1 Department of Surgery, University of Colorado, Denver, Colorado 80262; and 2 Department of Surgery, Northwestern University, Chicago, Illinois 60611
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ABSTRACT |
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ATP-sensitive
K+
(KATP) channels
have been implicated in the regulation of vasomotor tone in aortic,
mesenteric, and pulmonary vascular smooth muscle. Several investigators
have described an association between
KATP channels and isoproterenol
(Iso)-stimulated relaxation responses. To study the
relationship between receptor-dependent pulmonary vasorelaxation and
KATP channels, we examined the
response to agonists that generate adenosine 3',5'-cyclic
monophosphate at two distinct levels of the signal transduction pathway
after inhibition or activation of
KATP channels in isolated rat
pulmonary artery rings. Cumulative concentration responses to
-adrenergic receptor stimulation (Iso), purinergic receptor
stimulation [adenosine (Ado)], and direct stimulation of
adenylate cyclase [forskolin (FSK)] were studied with and
without concurrent inhibition of KATP channels (glibenclamide or
tolbutamide). In addition, the effect of direct
KATP channel activation
(cromakalim) on the response to
-adrenergic and purinergic receptor
stimulation was determined. Last, we investigated the influence of
KATP channel inhibition on
endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation linked to guanosine 3',5'-cyclic
monophosphate production. KATP
channel inhibition impaired the response to Iso and Ado. Activation of
KATP channels caused a leftward
shift in the dose responses of Iso and Ado, with a significant decrease in the 50% effective concentration for each agent.
KATP channel inhibition did not
impair the pulmonary arterial vasorelaxation response to FSK,
acetylcholine, or sodium nitroprusside.
KATP channels appear to contribute
to
-adrenergic and purinergic receptor-stimulated vasorelaxation in
rat pulmonary arteries.
glibenclamide; cromakalim; adenosine 3',5'-cyclic monophosphate; guanosine 3',5'-cyclic monophosphate; isoproterenol; adenosine 5'-triphosphate-sensitive potassium channel
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INTRODUCTION |
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PULMONARY VASOMOTOR TONE reflects the balance of the
mechanisms of pulmonary vasorelaxation and vasoconstriction.
-Adrenergic and purinergic receptor stimulation results in
activation of pulmonary vascular smooth muscle adenylate cyclase, an
increase in adenosine 3',5'-cyclic monophosphate (cAMP),
and, hence, vasorelaxation (9, 16). Recently, ATP-sensitive
K+
(KATP) channels have been
identified as mediators of systemic (22) and pulmonary (5) vasomotor
tone. Several investigators have linked
1-adrenoreceptor-stimulated
relaxation responses to KATP
channel activation in dog coronaries (12, 19), the hamster cheek pouch
microcirculation (11), the rat arterial mesenteric bed (23), and the
rabbit pulmonary artery (4). There has been comparable interest and
success linking purinergic receptor-induced vasodilation to
KATP channels (1, 11, 15, 18, 23).
It is currently unknown if KATP
channels influence receptor-dependent vasorelaxation mechanisms in the
pulmonary circulation that are associated with the generation of cAMP.
We hypothesized that 1) inhibition
of KATP channels would impair
-adrenergic and purinergic receptor-mediated pulmonary
vasorelaxation and 2) activation of
KATP channels would enhance
receptor-dependent pulmonary vasorelaxation responses that are linked
to the production of cAMP. To study this hypothesis, we inhibited
KATP channels (glibenclamide or
tolbutamide) in isolated rat pulmonary artery rings and investigated
vascular relaxation responses to receptor-dependent [isoproterenol (Iso) and adenosine (Ado)] and
receptor-independent [forskolin (FSK)] agonists that are
associated with the generation of cAMP. We also examined the influence
of KATP channel activation (cromakalim) on pulmonary vasorelaxation responses to
-adrenoreceptor and purinoceptor stimulation. Last, we observed the
influence of KATP channel
inhibition on endothelium-dependent and -independent guanosine
3',5'-cyclic monophosphate (cGMP)-mediated mechanisms of
pulmonary vasorelaxation.
The results of this study suggest that the response to -adrenergic
and purinergic receptor stimulation is mediated, in part, by
KATP channels.
KATP channels contribute to
receptor-dependent vasorelaxation mechanisms that are linked to the
generation of cAMP but not to receptor-independent cAMP-mediated or
cGMP-mediated vasorelaxation responses.
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METHODS |
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Animal housing and acclimation. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals, published by National Institutes of Health. Male Sprague-Dawley rats (Sasco, Omaha, NE), weighing 300-350 g, were quarantined in quiet, humidified, light-cycled rooms for 2-3 wk before use.
Experimental protocol.
Pulmonary vasomotor control mechanisms were studied in isolated
pulmonary arterial rings (25).
KATP channels were inhibited by
incubating isolated pulmonary arterial rings with 1 mM glibenclamide or
tolbutamide for 30 min before assessment of cumulative dose responses
to vasodilatory agonists. Cromakalim was used to activate KATP channels in the isolated
rings. We incubated rings with
107 M cromakalim after
phenylephrine (PE) preconstriction and observed cumulative
concentration responses to Iso and Ado. To determine if the effect of
KATP channel inhibition was
nonselective to mechanisms of pulmonary vascular smooth muscle
relaxation, we also examined the influence of glibenclamide and
tolbutamide on the vasorelaxation response to direct activation of
adenylate cyclase with FSK and the influence of
KATP channel inhibition on two
cGMP-mediated mechanisms of pulmonary vasorelaxation with the
endothelium-dependent agonist acetylcholine (ACh) and the
endothelium-independent agonist sodium nitroprusside (SNP).
Isolated pulmonary arterial ring preparation. Rats were anesthetized with 50 mg/kg ip pentobarbital sodium. Median sternotomy was performed, and 500 USP heparin sulfate was injected into the right ventricular outflow tract. After removal of the heart and lungs en bloc, the main pulmonary artery with the right and left branches was dissected out and was placed in Earle's balanced salt solution (EBSS) at 4°C. Under dissecting microscope magnification, the surrounding tissue was excised from the pulmonary arteries. The right and left main branch pulmonary arteries were cut into rings 3- to 4-mm wide; two rings were obtained from each rat. Care was taken during this process to avoid endothelial injury. EBSS is a standard physiological salt solution and contains (in mM) 1.80 CaCl2, 0.83 MgSO4 (anhydrous), 5.36 KCl, 116.34 NaCl, 0.40 NaPO4 (dibasic), 5.50 D-glucose, 19.04 NaHCO3, and 0.03 phenol red sodium (as pH indicator).
The pulmonary artery rings were placed on 11-mil steel wires and were suspended in individual 10-ml organ chambers containing EBSS. The organ chambers were surrounded by water jackets and were continually warmed (37°C). Ring tension was determined by use of a force-displacement transducer (Grass FTO3; Grass Instruments, Quincy, MA) attached to each steel wire apparatus. Force displacement was recorded at 0.67 Hz using a MacLab Data Interface Module (ADI Instruments, Milford, MA) on a Macintosh Quadra 650 computer (Apple Computer, Cupertino, CA). Organ chambers had continuous bubbling gas flow at 40 ml/min of 21% O2, 5% CO2, and 74% N2. This produced a PO2 of 100-110 mmHg and a pH of 7.4.Effect of inhibition of KATP channels on
equilibration, vasomotor tone, and
1-adrenergic-stimulated
pulmonary vasoconstriction.
The optimal resting mechanical tension (passive load) for pulmonary
artery rings of this size was determined to be 750 mg in a prior study
(10). Rings were suspended at 750 mg and were allowed to reach a steady
state for 1 h, during which time the EBSS was changed every 15 min.
Cumulative concentration responses to glibenclamide were observed in
pulmonary artery rings equilibrated at 750 mg of tension and after
preconstriction to 200-400 mg of tension with the
1-adrenergic agonist PE.
Pulmonary vasorelaxation responses to agonists that generate cAMP.
Cumulative concentration-response curves were generated for Iso, Ado,
and FSK. These rings were equilibrated at 750 mg of tension for 1 h,
with exchange of the oxygenated EBSS every 15 min. After equilibration,
the rings were preconstricted between 200 and 400 mg of tension with
PE. Cumulative concentration responses were generated over
109 to
10
6 M (Iso and FSK) and
10
9 to 10
3 M
(Ado). For determination of the cumulative concentration-response curve, the ring was allowed to reach a steady state, usually requiring 2-3 min, before advancing to the next higher concentration. The ring tension remaining in the rings in response to each dose of vasorelaxing agent was expressed in milligrams of PE-induced tension.
Influence of KATP channels on pulmonary vasorelaxation mechanisms associated with the generation of cAMP. Cumulative concentration-response curves were generated for Iso, Ado, and FSK after in vitro incubation of isolated pulmonary artery rings with 1 mM glibenclamide or tolbutamide for 30 min before PE preconstriction. The physiological salt solution was changed before assessment of cumulative concentration-response curves to these receptor-dependent and -independent mechanisms of pulmonary vasorelaxation.
Cumulative concentration-response curves were generated for Iso and Ado after PE-induced preconstriction and in vitro incubation of isolated pulmonary artery rings with 10Influence of KATP channel inhibition on
pulmonary vasorelaxation by cGMP-mediated mechanisms.
Cumulative concentration-response curves were generated over the
concentration range of 109
to 10
6 M (ACh and SNP)
after inhibition of KATP channels
with glibenclamide.
Reagents. All reagents were obtained from Sigma Chemical (St. Louis, MO). Fresh solutions were prepared daily with either deionized water or normal saline as the diluent. Glibenclamide, tolbutamide, and cromakalim were dissolved in dimethyl sulfoxide and were further diluted in ethanol. Final concentrations of solvents were <0.5% and were without pharmacodynamic effect. The concentrations are expressed as final molar concentrations in the organ chambers.
Statistical analysis. Statistical analysis was performed with a MacIntosh Quadra 650 computer and StatView 4.01 software (Brain Power, Calabasas, CA). Data are presented as means ± SE of the number of pulmonary rings studied at each point of data collection. Similarly, the means ± SE were determined for the 50% effective concentration (EC50) for each agonist. Statistical evaluation utilized standard one-way analysis of variance with post hoc Bonferroni-Dunn test. P < 0.05 was accepted as statistically significant.
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RESULTS |
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Effect of KATP channel inhibition on
equilibration vasomotor tone and
1-adrenergic-stimulated
vasoconstriction.
Cumulative concentration responses to
10
9 to
10
5 M glibenclamide on
rings equilibrated at 750 mg of tension and after PE-induced contraction demonstrated no significant vasoactive effect (data not
shown).
Influence of KATP channel inhibition on
-adrenoreceptor- and purinoreceptor-stimulated
pulmonary vasorelaxation.
Inhibition of KATP channels with
glibenclamide or tolbutamide impaired pulmonary
vasorelaxation cumulative concentration responses to
-adrenoreceptor stimulation with Iso. As illustrated in Fig. 1, control pulmonary artery rings were
preconstricted to 293 ± 29 mg of PE-induced tension and were
relaxed to 17 ± 4 mg of tension with
10
6 M Iso. Rings from
glibenclamide-treated rings were preconstricted to 309 ± 17 mg of
tension, and 94 ± 15 mg of PE-induced tension remained in response
to 10
6 M Iso
(P < 0.05 vs. control).
Tolbutamide-treated rings were preconstricted with PE to 305 ± 16 mg of tension, with 108 ± 23 mg of tension remaining in response to
10
6 M Iso. Thus inhibition
of KATP channels impaired the
response to Iso compared with controls.
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Effect of KATP channel activation on
pulmonary vascular smooth muscle.
Cromakalim, an activator of KATP
channels, resulted in a dose-dependent relaxation response in
PE-preconstricted pulmonary artery rings (Fig.
3). After PE preconstriction, the baseline tension of the rings was 277 ± 14 mg. Cromakalim relaxed the
PE-preconstricted rings to 40 ± 9 mg of tension at
105 M.
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KATP channel activation and cumulative
dose responses to receptor-dependent vasorelaxation agonists Iso and
Ado.
Incubation of PE-preconstricted rings with
107 M cromakalim
potentiated the vasorelaxation response to Iso (Fig.
4) and Ado (Fig.
5) as demonstrated by the leftward shift
in the cumulative concentration response and decreased
EC50 with
KATP channel activation. The
EC50 of control rings to a
cumulative concentration response to Iso was 8.5 × 10
8 ± 1.0 × 10
8 M, which decreased to
1.9 × 10
9 ± 9.0 × 10
10 M after
incubation with 10
7 M
cromakalim. A potency shift of greater magnitude was observed in the
cumulative concentration response to Ado in control rings with an
EC50 of 4.3 × 10
4 ± 1.4 × 10
4 M that decreased to 5.5 × 10
8 ± 2.6 × 10
8 M after
10
7 M cromakalim
incubation. Thus activation of
KATP channels potentiates the
pulmonary vascular smooth muscle relaxation response to
receptor-dependent agonists associated with the production of cAMP.
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Effect of inhibition of KATP channels
with a receptor-independent pulmonary vasorelaxation agonist, FSK.
Inhibition of KATP channels with
glibenclamide or tolbutamide did not influence receptor-independent
pulmonary vasorelaxation responses as observed with direct stimulation
of adenylate cyclase with FSK. As illustrated in Fig.
6, control pulmonary artery rings were
preconstricted to 300 ± 14 mg of PE-induced tension and relaxed to
4 ± 3 mg of tension with
106 M FSK.
Glibenclamide-treated rings were preconstricted to 309 ± 14 mg of tension, and 3 ± 1 mg of PE-induced tension remained in response to 10
6 M FSK.
Tolbutamide-treated rings were preconstricted with PE to 307 ± 20 mg of tension, with 5 ± 2 mg of tension
remaining in response to 10
6 M FSK. Thus
the pulmonary cumulative concentration response to FSK was unchanged
with inhibition of KATP channels compared with controls.
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Inhibition of KATP channels on
endothelium-dependent and -independent cGMP-mediated pulmonary
vasorelaxation.
Unlike the observed impairment of vasorelaxation with glibenclamide on
receptor-dependent cAMP-mediated vasorelaxation,
KATP channel inhibition with
glibenclamide did not impair the cumulative concentration responses to
either endothelium-dependent or -independent mechanisms of pulmonary
vasorelaxation that depend on the production of cGMP. As represented in
Fig. 7, pulmonary artery rings from controls were preconstricted to 277 ± 15 mg of PE-induced tension and were relaxed to 11 ± 4 mg of tension with
106 M ACh.
Glibenclamide-treated rings were preconstricted to 288 ± 10 mg of
tension, and 16 ± 7 mg of PE-induced tension remained in response
to 10
6 M ACh
(P > 0.05 vs. control). Thus
inhibition of KATP channels with
glibenclamide did not impair this endothelium-dependent mechanism of
pulmonary vasorelaxation.
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DISCUSSION |
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These findings suggest that KATP
channels contribute to receptor-dependent mechanisms of pulmonary
vasorelaxation that are associated with the production of cAMP.
KATP channel inhibitors glibenclamide and tolbutamide impaired the relaxation responses to Iso
and Ado. Activation of KATP
channels with cromakalim potentiated relaxation responses to Iso and
Ado, as demonstrated by a leftward shift in the cumulative
concentration-response curves and a decreased EC50. The influence of
KATP channels on mechanisms of
pulmonary vasorelaxation appears to be selective. Inhibition of
KATP channels with glibenclamide
or tolbutamide did not impair receptor-independent cAMP-mediated
relaxation responses, nor did these agents impair endothelium-dependent
or endothelium-independent mechanisms of pulmonary vasorelaxation that
require the generation of cGMP. These findings challenge the current
hypothesis that -adrenergic and purinergic vasorelaxation is
entirely cAMP dependent.
Although these results are provocative, inherent limitations of this
study design must be addressed. Large conduit vessels such as main
branch pulmonary arteries may not accurately reflect the pulmonary
resistance vessels such as arterioles. Despite this model limitation,
isolated main branch arterial rings allow precise interrogation of
endothelium-dependent and smooth muscle-dependent mechanisms of
vasomotor function without confounding variables such as formed blood
elements, neuromuscular interactions, and hormonal influences. A
second, but potential, limitation of this study is that membrane
potential data were not concurrently measured. Although direct
measurement of membrane potential was beyond the scope of this
physiological model, measurement of membrane potential in ex vivo
intact vascular preparations has been accomplished with the
KATP channel inhibitors
glibenclamide and tolbutamide as well as with the often-used
KATP channel activator cromakalim (3, 4, 26, 28). These investigations have confirmed the effects of
glibenclamide, tolbutamide, and cromakalim with simultaneous
physiological and membrane potential recordings, suggesting that these
pharmacological tools have specific and reproducible effects on the
KATP channel and membrane
potential in vascular models. A third explanation to the observed
results could reflect an interaction between the sulfonylurea compounds binding at the -adrenergic and purinergic receptors. This appears unlikely, however, because Randall and McCulloch (23) demonstrated that
100 mM glibenclamide did not influence the binding of
[3H]dihydoalprenolol
to rat mesenteric
-adrenoreceptors. A nonselective inhibition of
vasodilation by glibenclamide or tolbutamide may be ruled out as
vasorelaxation responses to FSK, ACh, and SNP were not affected by
these sulfonylurea compounds.
K+ channels inhibited by intracellular ATP concentration ([ATP]i) and opened as [ATP]i decreased were first described in the heart (20). Subsequently, these channels were also found in insulin-secreting cells and skeletal muscle (7). Standen and colleagues (26) initially described these channels in arterial smooth muscle. KATP channels in arterial smooth muscle are essentially Ca2+ (6) and voltage (21) independent, K+ selective, and half-maximally inhibited by [ATP]i in the range of ~30-40 mM in aortic smooth muscle in bilayers and portal vein (14, 21). Clapp and Gurney (5) inhibited whole cell KATP currents with larger concentrations of ATP (~1 mM). ADP activates single KATP channels in portal veins. A key pharmacological feature of KATP channels is their inhibition by antidiabetic sulfonylurea agents such as glibenclamide, tolbutamide, and external Ba2+ (22). A number of antihypertensive drugs appear to act through KATP channel activation. This class of antihypertensive drugs include older clinically used compounds such as minoxidil sulfate and diazoxide as well as newer drugs such as pinacidil, nicorandil, and cromakalim, to name only a few. Vasodilation to these compounds is blocked by glibenclamide (22).
Recent interest has focused on the regulation of vascular tone by
KATP channels, and investigators
have reported that these channels are important modulators of arterial
tone. Clapp and colleagues (4) observed that
KATP channel activation directly vasodilated rabbit pulmonary vascular smooth muscle. Narishige and
co-workers (19) linked
1-adrenoreceptor vasodilation
to KATP channels by blocking
coronary vasorelaxation induced by Iso in dogs. Katsuda and colleagues
(12) demonstrated that activation of
KATP channels selectively
augmented
1-adrenoreceptor-mediated coronary vasodilation. Jackson (11) found that inhibition of KATP channels also inhibited Ado-
and Iso-induced vasorelaxation in hamster microcirculatory beds. In the
isolated rat mesenteric arterial bed, Randall and McCulloch (23)
likewise observed impairment of
-adrenoreceptor-induced
vasodilation by inhibition of KATP channels with glibenclamide. Recent electrophysiological evidence from
cat ventricular myocytes has demonstrated that
-adrenergic receptors
are coupled to the activation of
KATP channels (24). Similar to
-adrenergic receptors, purinergic
A1 receptors have been previously
linked to K+ channels in cardiac
tissue (2). More recently, Ado has been shown to activate
KATP currents in single coronary
artery smooth muscle cells, acting via an
A1 receptor (8). It is plausable to suggest that Ado may open KATP
channels independently of adenylate cyclase through a direct G protein
pathway (8), as has been demonstrated in cardiac myocytes (13). Such
findings, including the results of this study, challenge the
traditional view that
-adrenergic and purinergic receptors
are solely coupled to adenylate cyclase and cAMP formation (27).
The data of the current study suggest that -adrenergic and
purinergic receptors are associated with
KATP channels, and this association appears to be proximal to the level of adenylate cyclase and protein kinase A. One possible mechanism of this interaction may be
that G proteins link the
-adrenergic and purinergic receptors to
adenylate cyclase as well as KATP
channels in pulmonary vascular smooth muscle. Several investigators
have linked KATP channels to
membrane-bound G proteins in pig coronary smooth muscle cells (8) and
rat ventricular myocytes (13). In the present study, FSK vasorelaxant
responses were not impaired by glibenclamide. Jackson (11) observed a
similar response in that KATP
channel blockade did not influence the vasodilator responses to
dibutyryl cAMP. On the other hand, Miyoshi and Nakaya (17) observed
that Iso, FSK, and dibutyryl cAMP activated
KATP channels in an inside-out patch configuration with porcine coronary artery. The experiments of
Miyoshi and Nakaya (17) required smooth muscle cell culture, whereas
both Jackson (11) and the present study examined vascular responses
with intact vascular rings. The findings of Jackson's work as well as
those of the current study suggest that cAMP does not activate
KATP channels. Although the
precise mechanism by which receptors are linked to
KATP channels in vascular smooth muscle remains unclear, it appears to be independent of cAMP in the
hamster cheek pouch microcirculation and the rat pulmonary artery.
Therefore, it is possible that
-adrenergic and purinergic receptor-stimulated vasorelaxation triggers two parallel signal transduction mechanisms: 1) the
primary signal through adenylate cyclase and protein kinase A and
2) a secondary signal through the
KATP channel.
The findings of the current study support the hypothesis that the
KATP channel contributes to
-adrenergic and purinergic receptor-stimulated vasorelaxation
mechanisms that also produce cAMP in rat pulmonary arteries. This role
of the KATP channel seems to be
limited to receptor-dependent cAMP-generating mechanisms of pulmonary
vasorelaxation, independent of FSK-stimulated and cGMP-mediated
vasorelaxation responses. These findings contribute to the growing body
of evidence that
-adrenergic and purinergic receptors are linked to
mechanisms of pulmonary vasorelaxation other than adenylate cyclase and
cAMP. The observation that these endogenous receptors are linked to
clinically accessible KATP channels creates a potential therapeutic opportunity to modulate vasomotor tone in perturbed states such as pulmonary hypertension.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant R29 HL-49398 (to D. A. Fullerton) and an American College of Surgery Faculty Research Grant (to R. C. McIntyre, Jr.).
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FOOTNOTES |
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Address for reprint requests: R. C. McIntyre, Jr., Dept. of Surgery, 4200 East Ninth Ave., Box C-313, Univ. of Colorado Health Sciences Center, Denver, CO 80262.
Received 14 March 1997; accepted in final form 24 July 1997.
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