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Asthma Research Group, Father Sean O'Sullivan Research Center, St. Joseph's Hospital, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 4A6
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The bronchial
vasculature plays an important role in airway physiology and
pathophysiology. We investigated the ion currents in canine bronchial
smooth muscle cells using patch-clamp techniques. Sustained outward
K+ current evoked by step depolarizations was significantly
inhibited by tetraethylamonium (1 and 10 mM) or by charybdotoxin
(10
6 M) but was not significantly affected by
4-aminopyridine (1 or 5 mM), suggesting that it was primarily a
Ca2+-activated K+ current. Consistent with
this, the K+ current was markedly increased by raising
external Ca2+ to 4 mM but was decreased by nifedipine
(106 M) or by removing external Ca2+. When
K+ currents were blocked (by Cs+ in the
pipette), step depolarizations evoked transient inward currents with
characteristics of L-type Ca2+ current as follows:
1) activation that was voltage dependent (threshold and
maximal at 
50 and 10 mV, respectively); 2) inactivation that was time dependent and voltage dependent (voltage causing 50%
maximal inactivation of 26 ± 22 mV); and 3) blockade
by nifedipine (106 M). The thromboxane mimetic U-46619
(106 M) caused a marked augmentation of outward
K+ current (as did 10 mM caffeine) lasting only 10-20
s; this was followed by significant suppression of the K+
current lasting several minutes. Phenylephrine (104 M)
also suppressed the K+ current to a similar degree but did
not cause the initial transient augmentation. None of these three
agonists elicited inward current of any kind. We conclude that
bronchial arterial smooth muscle expresses Ca2+-dependent
K+ channels and voltage-dependent Ca2+ channels
and that its excitation does not involve activation of Cl channels.
potassium; calcium; chloride; adrenergic; U-46619
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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THE BRONCHIAL VASCULATURE plays a very important role in maintaining the normal function of the respiratory system: it nourishes the airway wall, conditions inspired air, and is involved in defense and clearance of the airways. Dysfunction of bronchial vasculature may contribute to asthma, particularly exercise- and cold/dry air-induced bronchoconstriction (22), and to edema formation in the lung occurring after acute lung injury with smoke inhalation and acid aspiration (1, 4, 17); also, adequate bronchial blood flow is now recognized to be vital to postoperative success after lung transplantation (12, 16).
Like most systemic vasculature, the bronchial circulation is regulated primarily via an excitatory adrenergic innervation and inhibitory nonadrenergic noncholinergic innervation (3, 25) and is also regulated by blood-borne autacoids, including inflammatory mediators; the primary constrictor autacoid among the latter is thromboxane A2 (3, 15).
Constriction and relaxation of vascular smooth muscle is mediated in
part through changes in membrane conductances: in general, excitatory
stimuli cause opening of voltage-dependent Ca2+ channels,
usually via activation of Cl channels and subsequent
membrane depolarization, whereas vasodilators activate K+
channels, leading to membrane hyperpolarization and decreased Ca2+ influx (13). Although much work has been
done to investigate the ion channels and their regulation in other
systemic arteries, there have been no electrophysiological studies of
the bronchial vasculature. The purpose of this study, then, was to
classify the ion channels present in freshly dissociated canine
bronchial arterial smooth muscle cells and their regulation by
excitatory agonists.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell isolation. Adult mongrel dogs (15-30 kg; either sex) were killed by intravenous injection of pentobarbital sodium (30 mg/kg), and lobes of lung were excised. Bronchial vasculature (0.5-1 mm OD) on third- to fifth-order airways was exposed by removing overlying connective tissue and parenchyma. Bronchial veins were generally sparse or completely absent in these intraparenchymal airways (since the bronchial circulation drains into the pulmonary veins) and are easily distinguished from the bronchial arteries on the basis of diameter and relative wall thickness; we used only bronchial arteries in these studies.
Tissues were either used immediately or stored at 4°C for use the next day. We found no functional differences in tissues that were studied immediately compared with those used after 24 h of refrigeration. Tissues were transferred to digestion solution that contained collagenase and elastase (see composition in Solutions) and were incubated at 37°C for 1 h, after which they were gently triturated to liberate individual myocytes. These were allowed to settle and adhere to the bottom of a recording chamber (1 ml volume) and were superfused with standard Ringer solution at a rate of 2-3 ml/min; unless indicated otherwise, experiments were conducted at room temperature. The dissociated cells were studied within 8 h after dissociation. Electrophysiological responses were tested in cells that were phase dense and appeared relaxed.Electrophysiological study.
The majority of recordings were made using the nystatin
perforated-patch configuration of the conventional patch-clamp
recording technique. Pipette tip resistances ranged from 3 to 5 M
,
and access resistances ranged from 9 to 39 M (70-80%
compensated). Membrane currents were filtered at 5 kHz and sampled at 2 Hz. Acquisition and analysis of data were accomplished using Axopatch 200B and pCLAMP8 software (Axon Instruments, Foster City, CA).
Solutions. Digestion solution contained collagenase (blend F; 0.9 U/ml; Sigma), elastase (type IV, 12.5 U/ml), and BSA (1 mg/ml) in Ca2+- and Mg2+-free Hanks' solution (pH 7.4).
For most of the recordings, we used standard Ringer solution containing the following (in mM): 130 NaCl, 5 KCl, 1 CaCl2, 1 MgCl2, 20 HEPES, and 10 D-glucose (pH 7.4). Ca2+-free media was prepared by omitting CaCl2 and adding 1 mM EGTA. The pipette solution generally contained the following (in mM): 140 KCl, 1 MgCl2, 0.4 CaCl2, 20 HEPES, 1 EGTA, and 150 U/ml nystatin (pH 7.2). For recordings of Ca2+ currents, on the other hand, we used Ringer solution with Ca2+ substituted by 5 mM Ba2+ and a modified pipette solution. When the perforated-patch configuration was employed, we used a pipette solution consisting of the following (in mM): 130 CsCl, 10 tetraethylammonium (TEA), 1 MgCl2, 20 HEPES, 5 EGTA, and 150 U/ml nystatin (pH 7.2). For whole cell recordings of Ca2+ current, this pipette solution was supplemented with 4 mM ATP (Na+ salt) and 0.3 mM GTP (Na+ salt).Chemicals. All chemicals were obtained from Sigma Chemical. TEA, 4-aminopyridine, phenylephrine, and caffeine were prepared as aqueous stock solutions. Nifedipine and U-46619 were dissolved in absolute ethanol and then diluted with bathing medium; the final concentration of ethanol in the application pipette was 0.01%. Phenylephrine, caffeine, and U-46619 were applied by pressure ejection (Picospritzer II; General Valve, Fairfield, NJ) from micropipettes placed close to the cells, whereas ion channel blockers were applied directly via the bathing medium.
Statistics. Data are expressed as means ± SD. Statistical significance (P < 0.05) was determined using a two-tailed Student's t-test.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Outward K+ current.
At resting membrane potentials, the canine bronchial arterial smooth
muscle cells were quiescent, with an input resistance ranging from 1 to
10 G and no spontaneous current activity whatsoever (Fig.
1A); none of the cells we
studied (~100 cells from >25 animals) exhibited any spontaneous
transient inward currents like those we have described previously in
airway smooth muscle cells (8) or that others have found
in vascular smooth muscle (21, 23). At more depolarized
potentials, these cells generally exhibited spontaneous transient
outward currents (STOCs; Fig. 1, B and C).
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70 mV evoked large sustained outward currents often
accompanied by STOCs (Fig. 1; n = 44). The average
amplitude of the current at 70 mV was 49 ± 8 pA/pF
(n = 44). This outward current exhibited little or no
inactivation, decreasing <10% over the course of the depolarizing pulse.
Vascular smooth muscle cells generally exhibit two major types of
K+ currents (Ca2+ activated and delayed
rectifier) that can be distinguished on the basis of sensitivity to
TEA, 4-aminopyridine, and charybdotoxin. We found that TEA
significantly inhibited the sustained and transient outward currents,
leaving only a small outward current devoid of any spike-like outward
currents: currents at +70 mV were reduced to 50 ± 14 and 84 ± 3% of control in the presence of 1 mM TEA (6 cells;
n = 5) or 10 mM TEA (7 cells; n = 6;
Fig. 2A), respectively. These
inhibitory effects of TEA were reversible upon washout of TEA.
Likewise, charybdotoxin (106 M) also significantly
inhibited the sustained outward current (67 ± 13% of control at
+70 mV; 5 cells, n = 4) and abolished the large
spike-like outward currents in a reversible fashion (Fig.
2C). 4-Aminopyridine, on the other hand, had no significant effect on the currents at bath concentrations of 1 mM (7 cells; n = 6) nor 5 mM (6 cells; n = 5; Fig.
2B).
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Role of Ca2+ influx in K+ current activation. Given that the outward currents triggered by membrane-depolarizing pulses are predominantly Ca2+ dependent, we next investigated the contribution of external Ca2+ to their activation.
The magnitudes of the outward K+ currents were significantly reduced, but not abolished, when the external bathing medium was replaced with a Ca2+-free buffer and were restored to control levels by reintroduction of external Ca2+ (Fig. 3A). On the other hand, their magnitudes were markedly increased when external Ca2+ concentration was increased to 4 mM (Fig. 3A). On average, the magnitude of the current evoked by a depolarizing pulse to +70 mV was inhibited 61 ± 8% in Ca2+-free media (n = 6; P < 0.05) and augmented slightly (but not significantly) to 116 ± 68% of control in 4 mM Ca2+-containing buffer (7 cells from 6 dogs; Fig. 3C).
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6 M) also markedly reduced K+ currents in
a reversible fashion (Fig. 3B); on average, K+
currents evoked by step depolarizations to +70 mV were inhibited by
72 ± 4% (n = 4; P < 0.05; Fig.
3D).
Voltage-dependent Ca2+ current. The data presented above provide indirect evidence for voltage-dependent Ca2+ channels in these cells. We examined the Ca2+ currents directly by replacing K+ in the pipette solution with Cs+ to block K+ currents (TEA was also present in the pipette solution, for the same purpose) and by replacing Ca2+ in the bathing medium with Ba2+ (5 mM) to augment the inward current.
Depolarizing step commands (10-mV increments) from a holding potential of70 mV evoked transient inward currents (Fig.
4). Activation of these currents was time
dependent (peak activation occurring within 24 ± 13 ms;
n = 13) and voltage dependent (threshold approximately
equal to 30 mV, half-maximal at 3 ± 7 mV, and maximal at +20
mV; Fig. 4). The currents also inactivated in a fashion that was time
dependent; mean 
for inactivation at 10 mV was 206 ± 53 ms.
Repolarization to the holding potential did not evoke slowly
decaying tail currents reminiscent of Ca2+-dependent
Cl current (10) nor of T-type
Ca2+ currents (6).
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100 to +30 mV (10-mV increments) for 4.9 s ("conditioning pulses"), followed by return to the holding potential (of 70 mV) for 54 ms and then a test pulse to +10 mV (1 s
duration). A typical plot of the magnitude of the test pulses against
voltage of the conditioning pulses is shown in Fig. 4D. Voltage-dependent inactivation was incomplete, and Boltzmann analysis of the data yielded a mean voltage causing 50% maximal inactivation of
26 ± 2 mV (n = 5).
Effects of caffeine on membrane currents.
In addition to Ca2+ influx pathways, intracellular
Ca2+ concentration ([Ca2+]i) can
also be elevated by release of internally sequestered Ca2+
(2, 20). Millimolar concentrations of caffeine trigger
release of internal Ca2+ by enhancing the opening of
ryanodine receptors on the sarcoplasmic reticulum. This release is
transient, however, so it is generally not possible to characterize the
effects of caffeine on membrane currents evoked by a series of
depolarizing step commands. Instead, we examined the effects of
caffeine while holding the membrane potential constant at various
levels. When the cells were held under voltage clamp at 0 mV, caffeine
(10 mM) evoked a substantial outward current that was transient in
nature, rising to a mean peak value of 688 ± 248 pA and then
decaying to baseline over the course of 2-3 s even though caffeine
continued to be applied (Fig.
5A). Caffeine also evoked
contractions (data not shown). When the same cells were held at 60
mV, however, caffeine had no discernible effect on membrane current
(Fig. 5B).
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70 up to +50 mV at a rate of 120 mV/s. In this way, it is possible to capture the complete
current-voltage relationship of the caffeine-evoked currents, although
it must be understood that both [Ca2+]i (and
thus the degree of current enhancement) and membrane potential are
changing at the same time but at different rates and/or in different
directions. Before application of caffeine, ramp depolarizations evoked
only outward current with a similar current-voltage relationship as the
K+ currents described above (compare Fig. 1 with Fig.
5C); no inward currents were seen in any cell held at
negative membrane potentials (17 cells; n = 9). Upon
application of caffeine (10 mM), the outward currents were increased
499 ± 40% (8 cells, n = 5; P < 0.01), as shown in Fig. 5C. However, there was still no
indication whatsoever of any inward (i.e., Cl) current in
any of the cells tested (Fig. 5C).
Effect of phenylephrine and thromboxane mimetic on membrane
currents.
In general, the adrenergic innervation, through its actions on
-adrenoceptors, represents the primary excitatory neural input for
the bronchial vasculature (25). Thromboxane A2
is also a potent spasmogen in many vascular beds (15). We
therefore tested the effects of the -adrenoceptor agonist
phenylephrine and the thromboxane mimetic U-46619 on membrane currents
using the same protocol described above for caffeine-evoked responses.
4 M) did cause the cells to
contract (data not shown), it did not evoke any inward current during maintained voltage clamp at 60 mV or when a range of voltages was
tested using ramp depolarizations or incrementing step commands (n = 6; data not shown). Also, although adrenergic
agonists cause release of internally sequestered Ca2+ in
these cells (7), we did not observe a transient
augmentation of K+ currents upon application of
phenylephrine during step commands (Fig.
6A) or ramp depolarizations.
To the contrary, we noted a delayed but prolonged suppression of
K+ currents: for example, Fig. 6A shows the
magnitude of K+ currents evoked in one cell using
depolarizing step commands to +10 mV before and after 2 min of exposure
to phenylephrine (104 M). On average, K+
currents were suppressed to 65 ± 13% of control by phenylephrine when bath temperature was 37°C (n = 4); at room
temperature, however, phenylephrine had very little effect on the
currents, reducing them to only 94 ± 8% (n = 4).
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6 M) also did not evoke any inward current
whatsoever in any cells tested (e.g., Fig.
7A) but did cause a marked enhancement of K+ currents in many but not all of the cells
(5 of 11 cells studied, lasting 10-20 s), followed by a marked
suppression of the same (e.g., Fig. 7, A and B).
On average, K+ currents were reduced to 63 ± 11%
(n = 4); this electrophysiological response was
accompanied by contraction of the cells (data not shown). We did not
compare the effect of temperature on these responses to U-46619.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The bronchial circulation plays an important role in many aspects of airway physiology and pathophysiology. Thus a thorough understanding of the mechanisms underlying excitation-contraction coupling in this vascular bed would be highly clinically valuable. In this study, we provide the first electrophysiological description of bronchial arterial smooth muscle cells.
K+ currents. We found the K+ current evoked by depolarizing voltage commands in the bronchial artery to be predominantly Ca2+ dependent in nature, since it was 1) markedly and reversibly inhibited by TEA or charybdotoxin but not by 4-aminopyridine; 2) reduced substantially by interfering with Ca2+ influx using nifedipine or by removing external Ca2+ but increased by raising external Ca2+; and 3) enhanced by releasing internally sequestered Ca2+ using caffeine. Voltage-dependent K+ current, on the other hand, appears to make little or no contribution, since 4-aminopyridine had very little effect on the depolarization-evoked currents. In general, Ca2+-dependent K+ currents play an important role in the regulation of many vascular smooth muscles, as discussed in more detail below (13, 18, 19).
Ca2+ currents.
The Ca2+ currents that we recorded in these cells exhibited
many characteristics of "L-type" current, including: 1)
threshold and peak activation at approximately 30 and +20 mV,
respectively; 2) half-maximal inactivation at approximately
25 mV; 3) for inactivation of ~200 ms; 4)
absence of slowly decaying tail currents upon repolarization; and
5) sensitivity to dihydropyridines. Inactivation of these
currents was incomplete, leaving substantial "window current" at
all voltages more positive than 30 mV. This has tremendous physiological importance, since it allows for sustained influx of
Ca2+ during agonist stimulation, which leads to membrane
depolarization. Activation of these Ca2+ currents is
sufficient to evoke contraction, as indicated by the substantial
contractions that we have previously described in intact tissues
exposed to KCl (7).
Cl currents.
Although many vascular smooth muscle cells exhibit
Ca2+-dependent Cl currents spontaneously
and/or when internal [Ca2+]i is elevated by
various stimuli (14, 18, 23), some appear not to
(18). Interestingly, we found no evidence for inward current of any kind in these bronchial arterial smooth muscle cells,
neither spontaneously nor in response to voltage-dependent Ca2+ influx (Fig. 4) or release of internally sequestered
Ca2+ induced by caffeine (Fig. 5), phenylephrine (Fig. 6),
or U-46619 (Fig. 7), even though these stimuli are sufficient to cause
cell shortening and substantial augmentation of K+ current
(except for phenylephrine). Thus we conclude that these tissues do not
express functional Cl channels.
Spasmogen-evoked changes in membrane currents.
In most arterial preparations, agonist-evoked contractions
involve activation of inward Cl (14) and/or
nonselective cation currents (11), leading to membrane
depolarization and subsequent opening of voltage-dependent Ca2+ channels such as the ones described in this tissue. It
is for this reason that Ca2+ channel blockers are so
effective in the treatment of hypertension.
50 mV, as indicated by the current-voltage relationships in Fig. 2.
It is clear, then, that there is a physiologically relevant
K+ conductance active at rest, since only this type of
conductance can hyperpolarize the membrane to this degree; the
equilibrium potentials for all other ions are much more positive than
this (those for Cl and Mg2+ are both 
0 mV,
whereas those for Na+ and Ca2+ are both very
positive). As such, any decrease in the membrane permeability to
K+ will lead to depolarization; in preliminary experiments,
we have found that TEA (5 mM) does evoke substantial contraction in
intact tissues (data not shown). In fact, we did observe substantial suppression of outward K+ current after application of
either phenylephrine or U-46619 (although the latter often briefly
enhanced the K+ current). This suppression lasted several
minutes, long after application of the agonists had ended. Moreover,
adrenergic suppression was essentially abolished at room temperature,
whereas the effect of U-46619 was not; this parallels our previous
finding that adrenergic contractions were essentially abolished by
cooling to room temperature, whereas those evoked by U-46619 were
hardly affected (7). The mechanism underlying this
suppression was not investigated in the present study. However, the
inability of caffeine to suppress K+ currents suggests that
this is not related to changes in Ca2+ concentration (since
caffeine, phenylephrine, and U-46619 all release internal
Ca2+). Instead, it likely involves G proteins (which are
not normally activated by caffeine); these may act directly on the
channels or stimulate downstream events such as activation of
phospholipases and various kinases (20). The effects of
caffeine on membrane current and mechanical activity are not secondary
to inhibition of phosphodiesterase activity, since they were very
transient, resolving to baseline within 20 s after application of
caffeine; this time course mirrors that of caffeine-induced release of
internally sequestered Ca2+.
Thus it appears that excitation-contraction coupling in bronchial
smooth muscle involves membrane depolarization (via suppression of
outward current) with voltage-dependent Ca2+-influx and
nonelectromechanical coupling mechanisms (15). The latter
mechanism may be more important than the former,
particularly at lower temperatures (which are also
physiologically relevant given the cooling of the airway during
accelerated ventilation), since we have previously shown that
excitatory mechanical responses in this tissue involve increased
Ca2+ sensitivity of the contractile apparatus much more
than elevation of [Ca2+]i per se
(7).
In conclusion, canine bronchial artery smooth muscle cells exhibit
Ca2+-dependent K+- and voltage-dependent
(L-type) Ca2+ currents, with little or no evidence of
voltage-dependent "delayed-rectifier" K+ currents or
Cl currents. The thromboxane mimetic U-46619 caused a
transient increase of outward K+ currents, followed by
marked suppression of the same that lasted several minutes. Adrenergic
stimulation only produced the sustained suppression of K+
currents (not their enhancement), and only at a physiological temperature. Neither agonist activates inward (i.e., Cl)
current at all in this tissue. These electrophysiological data explain
the mechanical effects produced by these agonists.
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ACKNOWLEDGEMENTS |
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These studies were supported by operating funds from the Canadian Institutes of Health Research and a Scientist Award from the Medical Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. J. Janssen, Dept. of Medicine, McMaster Univ., 50 Charlton Ave. E., Hamilton, Ontario, Canada L8N 4A6 (E-mail: janssenl{at}mcmaster.ca).
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. Section 1734 solely to indicate this fact.
First published January 11, 2002;10.1152/ajplung.00421.2001
Received 30 October 2001; accepted in final form 10 January 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) and inactivation
(
) in one cell reveals incomplete voltage-dependent
inactivation and substantial "window current" at voltages more
positive than 
