumen of the arterial segment mounted in the experimental chamber. Air bubbles were slowly infused through the lumen for 10 min. A small volume (0.1 ml) of regular PSS was then injected through the same cannula. The effectiveness of endothelium removal was confirmed by the absence of relaxation to ACh (3 µM) in arteries contracted with a combination of serotonin (1 µM) and histamine (3 µM).

Solutions and drugs. We used PSS of the following composition (in mM): 130.0 NaCl, 4.7 KCl, 1.18 KH2PO4, 1.17 MgSO4, 14.9 NaHCO3, 0.026 EDTA, 11.1 glucose, and 1.6 CaCl2. To prepare K+-rich solutions, equimolar amounts of NaCl were replaced with KCl. The low-Na+ solution was made by equimolar substitution of 130 mM Na+ in regular PSS with N-methyl-D-glucamine. Superfusion solutions were equilibrated with 95% O2-5% CO2 (pH 7.4). To study the effects of Co2+, we used HEPES solution of the following composition (in mM): 135.0 NaCl, 5.6 KCl, 1.0 MgCl2, 10.0 HEPES, 10.0 glucose, and 1.8 CaCl2 (pH adjusted to 7.4 with 10.0 M NaOH).

Histamine hydrochloride, 5-hydroxytryptamine creatinine sulfate (serotonin), and ACh chloride were prepared as 10 mM stock solutions in distilled water daily. Nifedipine was prepared as a 10 mM stock solution in alcohol and kept refrigerated. BaCl2 and CoCl2 were dissolved in distilled water and kept refrigerated as a 10 mM stock solution until used. All chemicals were purchased from Sigma Chemical (St. Louis, MO).

Data analysis and statistics. In our study the membrane potential represents an absolute value measured during microelectrode impalement (e.g., resting membrane potential or membrane potential during treatment with histamine). Depolarization (or hyperpolarization) represents the difference between the resting membrane potential and the membrane potential during treatment measured from the same SMC.

In some experiments (~20%) we were unable to keep continuous recordings of membrane potential during histamine application, because a rapid force development dislodged the microelectrode tip. In such cases, the membrane potential was measured from another intracellular impalement obtained during the same application of histamine. A resting membrane potential was measured from the second impalement after a complete washout of the artery or was accepted from the first impalement, since we obtained fairly constant values of resting membrane potential from different cells of the same arterial segment during 4-6 h of observation (see Fig. 6A).

Histamine-induced depolarization and contraction usually reached a maximum after 2-3 min and were well maintained as long as histamine was present. In low-Na+ solution or in the presence of Co2+ (1 mM), histamine-evoked depolarization and contraction attained the maximum in 2-3 min and then declined to a considerably lower level. To characterize these responses, depolarization and contraction were first measured at maximum (initial component) and then 7-10 min later (sustained component). These values were compared with the values measured at the same time intervals from responses caused by histamine in regular PSS.

The data recorded were imported as ASCII files into Sigma Plot for graphical representation and statistical analysis. Values are means ± SE of n arterial segments. A Student's t-test was used to determine the significance of differences between sets of data. Differences were considered significant when P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of histamine on membrane potential and contractile force. All our experiments, except one set, were performed using arteries with intact endothelium. SMCs in the wall of rabbit MCA displayed a resting membrane potential of -55 to -70 mV (mean -65.6 ± 0.5 mV, n = 89). No spontaneous electrical or contractile activity was observed. Exposure to 0.01-0.3 µM histamine failed to produce any changes in membrane potential and contractile force. At higher concentrations (1-100 µM), histamine elicited a concentration-dependent contraction, which was associated with membrane depolarization (Fig. 1A). Short-lasting bursts of action potentials (APs) and slow waves were observed during the initial phase of depolarization in the majority of tested arteries. Occasionally, when histamine-induced depolarization did not exceed -40 mV, SMCs continuously generated APs or slow waves of depolarization (Fig. 1B). There was a close correlation between APs and associated phasic contractions. Typically, AP generation preceded the development of phasic contraction (see Fig. 9A for expanded time scale).


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  		Fig. 1.   Representative traces illustrating changes in membrane potential and contractile force induced by increasing concentrations of histamine (Hist) in 2 different arterial segments (A and B) from rabbit middle cerebral artery (MCA).

The concentration-response curves for histamine-induced depolarization and contraction were very steep: the threshold concentration for force generation and membrane depolarization was ~1 µM, and the maximal effect was observed at 10 µM. In ~20% of tested arteries, histamine induced only transient responses.

Effects of cimetidine. In rabbit MCA, histamine can simultaneously stimulate H1 receptors (located on SMCs) and H2-histamine receptors (located on endothelial cells and SMCs), mediating constrictor and dilator responses, respectively (38). To minimize the inhibitory effect of histamine, we treated arteries with cimetidine, an antagonist of H2-histamine receptors. Cimetidine (3 µM) caused no changes in the resting membrane potential (- 68.8 ± 1.3 and -70.0 ± 1.1 mV before and after cimetidine application, respectively, n = 10) but potentiated the contraction and depolarization evoked by threshold concentration of histamine. In arteries with a transient pattern of the responses to histamine, cimetidine converted a transient depolarization and contraction to a sustained one (Fig. 2A). Cimetidine displaced the dose-response curves for histamine-induced contraction and depolarization to the left (Fig. 2, B and C). These results indicate that the transient nature of the histamine-induced responses in some arteries and a low sensitivity to histamine are attributable to interaction between its excitatory and inhibitory effects. Because we were interested in the excitatory effect of histamine, all subsequent experiments were done in the presence of cimetidine (3 µM).


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  		Fig. 2.   Effect of cimetidine (Cimet) on responses elicited by histamine in rabbit MCA. A: cimetidine converted transient histamine-induced depolarization and contraction to sustained depolarization and contraction. B and C: concentration-response curves for histamine-evoked depolarization and contraction in absence and presence of 3 µM cimetidine. Force is expressed as a percentage of maximum K+-induced (66 mM) contraction. In some cases, amplitude of standard errors corresponds to or is smaller than symbols. * Significantly different from control (P < 0.05). Numbers near each symbol indicate number of arterial segments.

Effects of low-Na+ solution. Our results demonstrate that histamine-induced contraction in rabbit MCA was closely associated with smooth muscle depolarization. For better understanding of the role of this depolarization in development of the contraction, we first attempted to explore the underlying ionic mechanisms.

Numerous studies demonstrate that nonselective cation channels can contribute to the vasoconstrictor-induced sustained depolarization of smooth muscle (5, 20, 25). At physiological levels of resting membrane potential (-70 to -50 mV), inward current through these channels is mainly carried by Na+ and can be reduced by depletion of Na+ in the extracellular solution (5). We utilized this idea to evaluate the role of nonselective cation channels in histamine-induced depolarization. At 10-20 min after reduction of extracellular Na+ to 15 mM (equimolar replacement with N-methyl-D-glucamine), histamine caused depolarization and contraction that reached the maximum in 2-3 min and then gradually declined almost to resting levels (Fig. 3A). The amplitude of initial depolarization (28.1 ± 1.8 mV, n = 8) was only slightly different from the depolarization (32.2 ± 1.0 mV, n = 13) induced by histamine in arteries bathed in regular PSS (145 mM Na+). However, the sustained depolarization was significantly smaller [4.3 ± 0.7 mV (n = 7) vs. 30.6 ± 1.4 mV (n = 13) in regular PSS]. The histamine-induced transient contraction in low-Na+ solution was not different from the maximal initial contraction in control solution, but the sustained component was reduced to 10.3 ± 3.1% (n = 14). Restoration of Na+ in the superfusion solution resulted in development of the sustained depolarization (27.2 ± 1.3, n = 6) and contraction. These experiments revealed at least two different mechanisms contributing to histamine-induced depolarization: 1) sustained depolarization that was greatly attenuated by removal of Na+, suggesting the involvement of Na+ influx, most likely through nonselective cation channels, and 2) initial depolarization that was less sensitive to reduction in extracellular Na+, indicating the participation of a different mechanism.


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  		Fig. 3.   Effect of a reduction in extracellular Na+ on responses induced by histamine. A: original traces showing transient nature of depolarization and contraction in response to histamine in low-Na+ solution (15 mM) and restoration of sustained responses after an increase of Na+ in bath solution to 145 mM. B: summary of effects of a low-Na+ solution on histamine-induced depolarization and contraction. Force is expressed as percentage of initial and sustained contraction evoked by histamine in regular physiological salt solution (145 mM Na+). * Significantly different from control (P < 0.05). Numbers above bars indicate number of arterial segments.

Effects of Co2+. Nonselective cation channels can be blocked by some polyvalent cations, such as Cd2+, Co2+, Ni2+, and Gd3+ (5, 20, 25). If these channels contribute to histamine-induced depolarization, then it should be attenuated by polyvalent cations. Indeed, an application of Co2+ in low concentrations (100-200 µM) during histamine-induced response resulted in repolarization of the membrane and complete relaxation (Fig. 4A). Washout of Co2+ was followed by the restoration of the membrane depolarization and contraction. It is well known that polyvalent cations are also effective inhibitors of voltage-dependent Ca2+ channels (25, 26, 28, 33). Therefore, we also studied the effect of Co2+ in different concentrations on contraction induced by high-K+ depolarization. An application of Co2+ at low concentration (100-200 µM) produced only a minor change in the contraction evoked by a high-K+ solution (35 and 66 mM). However, at higher concentrations (500 µM-1 mM) Co2+ caused a significant relaxation of K+-contracted arteries, with a maximal effect at 1 mM (Fig. 4B). These experiments demonstrate that Co2+ in low concentrations (100-200 µM) does not inhibit significantly voltage-dependent Ca2+ channels. However, Co2+ in higher concentrations (500 µM-1 mM) is a potent blocker of voltage-dependent Ca2+ influx in rabbit MCA.


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  		Fig. 4.   Effects of Co2+ on histamine- and K+-induced responses of rabbit MCA. A: Co2+ application during histamine-induced response resulted in repolarization of smooth muscle cells and relaxation. Washout of Co2+ was followed by restoration of histamine-induced depolarization and contraction. Break in trace represents interruption in computer recording during continuous microelectrode impalement. B: relaxation of K+-evoked contraction produced by cumulative addition of Co2+. C and D: summary of Co2+ effects on sustained depolarization and contraction induced by histamine (3 µM). Force is expressed as percentage of sustained contraction induced by histamine in control. E: summary of Co2+ effects at different concentrations on contractions induced by high-K+ solution. Force is expressed as percentage of K+-induced (35 and 66 mM) contraction in control. * Significantly different from control (P < 0.05). Numbers above bars indicate number of arterial segments.

In low-Na+ solution, histamine induced a transient depolarization and contraction, suggesting that a mechanism different from activation of nonselective cation channels might contribute to the initial depolarization. Consistent with this observation was the transient nature of the responses induced by histamine after 10-15 min of exposure of arteries to 1 mM Co2+, used to block the influx of Ca2+ into cells through nonselective and voltage-dependent Ca2+ channels. In Co2+-treated arteries, histamine induced a transient contraction (36.7 ± 6.3% of control; Fig. 5A). The transient component of depolarization (17.9 ± 1.4 mV, n = 6) was not significantly different from maximal initial depolarization in the control (19.3 ± 1.0 mV, n = 6). The sustained component of depolarization was significantly smaller (7.3 ± 0.8 mV, n = 6; Fig. 5B). No APs or membrane oscillations occurred in the presence of 1 mM Co2+. These data suggest a contribution of Ca2+ mobilization from internal stores in the initial histamine-induced depolarization and contraction.


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  		Fig. 5.   Effects of histamine on rabbit MCA treated with 1 mM Co2+. A: original recordings of transient changes in membrane potential and force induced by histamine in presence of Co2+. B: summary of Co2+ effects on initial and sustained components of histamine-induced depolarization and contraction. Contractile force is expressed as percentage of control histamine-induced contraction. * Significantly different from control (P < 0.05). n, Number of arterial segments.

Effect of elevation in extracellular K+ concentration on membrane potential and isometric force. To further explore the role of histamine-induced depolarization in excitation-contraction coupling, we compared the responses caused by histamine and high-K+ solution. An elevation of K+ concentration in the superfusion solution from 5.9 to 127 mM caused a concentration-dependent depolarization of SMCs, which was a linear function of the logarithm of extracellular K+ concentration over the range 12-127 mM. Application of high-K+ solution (<20 mM) resulted in sustained depolarization but no contraction. At higher concentrations (20-66 mM), K+-induced depolarization was associated with a dose-dependent contraction. SMCs did not generate APs or membrane oscillations at any level of K+-evoked depolarization (Fig. 6). The threshold depolarization for production of a detectable contraction was around -40 mV.


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  		Fig. 6.   Effects of elevation in external K+ concentration on contractile force and membrane potential in rabbit MCA. A: simultaneous recording of changes in membrane potential and force induced by different concentrations of K+ in same arterial segment. Note absence of action potentials or membrane oscillations at any level of K+-evoked depolarization. B and C: contractile force and membrane potential as a function of extracellular K+ concentration (logarithmic scale). Force is given as percentage of maximal response induced by K+ (66 mM). Numbers near each symbol indicate number of arterial segments.

Figure 7A illustrates contractile responses associated with the identical membrane depolarization induced by high-K+ solution and histamine in the same arterial segment. AP generation was observed during histamine- but not K+-induced depolarization. As evident from original records in Fig. 7A and graphs in Fig. 7B, the K+-evoked depolarization was associated with a much smaller contractile response than the same histamine-induced depolarization.


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  		Fig. 7.   Relationship between contraction and changes in membrane potential caused by high-K+ solution and histamine in rabbit MCA. A: comparison of histamine- and K+-induced changes in contractile force under identical level of membrane depolarization obtained from same arterial segment. B: contractile force as a function of membrane potential induced by histamine and K+. Force is expressed as percentage of maximum K+-induced response (66 mM). C: effects of BaCl2 (50 µM) on membrane potential and isometric force of endothelium-denuded artery in control and in presence of histamine (0.1 µM). Effects of histamine (3 µM) alone are shown for comparison.

We did not observe APs or slow waves in the membrane potential when arterial SMCs were depolarized by BaCl2 (50 µM), a potent inhibitor of the inward rectifier K+ channels in cerebral arteries (32). However, APs were generated during BaCl2-induced depolarization in the presence of 0.1 µM histamine or on exposure to 3 µM histamine alone (Fig. 7C).

Effects of nifedipine. In addition to Ca2+ entry through voltage-dependent Ca2+ channels, histamine may also stimulate Ca2+ influx through nonselective cation channels, thereby producing a larger contraction than that caused by K+-induced depolarization. This possibility was evaluated in experiments with nifedipine, a dihydropyridine inhibitor of voltage-dependent Ca2+ channels. Nifedipine at 2 µM caused an immediate and complete relaxation of contraction evoked by K+-induced depolarization (Fig. 8B). Application of high-K+ solution during exposure to nifedipine caused only negligible contraction (5.8 ± 1.5% of control, n = 6; Fig. 8D). Histamine-induced contraction of arteries treated with the same concentration of nifedipine consisted of an initial transient (58.6 ± 4.6% of control, n = 9) and a much smaller sustained component (22.5 ± 2.5% of control, n = 9; Fig. 8C). Histamine caused a sustained depolarization that was not different from control: 28.0 ± 3.9 and 28.8 ± 4.2 mV before and after treatment with nifedipine, respectively (n = 5). APs generated by SMCs at the beginning of the histamine-evoked depolarization were greatly suppressed by nifedipine (Fig. 9A). When nifedipine was applied during histamine-induced contraction, an immediate, but incomplete, relaxation to 18.2 ± 2.1% of the control occurred (n = 5; data not shown). These experiments indicate that histamine-evoked sustained contraction is mainly provided by Ca2+ influx through voltage-dependent Ca2+ channels. The initial component of the contraction was less sensitive to nifedipine, suggesting a contribution of Ca2+ mobilized from intracellular stores.


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  		Fig. 8.   Nifedipine (Nifed) abolished contraction but not depolarization induced by histamine and high-K+ solution in rabbit MCA. A: changes in membrane potential and force induced by histamine before nifedipine treatment. B: application of nifedipine during K+-induced contraction was followed by complete relaxation. C and D: histamine- and K+-induced depolarization and contraction in presence of nifedipine (2 µM). All recordings were obtained from same arterial segment.



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  		Fig. 9.   Effects of nifedipine on histamine- and K+-induced responses in rabbit MCA. A and B: original traces showing influence of nifedipine on action potentials generated during histamine-induced depolarization. C and D: summary of nifedipine effects on initial and sustained components of histamine- and K+-induced contraction. Force is expressed as percentage of responses evoked by 66 mM K+ or 3 µM histamine before nifedipine treatment (control). * Significantly different from control (P < 0.05). n, Number of arterial segments.

Histamine- and K+-induced responses in endothelium-denuded arteries. It has been shown that, in rabbit basilar artery, generation of APs during norepinephrine-induced depolarization was dependent on the integrity of vascular endothelium (10). To examine whether the generation of histamine-induced APs in our experiments is also endothelium dependent, we studied the effects of histamine in endothelium-denuded arteries. Removal of endothelium from arteries resulted in the decrease of ACh-induced relaxation of cerebral arteries from 96.3 ± 0.7 (n = 47) to 4.4 ± 1.1% (n = 24) of the contraction induced by the combined application of histamine (3 µM) and serotonin (1 µM). SMCs in denuded arteries were slightly, but significantly, depolarized (-59.5 ± 1.0 mV, n = 24) compared with those in intact arteries (-65.6 ± 0.5 mV, n = 89). In endothelium-denuded arteries, histamine was tested in a concentration of 3 µM and in the presence of cimetidine (3 µM). Exposure to histamine resulted in a sustained contraction associated with a sustained depolarization from -66.3 ± 0.9 to -35.0 ± 0.7 mV (n = 6) that was not different from the level of histamine-induced depolarization in intact arteries (-35.8 ± 0.4 mV, n = 26). As in intact arteries, APs were generated during the initial phase of depolarization (Fig. 7C). SMCs in denuded vessels did not generate APs or membrane oscillations during depolarization induced by high-K+ solution (35 and 66 mM) or BaCl2 (50 µM; Fig. 7C).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The present study demonstrates that histamine-induced contraction of smooth muscle in rabbit MCA is closely associated with a strong concentration-dependent depolarization. The depolarization and contraction were observed in intact as well as endothelium-denuded arteries, indicating that SMCs in the cerebral artery wall are the principal targets of the histamine effect.

Ionic mechanisms contributing the sustained depolarization caused by histamine. Several ionic mechanisms might underlie the histamine-induced depolarization of cerebrovascular smooth muscle. K+ channels are the major contributors to the resting membrane potential in vascular SMCs, and their inhibition can be a powerful mechanism of membrane depolarization (3, 5, 25, 32). Some depolarizing vasoconstrictors (serotonin, histamine, and neuropeptide Y) have been shown to inhibit the ATP-sensitive or Ca2+-activated K+ channels in SMCs from mesenteric and coronary arteries (2, 37). Histamine-induced constriction or depolarization of the rabbit cerebral arteries was not affected or was enhanced by inhibitors of K+ channels (6, 12, 29). Although a role for K+ channels cannot be ruled out, these data suggest that their inhibition probably is not the major mechanism of the histamine-induced depolarization.

Two other classes of ion channels, nonselective cation and Ca2+-activated Cl- channels, have been described in a variety of smooth muscle and play an important role in depolarization by hormones and neurotransmitters (5, 20, 25, 27, 47). In our study in low-Na+ solution, histamine caused a transient, but not sustained, depolarization, suggesting that the latter might result from Na+ influx into cells (Fig. 3). Similar inhibition of serotonin-evoked depolarization in low-Na+ solution has been reported for rabbit basilar artery (9). In contrast, reduction in external Na+ did not modify the pressure-induced depolarization in small rat cerebral arteries, indicating a contribution of some other mechanisms (30). Specific tetrodotoxin-sensitive Na+ channels have not been found in cerebrovascular SMCs (18, 41); therefore, it seems likely that Na+ ions enter the cells through histamine-activated nonselective cation channels.

Additional evidence in favor of this hypothesis came from our experiments with Co2+. Some polyvalent cations are known to block nonselective cation channels and can be used in evaluating the role of these channels in agonist-induced depolarization. Ni2+ (100-500 µM) has been shown to attenuate the inward current through nonselective cation channels and depolarization induced by ACh in colonic smooth muscle (27). Gd3+ (10 µM) abolished neuropeptide Y-induced depolarization in small mesenteric arteries (36). Interpretation of such experiments is often complicated by the fact that polyvalent cations can also inhibit voltage-dependent Ca+ channels (25, 26, 28, 31). The latter can reduce cytosolic Ca2+ with a subsequent decrease in activity of Ca2+-dependent ion channels (e.g., Ca2+-activated Cl- channels) and modulation of the membrane potential. In our experiments, application of Co2+ in low concentrations (100-200 µM) during the sustained histamine-induced depolarization resulted in rapid repolarization of the SMCs (Fig. 4A). On the other hand, Co2+ at the same low concentration (100-200 µM) caused only a minor change in K+-induced contraction and, therefore, only moderately affected voltage-dependent Ca2+ channels. It seems that inhibition of histamine-induced depolarization by Co2+ is due to blockade of nonselective cation channels rather than blockade of voltage-dependent Ca2+ channels, with a subsequent reduction in cytoplasmic Ca2+ and decrease in the activity of Ca2+-activated Cl- channels. This conclusion is also supported by the fact that the blockade of Ca2+ entry through voltage-dependent Ca2+ channels by nifedipine strongly attenuated the histamine-induced sustained contraction but did not affect the depolarization (Fig. 8). Nifedipine also abolished the histamine-induced contraction of the arteries treated with ryanodine, with almost no change in associated depolarization (12). It has been reported that, under similar conditions, histamine caused no elevation of cytosolic Ca2+ in rabbit MCA (39). Therefore, our findings that histamine-induced sustained depolarization can be inhibited by Co2+ and in low-Na+ solution favor the role of nonselective cation channels as an important contributor to this depolarization.

Activation of these channels will cause depolarization resulting in opening of voltage-dependent Ca2+ channels and stimulation of sustained contraction. Blockade of nonselective cation channels with Co2+ attenuated the histamine-induced sustained depolarization and, as a consequence, decreased the open state probability of voltage-dependent Ca2+ channels, with a subsequent reduction in influx Ca2+ and relaxation of the artery. Part of the relaxing effect of Co2+, however, also might be related to a direct inhibition of voltage-dependent Ca2+ channels.

We found that, in the presence of Co2+ or after reduction in external Na+, histamine induced a transient depolarization and contraction (Figs. 3 and 5). The latter was also nifedipine resistant. This suggests a contribution of at least two different mechanisms in histamine-induced depolarization. It is well documented that, in smooth muscle, histamine can release Ca2+ from intracellular stores (15, 17, 39, 47). Subsequent elevation of cytosolic Ca2+ not only initiates a contraction but also modulates the activity of a number of ionic channels affecting the SMC membrane potential (5, 20, 25). We hypothesized that an activation of Ca2+-dependent Cl- channels due to Ca2+ mobilization from intracellular stores might contribute to the initial component of histamine-induced depolarization. This issue is addressed in our companion article (12).

Membrane depolarization as a necessary mechanism for sustained histamine-induced contraction. Several lines of evidence support the importance of depolarization in histamine-induced sustained contraction of rabbit MCA. In our experiments, histamine did not cause a sustained contraction of rabbit MCA in the absence of sustained membrane depolarization. For example, in some intact arteries before application of cimetidine, histamine caused a transient contraction associated with a transient depolarization (Fig. 2A). In low-Na+ solution, the sustained depolarization, as well as the sustained contraction, was abolished, and we observed mainly a transient response. Subsequent reintroduction of Na+ into the superfusion solution resulted in the development of sustained depolarization and contraction (Fig. 3A). These observations suggest that membrane depolarization represents a necessary mechanism for histamine-induced sustained force development in rabbit MCA.

A primary physiological role of agonist-induced depolarization in excitation-contraction coupling in smooth muscle is an activation of voltage-dependent Ca2+ channels with subsequent influx of Ca2+ and stimulation of contraction (3, 5, 19, 25, 31, 32). As evident from our experiments, a threshold K+-induced depolarization for activation of a detectable contraction and, therefore, voltage-dependent Ca2+ channels was around -40 mV. Because histamine-induced depolarization associated with contraction was in the range -40 to -35 mV, it is reasonable to suggest that influx of Ca2+ through voltage-dependent Ca2+ channels will participate in activation of the contraction. We demonstrated that nifedipine effectively (by 80%) attenuated the sustained component of the histamine-evoked contraction. Histamine-induced contraction of large human cerebral arteries was also abolished by nifedipine (43). Treatment of arteries with nimodipine, another inhibitor of L-type Ca2+ channels, attenuated the contraction caused by histamine in guinea pig basilar artery by 70% (35). Therefore, Ca2+ influx through L-type voltage-dependent Ca2+ channels represents the major source for activation of histamine-induced sustained contraction in cerebral arteries. However, we found that histamine-induced contraction was much greater than contraction associated with the same depolarization induced by high-K+ solution. Therefore, we concluded that, in rabbit MCA, histamine-induced depolarization itself is not sufficient to cause a strong sustained contraction. A direct enhancement of voltage-dependent Ca2+ channels and sensitization of the contractile process might be the mechanisms operating in addition to depolarization.

The augmentation of voltage-dependent Ca2+ current by histamine has been described in rabbit saphenous and coronary arteries (21, 34). As evident from patch-clamp experiments, serotonin and norepinephrine increased the open state probability of voltage-dependent Ca2+ channels in vascular SMCs with subsequent enhancement of Ca2+ current (31). This mechanism could also operate in the rabbit MCA, and the histamine-provoked ability of SMC to generate APs favors this suggestion. Histamine might enhance the Ca2+ currents in rabbit MCA, yielding a considerably increased Ca2+ influx and much stronger force production at the same level of membrane depolarization.

An additional or alternative mechanism contributing to histamine-induced contraction in rabbit MCA might be an increase in the Ca2+ sensitivity of the contractile process. Such a mechanism has been demonstrated in some smooth muscle stimulated with norepinephrine, endothelin, or histamine (11, 19, 24, 33, 44). There is evidence that activation of protein kinase C might be responsible for enhancement of Ca2+ sensitivity (19). We recently demonstrated that the constriction of pressurized rat cerebral arteries induced by protein kinase C activators was mainly due to increased Ca2+ sensitivity of the contractile process (14). At the same time, this constriction required Ca2+ influx through voltage-dependent Ca2+ channels. The Ca2+ requirement for endothelin-induced Ca2+ sensitization has also been demonstrated in canine basilar artery (44). In the present study, histamine-induced contraction was strongly attenuated by nifedipine; therefore, influx of Ca2+ through voltage-dependent Ca2+ channels opened by depolarization might be essential not only for stimulation of contraction, but also for the Ca2+ sensitization of the contractile process.

Which of the two proposed mechanisms contributes to histamine-induced contraction in cerebral arteries is not known. However, it seems that histamine-induced depolarization with subsequent activation of voltage-dependent Ca2+ channels is a necessary mechanism for an additional augmentation of Ca2+ channel activity or an increase of Ca2+ sensitivity of the contractile process through as yet unknown mechanisms.

There is evidence that nonselective cation channels are also somewhat permeable to Ca2+ (5, 20, 25). Therefore, these channels may modulate the membrane potential and, at the same time, serve as a pathway for Ca2+ entry. We found that a sustained component of histamine-induced contraction was suppressed by 80-90% with nifedipine, combined treatment with nifedipine and ryanodine (12), and low-Na+ solution. Reduction in external Na+ prevented the influx of Na+, but not Ca2+, through nonselective cation channels. Our data are in good agreement with a recently published observation that histamine-induced elevation of intracellular Ca2+ is abolished by application of ryanodine and nicardipine in the same tissue (39). This suggests that Ca2+ influx through nonselective cation channels plays a minor role in histamine-induced sustained contraction in rabbit MCA. In contrast, in rat cerebral arterioles, influx of Ca2+ through receptor-operated channels was the only source for sustained nifedipine-insensitive constriction induced by endothelin (16).

Histamine and excitability of cerebrovascular SMCs. Histamine consistently induced the generation of APs during the initial phase of depolarization followed by phasic contractions, an important contributor to force development. Histamine-induced APs in our study were similar to serotonin-, norepinephrine-, or histamine-induced APs described in rabbit basilar artery (9, 10, 41). Norepinephrine-evoked APs in this artery were eliminated by the removal of vascular endothelium, suggesting that release of some excitatory endothelium-derived factor might be responsible (10). In our study, histamine caused APs in denuded as well as intact arteries, indicating that they result from a direct effect on SMCs. In contrast to human cerebral arteries (13), APs were not observed during K+-induced depolarization in intact and denuded rabbit MCA.

Depolarization with high-K+ solution produced no APs in rabbit basilar artery (9). We also did not observe generation of APs when arteries were depolarized with BaCl2 (Fig. 7C). However, APs were generated during BaCl2-induced depolarization in the presence of histamine. These findings indicate that histamine increased the excitability of SMCs of cerebral arteries. Smooth muscle from different vascular beds do not readily generate APs in response to depolarization by high-K+ solution or by direct electrical stimulation (25). Normally, the early and rapidly activated K+ current overlaps the inward Ca2+ current and prevents AP generation. An enhancement of net inward current due to a decrease in K+ current or an augmentation of Ca2+ current facilitates the generation of APs in smooth muscle (18, 22, 25, 41). Therefore, inhibition of K+ channels and augmentation of current through voltage-dependent Ca2+ channels might be responsible for histamine-evoked AP generation in our study.

Histamine-induced APs and slow waves, as well as associated phasic contractions, were considerably but incompletely suppressed by nifedipine. At the same time, we did not observe APs during histamine-induced transient depolarization in the presence of 1 mM Co2+, a concentration that abolished high-K+-induced contraction. This indicates that influx of Ca2+ through voltage-dependent Ca2+ channels is involved in the production of APs and phasic contractions. Partial resistance of APs to nifedipine might be due to an additional activation of voltage-dependent dihydropyridine-insensitive T-type Ca2+ channels demonstrated in some vascular SMCs (25, 28). However, there is no evidence for their existence in cerebrovascular SMCs (26, 40). Therefore, the precise ionic mechanisms contributing to the histamine-stimulated APs in rabbit cerebral artery remain to be elucidated.

In conclusion, we demonstrate that histamine caused a significant (up to 30 mV) and sustained depolarization of smooth muscle in rabbit MCA. This depolarization is inhibited by Co2+ and by reduction in extracellular Na+, suggesting the involvement of nonselective cation channels. Histamine-induced depolarization stimulates Ca2+ influx through voltage-dependent Ca2+ channels, which is a major source of Ca2+ for activation of histamine-induced sustained contraction. This depolarization, although an important and necessary mechanism, cannot fully account for histamine-induced contraction, which may be due in part to augmentation of currents through voltage-dependent Ca2+ channels and Ca2+ sensitization of the contractile process.


    ACKNOWLEDGEMENTS

We are grateful to Dr. J. E. Brayden (University of Vermont) for helpful discussions and advice.


    FOOTNOTES

This study was supported by National Heart, Lung, and Blood Institute Grant HL-32985.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: N. I. Gokina, Dept. of Obstetrics and Gynecology, College of Medicine, The University of Vermont, Burlington, VT 05405 (E-mail: gokina{at}salus.med.uvm.edu).

Received 29 January 1999; accepted in final form 14 December 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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