© 1996 American Heart Association, Inc.
Articles |
Distribution and Physiological Roles of ATP-Sensitive K+ Channels in the Vertebrobasilar System of the Rabbit
From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Correspondence to Tetsuhiko Nagao, MD, PhD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Fukuoka 812, Japan.
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Abstract |
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Abstract The effect of an opener (levcromakalim) and a blocker (glibenclamide) of ATP-sensitive K+ (KATP) channels was investigated in the vertebrobasilar system of the rabbit. Arterial tension and membrane potential were measured by the isometric tension recording method and the microelectrode technique, respectively. Glibenclamide (10-6 mol/L) depolarized the membrane and potentiated the contraction to histamine in vertebral arteries. The sensitivity to the relaxant effects of levcromakalim was in the following descending order: vertebral>proximal basilar>distal basilar>superior cerebellar arteries. Vertebral arteries were
50
times more sensitive to levcromakalim than were superior cerebellar
arteries. The relaxation to levcromakalim was abolished by
glibenclamide (10-6 mol/L). Glibenclamide
attenuated vasorelaxation to adenosine in proximal
arteries (vertebral and proximal basilar) but not in superior
cerebellar arteries. Levcromakalim
(7x10-8 mol/L) and adenosine
(10-5 mol/L) induced
glibenclamide-sensitive membrane
hyperpolarization in vertebral arteries but not in
distal basilar arteries. These results suggest that KATP
channels contribute to the determination of resting membrane potential
and resting tone in vertebral arteries. Furthermore, there is a marked
heterogeneity in the sensitivity to an opener of
KATP channels, and the heterogeneity has a
functional link to the mechanism underlying vasorelaxation to
adenosine in the vertebrobasilar system of the rabbit.
Key Words: electrophysiology • regional difference • hyperpolarization • levcromakalim • glibenclamide
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Introduction |
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The opening of ATP-sensitive K+ (KATP) channels hyperpolarizes the membrane of vascular smooth muscle cells and thereby causes vasorelaxation. The open probability of the channels is regulated by intracellular concentrations of ATP.1 These channels are possibly involved in certain types of vasorelaxation, such as those induced by hypoxia,2 3 endothelium-dependent agonists,4 vasoactive intestinal polypeptide,4 adenosine,2 prostacyclin,5 norepinephrine,6 and calcitonin gene-related peptide.7 8 However, their functional importance and distribution are poorly understood in the cerebral circulation.
The responsiveness to levcromakalim, an opener of KATP channels, is variable among different systemic arteries; the maximal relaxation to levcromakalim was smaller in large conduit arteries (aorta and main pulmonary arteries) than in smaller peripheral arteries (mesenteric, renal, and femoral arteries).9 The results suggest an uneven distribution of KATP channels in the cardiovascular system. The following experiments were designed to examine (1) the role of KATP channels in the determination of vascular resting membrane potential and tone and (2) regional differences in the distribution of KATP channels and their functional roles in the vertebrobasilar system of the rabbit.
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Materials and Methods |
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Thirty-seven male albino rabbits (1.7 to 2.3 kg) were anesthetized with intravenous infusions of pentobarbital (40 mg/kg) and were exsanguinated from the femoral artery. After the brain was removed and intracranial vertebral, basilar, and superior cerebellar arteries were isolated from surrounding connective tissues, the arteries were kept in ice-cold physiological salt solution (mmol/L: Na+ 141, K+ 4.7, Ca2+ 2.5, Mg2+ 1.2, Cl- 126.9, H2PO4- 1.2, HCO3- 25, and glucose 11 [control solution]). The control solution was aerated with 93% O2/7% CO2. The vertebral, basilar, and superior cerebellar artery had inner diameters of approximately 300 to 500 µm, 400 to 500 µm, and 250 to 300 µm, respectively. The diameter of stainless steel stirrups put through the lumen for support was 80 µm for vertebral, 100 µm for basilar, and 50 µm for superior cerebellar arteries. In some rings, endothelial cells were removed by rubbing the intimal surface with a stainless steel rod. The successful removal of the endothelium was confirmed by the absence of acetylcholine-induced relaxations. All experiments were performed in tissues with an intact endothelium unless otherwise stated.
Organ Chamber Study
The arteries were cut into rings (3
to 5 mm in length) and
were suspended between two stainless steel stirrups in an organ chamber
(5-mL volume). After 90 minutes of incubation, the arteries were
stretched to the point at which they produced maximal contractile
responses in a stepwise manner (0.23±0.02, 0.25±0.02,
0.30±0.04,
and 0.15±0.02 g for vertebral, proximal basilar, distal basilar, and
superior cerebellar arteries, respectively; determined in preliminary
experiments with histamine [10-5
mol/L]). Another 30 minutes of incubation was allowed before
experimental procedures were started. At the end of each experiment,
the arteries were fully relaxed to their baseline tension with a
supramaximal concentration of papaverine
(10-4 mol/L).
In some vertebral arteries, glibenclamide (10-6 mol/L) was applied before and after histamine (3x10-6 to 3x10-5 mol/L) under 0.1 g of passive tension in order to examine the effect of KATP channels on the resting tone and contractile responses to histamine.
We used histamine to induce contractions of vertebral arteries of the rabbit, since histamine is one of the most potent contractile agents of these arteries.
Electrophysiological Study
Ring segments of vertebral
arteries were suspended between a
pair of stainless steel stirrups, one of which was anchored to the
bottom of an organ chamber designed for membrane potential measurements
(2-mL volume) and the other connected to a manipulator. Thus, a desired
level of stretch was given to the rings by using the manipulator where
necessary. In other experiments, a ring segment of vertebral and
basilar arteries was pinned down on the bottom of an organ chamber
(2-mL volume) with the adventitial side facing upward. The arteries
were superfused with warm (37°C) control solution (3 mL/min) for 90
minutes before experimental procedures were started. The membrane
potential of arterial smooth muscle cells was measured with
glass microelectrodes filled with 3 mol/L KCl solution (tip resistance,
40 to 80 M
). Microelectrodes were held by means of a
micromanipulator (Narishige). The electrical signal was recorded
from the adventitial side of the arteries and was amplified by a
recording amplifier (Nihon Kohden MEZ-7200). The membrane
potential was monitored on an oscilloscope (Nihon Kohden VC-11) and was
recorded on a pen recorder (Nihon Kohden RTG-4002). The
following criteria were used to assess the validity of a successful
impalement: (1) a sudden negative shift in voltage, followed by (2) a
stable negative voltage for >1 minute, and (3) an instantaneous return
to the previous voltage level on dislodgment of the
microelectrode.10
Drugs
The following drugs were used in the experiments:
adenosine, glibenclamide, histamine hydrochloride,
serotonin, papaverine (Sigma Chemical Co), levcromakalim
(SmithKline Beecham), and pinacidil (Shionogi). Glibenclamide and
levcromakalim were dissolved in dimethyl sulfoxide (final bath
concentration, <0.1% [vol]) and ethanol (<0.01%
[vol]),
respectively. In experiments in which the effect of glibenclamide was
tested, control experiments without glibenclamide were performed in the
presence of dimethyl sulfoxide (0.1% [vol]) as a vehicle.
Statistics
The data are expressed as mean±SEM; n
represents the
number of animals studied. Statistical significance was tested with
paired Student's t test or ANOVA followed by
Scheffé's test. Values of P<.05 were regarded as
statistically significant.
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Results |
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Organ Chamber Studies
Histamine induced contractions of the proximal and distal basilar and superior cerebellar arteries of the rabbit. In preliminary experiments, histamine at 3x10-6 mol/L produced a 70% contraction compared with maximal responses except in vertebral arteries. Vertebral arteries displayed a more variable response to histamine. Accordingly, the concentration of histamine to induce contraction was determined in each ring to give
70% of the
maximal contraction (3x10-6 to
2x10-5 mol/L).
The effects of glibenclamide on
the mechanical activities were
examined. Although glibenclamide (10-6
mol/L) itself had no effect on the basal tone, it potentiated the
contractions induced by histamine
(3x10-6 to
3x10-5 mol/L) in slightly stretched
vertebral arteries (0.1 g of passive tension) when applied before (Fig
1a
and 1c) and after (Fig 1b)
histamine. Such a
potentiation of histamine-induced contraction was also observed in
tissues denuded of the endothelium. Glibenclamide
(10-6 mol/L) potentiated contractions to
serotonin in a similar fashion (data not shown).
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Levcromakalim
(10-8 to
10-6 mol/L) induced
concentration-dependent relaxations of vertebral, proximal basilar,
distal basilar, and superior cerebellar arteries (Fig 2). The
responses to levcromakalim were determined
against equivalent contractile responses to histamine. The sensitivity
of these arteries to levcromakalim was in the following descending
order: vertebral>proximal basilar>distal basilar>superior
cerebellar arteries. Vertebral arteries were 50 times more sensitive
to levcromakalim than were superior cerebellar arteries. In distal
basilar and vertebral arteries, levcromakalim induced comparable
relaxation in tissues with and without the endothelium
(data not shown). The relaxations induced by levcromakalim were
abolished by glibenclamide (10-6 mol/L)
in all arteries examined (n=4 or 5, data not shown).
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To further
confirm the above-mentioned results, the effect of
another opener of KATP channels, pinacidil, was examined in
four arteries. Pinacidil, at a submaximal concentration
(10-7 mol/L), induced potent relaxation
in vertebral and proximal basilar arteries contracted with histamine
(Table). By contrast, the same concentration of
pinacidil was less effective in relaxing distal basilar arteries.
Superior cerebellar arteries were most resistant to pinacidil
(10-7 mol/L). The sensitivity of the
examined arteries to pinacidil was in the same order as that to
levcromakalim (Table).
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The possible link between
adenosine-induced relaxation and
KATP channels was investigated in proximal arteries
(vertebral or proximal basilar arteries) and superior cerebellar
arteries in the following experiments. Adenosine
(10-7 to
10-5 mol/L) relaxed both proximal
arteries and superior cerebellar arteries in a
concentration-dependent manner (Fig 3). Proximal
arteries were more sensitive and responsive to adenosine than
were superior cerebellar arteries. The relaxation induced by
adenosine was significantly inhibited by glibenclamide
(10-6 mol/L) in proximal arteries but not
in superior cerebellar arteries (Fig 3).
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Electrophysiological Studies
The arterial smooth muscle cells
of unstretched rabbit
vertebral arteries had a resting membrane potential of -72±0.5
mV (33 impalements [n=11]) and were electrically quiescent.
Glibenclamide (10-6 mol/L) depolarized
the membrane by 23 mV (-49±0.7 mV and 21 impalements
[n=7],
P<.05 versus control; Fig 4), whereas
dimethyl sulfoxide (0.1% [vol]) itself did not change the resting
membrane potential (-70±0.6 mV and 33 impalements
[n=11] and
-70±0.9 mV and 39 impalements [n=13] in the
absence and
presence of dimethyl sulfoxide, respectively). Although histamine
(3x10-6 mol/L) had no measurable effect
on the membrane potential of unstretched arteries, it significantly
depolarized the membrane in the presence of glibenclamide
(10-6 mol/L, Fig 4).
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In relation to the
myogenic control of arterial tone, the
effect of stretch on membrane potential was examined. When the arteries
were mechanically stretched 1.2 times longer than their unstretched
original length (=circumferential length/2), the resting membrane
potential decreased by 7 mV (-65±0.7 mV and 24 impalements
[n=8], P<.05; Fig 5). Histamine
(3x10-6 mol/L) significantly depolarized
the membrane in stretched but not in unstretched arteries (Fig
5).
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Since unstretched vertebral arteries were not depolarized by histamine (3x10-6 mol/L), these arteries were stretched 1.2 times longer than their original length in the following experiments. One arterial ring did not depolarize upon stretching and was not responsive to histamine (3x10-6 mol/L). We excluded this unresponsive artery from the study. Thus, the membrane potential of vertebral arteries was measured in stretched rings, whereas that of distal basilar arteries was recorded under conventional unstretched conditions unless otherwise stated.
In vertebral arteries, histamine
(3x10-6
mol/L) depolarized the membrane by 15 mV (15 impalements
[n=5],
P<.05; Fig 6a). Levcromakalim
(7x10-8 mol/L) hyperpolarized the
membrane in the continuous presence of histamine (15 impalements
[n=5], P<.05; Fig 6a).
Glibenclamide
(10-6 mol/L), when applied to stretched
vertebral arteries, significantly depolarized the membrane by 10 mV
(15 impalements [n=5]; Fig 6a and
6b). As a consequence, the membrane
potential in the presence of glibenclamide
(10-6 mol/L) was -52 mV.
Histamine (3x10-6 mol/L) further
depolarized the membrane to -40 mV in the presence of
glibenclamide (10-6 mol/L) in stretched
vertebral arteries (15 impalements [n=5], P<.05;
Fig 6b).
Levcromakalim failed to hyperpolarize the membrane in the combined
presence of glibenclamide and histamine in vertebral arteries (Fig
6b).
By contrast, in distal basilar arteries, histamine
(3x10-6 mol/L) depolarized the membrane
to a similar level (-40 mV and 15 impalements [n=5],
P<.05), whereas the same concentration of levcromakalim was
without effects on the membrane potential (15 impalements
[n=5]; Fig 6c). In a similar manner, adenosine
(10-5 mol/L) induced
glibenclamide-sensitive membrane
hyperpolarizations (P<.05) in vertebral
arteries but not in distal basilar arteries (15 impalements
[n=5];
Fig 7) in the presence of histamine.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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The role of KATP channels in the determination of resting membrane potential of vascular smooth muscle cells is controversial. Glibenclamide (10-6 to 10-5 mol/L) does not depolarize the membrane in carotid arteries of the guinea pig11 and mesenteric arteries of the rat.12 By contrast, glibenclamide depolarizes the membrane by
5 mV in mesenteric
arteries13 and distal coronary
arteries14 of the rabbit. However, it is not clear to what
extent such a relatively minor change in resting membrane potential
affects basal arterial tone. The present experiments
demonstrated considerable depolarization by glibenclamide in vertebral
arteries of the rabbit. The results are consistent with the
view that KATP channels are open under resting conditions
in these arteries of the rabbit. This is in agreement with a previous
observation in guinea pigs, that glibenclamide depolarizes by 24 mV the
membrane of a population of coronary arterioles that have large
negative resting membrane potentials.15 Although these
observations do not necessarily mean that KATP channels are
open in vivo, the decrease in flow induced by glibenclamide in some
vascular beds supports the basal activation of the channels in
vivo.16 17 18
In general, membrane depolarization activates
voltage-dependent (L-type) Ca2+ channels and leads to
contraction of vascular smooth muscle. Although glibenclamide
(10-6 mol/L) depolarized the membrane by
20 mV, the compound did not increase the basal tone of the vertebral
artery. This rather unexpected dissociation between the electrical and
mechanical responses is probably explained by the fact that
glibenclamide did not depolarize the membrane beyond -50 mV.
Since a few voltage-dependent L-type Ca2+ channels are
activated around this membrane potential level,19
even 20 mV of depolarization in amplitude does not induce sufficient
Ca2+ influx to induce measurable contraction. In support of
this view, the threshold membrane potential to elicit contraction was
from -38 to -32 mV in coronary arteries of the
rabbit.20 In contrast, histamine-induced contraction
was potentiated by glibenclamide. This effect was achieved, at least in
part, by the unmasking of membrane depolarization to histamine. It must
be pointed out here that the potentiation of contractile responses is
not unique to glibenclamide and that any stimulus that depolarizes
smooth muscle tends to augment contractions.
Another interesting point drawn from the present results is that active stretch induced depolarization in vertebral arteries. Furthermore, histamine (3x10-6 mol/L) depolarized the membrane only in stretched but not in unstretched arteries. These observations support the view that KATP channels may be involved in the pressure-dependent myogenic autoregulation of cerebral arteries (the property of the artery to contract in response to pressurization). Under low perfusion pressure (less stretched conditions), the arteries would be in a dilatory state due to the vasodepressant effect of KATP channels. In contrast, the arteries would be more prone to contract under high perfusion pressure (more stretched conditions), since the vasodepressant effect of KATP channels is counteracted by arterial stretching. Indeed, glibenclamide inhibits coronary autoregulation in anesthetized dogs.21 22 However, this putative mechanism for myogenic autoregulation may not be definitive, since myogenic autoregulation is a rather common phenomenon in cerebral arteries,23 24 25 whereas the functional distribution of KATP channels is heterogeneous in cerebral arteries, as shown in this and other studies.25 26
The mechanism(s) underlying the depolarization and the subsequent unmasking of histamine-induced depolarization by stretch is not clear from the present experiments. However, one possible explanation, although speculative, would be that stretch turns off KATP channels, which leads not only to the depolarization but also to the increase in electrical resistance of the membrane. The increase in membrane resistance would result in larger depolarization, assuming that histamine-induced depolarizing currents are constant. Alternatively, the membrane depolarization itself may increase histamine-induced depolarizing currents.
The vasodilatory effect of cromakalim or levcromakalim (L-cromakalim) is mediated by the opening of KATP channels and is heterogeneous along cerebral arteries; cromakalim relaxes basilar26 and superior cerebellar25 arteries but not posterior cerebral arteries26 of the rat. The present study provides further evidence for a marked difference in the sensitivity to levcromakalim and pinacidil in cerebral arteries of the rabbit. The different sensitivity to openers of KATP channels presumably results from the difference in density of KATP channels in examined arteries. The fact that the extent of stretch is not the same between vertebral and distal basilar arteries in some electrophysiological studies may limit the validity of the information about membrane potential. However, such an inconsistency could not be avoided since it was necessary to set comparable membrane potentials just before the application of levcromakalim and adenosine in the two kinds of arteries.
Although adenosine is regarded as one of the candidates for physiological openers of KATP channels,27 28 the conclusion is largely based on the in vivo effects of glibenclamide. Some electrophysiological studies have demonstrated membrane hyperpolarization of arterial smooth muscle cells by adenosine,29 30 although the K+ channels activated by adenosine were not well characterized. In the present study, hyperpolarization induced by adenosine was abolished by glibenclamide (10-6 mol/L), which is considered to be a specific blocker of KATP channels at this concentration in vertebral arteries. Daut et al31 also demonstrated glibenclamide-sensitive hyperpolarization to adenosine in coronary arteries of the guinea pig. These results provide direct electrophysiological evidence that adenosine activates glibenclamide-sensitive K+ channels (most likely KATP channels) and induces membrane hyperpolarization. In further support of this notion, adenosine activated glibenclamide-sensitive K+ current in smooth muscle cells from the porcine coronary artery.32 It is believed that the major mechanism underlying adenosine-induced relaxation is the increase in cytosolic cAMP.33 34 35 This concept does not contradict the involvement of hyperpolarization in adenosine-induced relaxation, since it is suggested that cAMP opens KATP channels in vascular smooth muscle cells through the activation of protein kinase A.36
Adenosine induced glibenclamide-sensitive hyperpolarization and relaxation in arteries sensitive to levcromakalim (vertebral and proximal basilar) but not in those insensitive to levcromakalim (distal basilar and superior cerebellar). These results suggest a functional coupling of adenosine-induced relaxation to KATP channels. Another point of interest is that adenosine is a more potent dilator in levcromakalim-sensitive than in levcromakalim-insensitive arteries. The component of relaxation mediated by KATP channels may be important in the determination of the sensitivity and responsiveness of a blood vessel to adenosine. The adenosine-induced relaxation that is resistant to glibenclamide is presumably mediated by cAMP-dependent mechanisms unrelated to hyperpolarization.
In conclusion, KATP channels contribute to the determination of the resting membrane potential and the tone in the cerebral circulation. The present study indicates that they distribute more densely in proximal than in distal arteries of the vertebrobasilar system of the rabbit.
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Acknowledgments |
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Levcromakalim was kindly provided by SmithKline Beecham Pharmaceuticals. The authors are grateful to Dr T.C. Hamilton, SmithKline Beecham Pharmaceuticals, for valuable comments on the manuscript.
Received October 18, 1994; accepted October 11, 1995.
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T. Horiuchi, H. H. Dietrich, S. Tsugane, R. G. Dacey Jr, C. G. Sobey, and F. M. Faraci Role of Potassium Channels in Regulation of Brain Arteriolar Tone : Comparison of Cerebrum Versus Brain Stem Editorial Comment: Comparison of Cerebrum Versus Brain Stem Stroke, January 1, 2001; 32(1): 218 - 224. [Abstract] [Full Text] [PDF]
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 N. I. Gokina and J. A. Bevan Histamine-induced depolarization: ionic mechanisms and role in sustained contraction of rabbit cerebral arteries Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2094 - H2104. [Abstract] [Full Text] [PDF]
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N. I. Gokina and J. A. Bevan Role of intracellular Ca2+ release in histamine-induced depolarization in rabbit middle cerebral artery Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H2105 - H2114. [Abstract] [Full Text] [PDF]
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E. P. Wei, H. A. Kontos, and F. M. Faraci Blockade of ATP-Sensitive Potassium Channels in Cerebral Arterioles Inhibits Vasoconstriction From Hypocapnic Alkalosis in Cats • Editorial Comment Stroke, April 1, 1999; 30(4): 851 - 854. [Abstract] [Full Text] [PDF]
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 F. M. FARACI and D. D. HEISTAD Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels Physiol Rev, January 1, 1998; 78(1): 53 - 97. [Abstract] [Full Text] [PDF]
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 H. Yokoshiki, M. Sunagawa, T. Seki, and N. Sperelakis ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C25 - C37. [Abstract] [Full Text] [PDF]
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H. Kinoshita, Z. S. Katusic, and E. P. Wei Role of Potassium Channels in Relaxations of Isolated Canine Basilar Arteries to Acidosis Stroke, February 1, 1997; 28(2): 433 - 438. [Abstract] [Full Text]
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K. Toyoda, K. Fujii, Y. Takata, S. Ibayashi, T. Kitazono, T. Nagao, M. Fujikawa, M. Fujishima, and F. M. Faraci Age-Related Changes in Response of Brain Stem Vessels to Opening of ATP-Sensitive Potassium Channels Stroke, January 1, 1997; 28(1): 171 - 175. [Abstract] [Full Text]
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