© 1995 American Heart Association, Inc.
Articles |
Relaxation of the Carotid Artery to Hypoxia Is Impaired in Watanabe Heritable Hyperlipidemic Rabbits
From the Departments of Internal Medicine (H.T., F.M.F., T.K., D.D.H.) and Pharmacology (F.M.F., D.D.H.), Center on Aging and Cardiovascular Center, University of Iowa College of Medicine, and the Veterans Administration Medical Center, Iowa City.
Correspondence to Donald D. Heistad, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Abstract We tested the hypothesis that relaxation of the carotid artery during hypoxia is mediated by activation of glibenclamide-sensitive potassium channels and that this response is impaired in hyperlipidemic rabbits. In New Zealand White rabbits (plasma cholesterol, 69±12 mg/dL, mean±SEM) and Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 677±99 mg/dL), tension of the carotid artery was measured in an organ bath under control conditions and during two levels of hypoxia. In normal rabbits, mild hypoxia produced 21±2% relaxation in arteries precontracted with phenylephrine. Removal of endothelium or the nitric oxide synthase inhibitor NG-nitro-L-arginine (10-4 mol/L) almost abolished relaxation in response to mild hypoxia in normal rabbits. Glibenclamide (10-6 mol/L), an inhibitor of ATP-sensitive potassium channels, attenuated relaxation during mild hypoxia by almost 60%. In WHHL rabbits mild hypoxia relaxed the carotid artery by only 9±4% (P<.05 versus normal rabbits). Severe hypoxia produced greater relaxation of the carotid artery in normal than in WHHL rabbits (85±5% versus 52±8%, respectively, P<.05). Glibenclamide but not endothelial denudation or NG-nitro-L-arginine attenuated relaxation during severe hypoxia in normal and WHHL rabbits. Relaxation of the carotid artery to sodium nitroprusside was similar in normal and WHHL rabbits. These findings suggest that relaxation of the carotid artery in response to mild and severe hypoxia is impaired in WHHL rabbits and is mediated, in large part, by activation of glibenclamide-sensitive potassium channels. Relaxation of the carotid artery in response to mild hypoxia is mediated primarily by endothelium-derived relaxing factor in normal rabbits and impairment of response to mild hypoxia in WHHL is probably secondary to endothelial dysfunction.
Key Words: glibenclamide • ATP-sensitive potassium channels • iberiotoxin • endothelium-derived relaxing factor • NG-nitro-L-arginine
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Introduction |
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Hypoxia produces relaxation of blood vessels in vivo and in vitro.1 2 3 4 Some findings suggest that EDRF contributes to the relaxation of blood vessels during hypoxia,5 6 others that relaxation of blood vessels in response to hypoxia is mediated by activation of potassium channels.3 7 8
Endothelium-dependent relaxation is impaired during hypercholesterolemia and atherosclerosis,9 10 11 12 and relaxation of arteries in response to activation of potassium channels may also be impaired by atherosclerosis.13 If hypoxia-induced vasorelaxation is mediated by either release of EDRF or activation of potassium channels, we anticipated that vasorelaxation in response to hypoxia would be impaired during atherosclerosis. Thus, the goal of the present study was to examine mechanisms of vascular relaxation to hypoxia in normal and WHHL rabbits and to determine whether relaxation of the carotid artery in response to hypoxia is impaired in WHHL rabbits.
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Methods |
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Animal Preparation
NZW and homozygous WHHL rabbits of either sex were used in this study. WHHL rabbits (8 to 24 months old) in our colony have a plasma cholesterol of 400 to 500 mg/dL and atherosclerotic lesions in the thoracic aorta, branch points in the carotid artery, and carotid sinus but not in the common carotid artery. To increase the severity of atherosclerosis, WHHL rabbits received a diet intermittently supplemented with 0.25% cholesterol (8 weeks of atherogenic diet followed by 8 weeks of normal diet). The atherogenic diet was prepared by mixing 1 kg normal rabbit chow (Teklab Highfiber, Harlan) with 25 g cholesterol dissolved in 1 L warm corn oil. Control rabbits received the normal rabbit chow. After the dietary interventions the plasma cholesterol level was 677±99 mg/dL in WHHL and 69±12 mg/dL in normal NZW rabbits.
Rabbits were anesthetized with sodium pentobarbital (40 to 60 mg/kg IV), and the carotid artery was immediately removed and placed in Krebs' buffer with the following composition (in mmol/L): NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25, and glucose 12. Connective tissue and fat on the adventitia vascular surface were carefully removed, and the vessel was cut into rings 3 to 4 mm in length. The rings were suspended in an organ bath with 20 mL Krebs' buffer maintained at 37°C and bubbled with a mixture of 95% O2 and 5% CO2.14 The rings were connected to a force transducer to measure isometric tension. Resting tension was increased in a stepwise manner to reach the final tension of 2 g over 30 minutes, and the rings were allowed to equilibrate for 30 minutes, during which the buffer was replaced at 15-minute intervals. Vessels were contracted twice with 85 mmol/L KCl, with 45 minutes between contractions. In preliminary experiments, concentration-response curves to phenylephrine (10-8 to 10-4 mol/L) were obtained, and the concentration of phenylephrine that produced 50% to 60% of the maximum contractile response (EC50-60) was used in subsequent studies. Results are expressed as percent relaxation of contraction produced by phenylephrine.
Experimental Protocol
After contraction with phenylephrine reached a
plateau, the gas aerating the organ bath was switched from the control
mixture (95% O2 and 5% CO2) to a mild hypoxic
mixture (5% O2, 5% CO2, and
90% N2), and changes in vascular tension were measured.
After relaxation of the carotid artery in response to mild
hypoxia reached a plateau, the tank was switched to produce a
severe hypoxia (5% CO2 and 95% N2).
During mild and severe hypoxia, PO2
in the Krebs' buffer decreased from 449±17 mm Hg to 72±2 and 44±2
mm Hg, respectively. pH and PCO2 were not
altered.
In normal rabbits, we examined the effects of the nitric oxide synthase inhibitor L-NNA (10-4 mol/L)15 and denudation of the endothelium on vasorelaxation during mild and severe hypoxia. L-NNA was dissolved in Krebs' solution and was applied 30 minutes before and during exposure to hypoxic conditions. The concentration of L-NNA abolished acetylcholine-induced relaxation of the carotid artery without inhibiting vasorelaxation in response to sodium nitroprusside (data not shown). To produce endothelial cell denudation, the intima was gently rubbed with forceps inserted into the lumen. Vessels did not relax in response to acetylcholine after endothelial denudation but relaxed normally in response to sodium nitroprusside (data not shown).
We also examined the effects of two potassium-channel inhibitors on relaxation of the carotid artery during hypoxia in NZW and WHHL rabbits. Glibenclamide (10-6 mol/L), an inhibitor of ATP-sensitive potassium channels,16 17 or iberiotoxin (5x10-8 mol/L), an inhibitor of calcium-activated potassium channels,18 19 20 was applied 10 minutes before exposure to hypoxic conditions. Glibenclamide was dissolved in dimethyl sulfoxide (0.1%), and control experiments were performed in the presence of 0.1% dimethyl sulfoxide alone.
We also examined changes in tension of the carotid artery in response to aprikalim (10-7 to 10-6 mol/L), a direct activator of ATP-sensitive potassium channels,16 17 acetylcholine (10-8 to 10-7 mol/L), and sodium nitroprusside (10-8 to 10-6 mol/L) in control and WHHL rabbits.
Histological Procedures
After measurements were made in the organ bath, the vascular
rings were fixed, processed for paraffin embedding, and stained with
hematoxylin and eosin.
Statistical Analysis
All data are expressed as mean±SEM. Student's t
test was used to compare absolute values, and the Mann-Whitney
U test was used to compare percent changes. A probability of
<.05 was considered significant.
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Results |
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Hypoxia in Normal Rabbits
Mild and severe hypoxia induced pronounced relaxation of the carotid artery from normal rabbits (Fig 1
). L-NNA
(10-4 mol/L) inhibited relaxation of the carotid artery
during mild hypoxia (P<.05 versus control). In
contrast, L-NNA did not significantly impair relaxation of the carotid
artery in response to severe hypoxia (Fig 1). Removal of
endothelium also inhibited relaxation of the carotid
artery during mild hypoxia but did not affect vasorelaxation
during severe hypoxia (Fig 1). Glibenclamide (10-6
mol/L) inhibited relaxation of the carotid artery during mild and
severe hypoxia by 56±18% and 50±13%, respectively (Fig 2). In contrast, glibenclamide did not attenuate
relaxation of the carotid artery in response to sodium nitroprusside
(data not shown).
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In other experiments we tested the effects of iberiotoxin (5x10-8 mol/L), an inhibitor of calcium-activated potassium channels,18 19 20 on hypoxia-induced vasorelaxation. In contrast to glibenclamide, iberiotoxin did not significantly impair relaxation in response to either mild or severe hypoxia. In response to mild and severe hypoxia, respectively, the carotid artery relaxed by 22±3% and 94±5% in the absence and 14±6% and 83±8% in the presence of iberiotoxin (P>.05 for both).
Hypoxia in WHHL Rabbits
Relaxation of the carotid artery in response to mild and severe
hypoxia was less in WHHL than in normal rabbits
(P<.05; Fig 3). Glibenclamide
(10-6 mol/L) tended to reduce relaxation in response to
mild hypoxia and inhibited responses to severe hypoxia
by 71±10% in WHHL rabbits (Fig 4). In contrast,
glibenclamide did not attenuate relaxation of the carotid artery in
response to nitroprusside in WHHL rabbits (data not shown).
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Responses of the Carotid Artery to Acetylcholine, Nitroprusside,
and Aprikalim
Relaxation of the carotid artery in response to acetylcholine was
less in WHHL than in normal rabbits (P<.05; Fig 5). Responses to sodium nitroprusside were generally
similar in normal and WHHL rabbits (Fig 5).
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Aprikalim, an activator of ATP-sensitive potassium
channels,16 17 produced relaxation of the carotid artery
that was similar in normal and WHHL rabbits (Fig 6).
Glibenclamide (10-6 mol/L) almost abolished relaxation of
the carotid artery in response to aprikalim (data not shown). These
findings suggest that ATP-sensitive potassium channels are present
and functional in the carotid artery of normal and WHHL rabbits.
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Histological Study
The common carotid artery from NZW and WHHL rabbits had no visible
macroscopic or microscopic evidence of atherosclerotic lesions. In
contrast, the thoracic aorta from WHHL rabbits had lesions
characterized by pronounced intimal thickening and lipid
deposition.
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Discussion |
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There are three major findings in this study. First, relaxation of the carotid artery in response to mild and severe hypoxia in normal and WHHL rabbits appears to be mediated, in part, by activation of glibenclamide-sensitive potassium channels. Second, relaxation of the carotid artery in response to mild hypoxia in normal rabbits is endothelium dependent. Third, hypoxia-induced relaxation of the carotid artery is impaired in WHHL rabbits even though atherosclerotic lesions in the carotid artery from these rabbits are absent or minimal.
Responses to Acetylcholine and Sodium Nitroprusside
There is substantial evidence that
endothelium-dependent relaxation is impaired by
hypercholesterolemia or
atherosclerosis in humans and animals.9 10 11 12
The present findings support this concept. Relaxation of the
carotid artery in response to acetylcholine was less in WHHL than in
normal rabbits. Endothelium-dependent relaxation of
the carotid artery in response to acetylcholine was decreased in WHHL
rabbits even though the vessels appeared morphologically normal.
Relaxation of the carotid artery in response to nitroprusside was generally similar in WHHL and normal rabbits, with a very modest reduction in relaxation to the highest concentration of nitroprusside in WHHL rabbits. Preservation of responses to nitroprusside suggests that impaired relaxation in response to acetylcholine in WHHL rabbits is relatively specific and not due to generalized dysfunction of the vascular muscle.
Responses to Aprikalim
Activation of ATP-sensitive potassium channels is an
important mechanism of vasorelaxation.12 21 22 23
Aprikalim, a direct activator of ATP-sensitive
potassium channels,16 17 produced similar relaxation of
the carotid artery in normal and WHHL rabbits. Glibenclamide, an
inhibitor of ATP-sensitive potassium channels, produced
marked inhibition of relaxation in response to aprikalim. High
concentrations of glibenclamide may inhibit large-conductance
calcium-activated potassium channels24 as well
as ATP-sensitive potassium channels. The concentration of glibenclamide
used in this study, however, is considered to be relatively specific
for ATP-sensitive potassium channels.18 Thus, our findings
suggest that ATP-sensitive potassium channels are present in the
carotid artery in normal and WHHL rabbits and that relaxation in
response to activation of ATP-sensitive potassium channels is not
affected by hypercholesterolemia.
Relaxation of the carotid artery in response to aprikalim is less in atherosclerotic than in normal monkeys.13 In the present study, we used segments of the carotid artery that had no detectable atherosclerotic lesions. Thus, preservation of responses to aprikalim in the present studies may be related to the absence of atherosclerotic lesions. Taken together, the present findings and the study in monkeys13 suggest that atherosclerosis but not hypercholesterolemia without atherosclerotic lesions impairs responses to activation of glibenclamide-sensitive potassium channels.
Vasorelaxation in Response to Hypoxia
Removal of the endothelium inhibited relaxation of
the carotid artery from normal rabbits during mild hypoxia.
This relaxation was also partially inhibited by L-NNA, suggesting that
relaxation of the carotid artery from normal rabbits during mild
hypoxia is mediated, in part, by EDRF. Because vasorelaxation
during mild hypoxia was not completely inhibited by L-NNA, it
is possible that other mechanisms, such as release of an
endothelium-derived hyperpolarizing factor, are
also involved. Although endothelium-derived nitric
oxide may act as an endothelium-derived
hyperpolarizing factor in some vessels, earlier data in normal rabbit
carotid arteries suggest that this is not the case.25
Glibenclamide also produced some inhibition of the relaxation response, suggesting that activation of glibenclamide-sensitive potassium channels may be involved in relaxation of the carotid artery during mild hypoxia. It is not clear whether mild hypoxia increases production of EDRF or prolongs its activity. Vascular endothelium appears to contain ATP-sensitive potassium channels,26 and hyperpolarization produced by activation of potassium channels in endothelium may activate calcium influx through receptor-operated cation channels27 and thereby release EDRF. Alternatively, reduction in formation of oxygen radicals, which inactivate EDRF,28 during mild hypoxia may also contribute to enhanced activity of EDRF in isolated vessels.
Glibenclamide inhibited relaxation of the carotid artery during both mild and severe hypoxia. Because removal of endothelium did not affect vasorelaxation in response to severe hypoxia, glibenclamide-sensitive potassium channels (but not EDRF) appear to be activated in vascular muscle during severe hypoxia. Because glibenclamide did not completely inhibit vasorelaxation during hypoxia, other mechanisms may also contribute to relaxation in response to hypoxia.
To examine the specificity of glibenclamide and the possible contribution of other potassium channels, we also tested effects of iberiotoxin, an inhibitor of calcium-activated potassium channels,19 20 on hypoxia-induced vasorelaxation. Iberiotoxin did not affect relaxation of the carotid artery in response to mild or severe hypoxia, which suggests that activation of calcium-dependent potassium channels does not contribute to vasorelaxation during hypoxia.
Hypoxia-Induced Vasorelaxation in WHHL
Rabbits
Mild hypoxia produced less relaxation of the carotid
artery in WHHL than in normal rabbits. Our data suggest that
vasorelaxation in response to mild hypoxia is mediated
primarily by EDRF in normal rabbits, and
endothelium-dependent relaxation of the carotid
artery is impaired in WHHL rabbits. Thus, impaired responses of the
carotid artery to mild hypoxia may be due to impaired
endothelium-dependent relaxation in WHHL
rabbits.
Severe hypoxia produced less relaxation of the carotid artery in WHHL than in normal rabbits, and glibenclamide inhibited this response. Thus, although vasorelaxation during severe hypoxia is impaired in WHHL rabbits, activation of glibenclamide-sensitive potassium channels is the primary mechanism by which severe hypoxia produces vasorelaxation, and the glibenclamide-dependent response is preserved in WHHL rabbits. This finding is compatible with our finding that responses to activation of ATP-sensitive potassium channels by aprikalim are preserved in WHHL rabbits. Because relaxation of the carotid artery during severe hypoxia is endothelium independent, these findings suggest that impaired responses to severe hypoxia occur at the level of vascular muscle.
In conclusion, relaxation of the carotid artery in response to mild and severe hypoxia is mediated by glibenclamide-sensitive potassium channels in both normal and hyperlipidemic rabbits. The response to mild hypoxia is largely mediated by EDRF in normal rabbits. Vasorelaxation in response to mild hypoxia is impaired in WHHL rabbits, probably because endothelium-dependent relaxation is impaired.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL16066, NS24621, AG10269, HL14388, and HL38901, by research funds from the Veterans Administration, and by a Grant-In-Aid (95014510) from the American Heart Association. Dr Faraci is an Established Investigator of the American Heart Association. We thank Pam Tompkins for assistance in the preparation of histological specimens, Arlinda LaRose in the preparation of the manuscript, and Rhone-Poulenc Rorer for the supply of aprikalim.
Received March 16, 1995; accepted July 11, 1995.
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References |
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