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Department Of Physiology, Medical College Of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study determined the effects of hypoxia on diameter, vascular smooth muscle (VSM) transmembrane potential (Em), and vascular cAMP levels for in vitro cannulated skeletal muscle resistance arteries (gracilis arteries) from Sprague-Dawley rats fed a low-salt (LS) or a high-salt (HS) diet. Arterial diameter and VSM Em were measured in response to hypoxia, iloprost, cholera toxin, forskolin, and aprikalim. In HS rats, arterial dilation and VSM hyperpolarization after hypoxia, iloprost, and cholera toxin were impaired versus responses in LS rats, whereas responses to forskolin and aprikalim were unaltered. Blockade of prostaglandin H2 and thromboxane A2 receptors had no effect on responses to hypoxia or iloprost in vessels from both rat groups, suggesting that inappropriate activation of these receptors does not contribute to the impaired hypoxic dilation with HS. Hypoxia, cholera toxin, and iloprost increased vascular cAMP levels in vessels of LS rats only, whereas forskolin increased cAMP levels in all vessels. These data suggest that reduced hypoxic dilation of skeletal muscle microvessels in rats on a HS diet may reflect an impaired ability of VSM to produce cAMP after exposure to prostacyclin.
oxygen; microcirculation; hypoxic dilation; prostacyclin; electrophysiology; autoregulation; vascular reactivity; vascular smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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STUDIES by Boegehold (3, 4) and Lenda et al. (13) clearly demonstrated that chronic elevations in dietary salt intake are associated with an impaired reactivity of in situ skeletal muscle microvessels of normotensive rats to endothelium-dependent dilator agonists (e.g., acetylcholine) and physiological stimuli (e.g., elevated blood flow). However, dilator responses to direct activation of intracellular second messenger systems were unaffected by a high-salt (HS) diet in those studies. In the interim, there has been continued investigation to more fully characterize the nature and mechanisms of the impaired reactivity of skeletal muscle microvessels in normotensive rats on a HS diet (6-8, 14, 19-21, 28).
Previous studies in our laboratory demonstrated that dilation of isolated skeletal muscle resistance arteries in response to reduced oxygen tension is impaired in normotensive rats on a HS diet compared with responses in rats on a low-salt (LS) diet (14, 28). Liu et al. (14) also demonstrated that this impaired response of skeletal muscle resistance arteries to hypoxia was not due to compromised endothelial function because the ability of the vascular endothelium to produce and/or release prostacyclin (PGI2) in response to hypoxia was unaffected by elevated dietary salt intake. Rather, results from that study, and from subsequent studies (6-8) of in situ arterioles in the cremaster muscle, suggest that this impaired dilator reactivity to hypoxia may reflect an altered sensitivity of the VSM cells to PGI2 because dilator responses of skeletal muscle microvessels to the PGI2 analog iloprost were impaired in rats on a HS diet compared with responses in rats on a LS diet. However, dilator responses to agonists that directly activate adenylyl cyclase (forskolin) were unaltered in rats on a HS diet throughout the course of those studies (6-8, 14).
When integrated, these observations suggest that impaired hypoxic dilation of skeletal muscle microvessels from normotensive rats on a HS diet may reflect alterations of VSM sensitivity to PGI2 at the level of its membrane-bound receptor complex and that this impairment of function may be localized to this receptor complex only because activation of the downstream intracellular second messenger systems associated with this signaling pathway results in normal dilator responses. The purpose of the present study was to more accurately determine the specific nature of the alterations in the mechanisms of hypoxic dilation of skeletal muscle resistance arteries that develop with a HS diet.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. All experiments used 9- to 12-wk-old male Sprague-Dawley rats fed either a LS diet [0.4% NaCl, weight = 311 ± 11 g, mean arterial pressure (MAP) = 114 ± 4.6 mmHg] or a HS diet (4.0% NaCl, weight = 316 ± 14 g; MAP = 117 ± 5.3 mmHg) for 1 wk with tap water to drink ad libitum. Rats were housed in an animal care facility at the Medical College of Wisconsin, which is approved by the American Association for the Accreditation of Laboratory Animal Care; all protocols were approved by the Institutional Animal Care and Use Committee. Before all experimental procedures, rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg, supplemented as necessary), and a carotid artery was cannulated for determination of arterial pressure.
Preparation of isolated vessels. The small muscular branch of the femoral artery supplying the gracilis muscle was removed from the anesthetized rat, by taking care to minimize vessel stretching and to handle the artery by its surrounding connective tissue only. Vessels were then immersed in warmed physiological salt solution (PSS) bubbled with 21% O2-5% CO2-74% N2. The PSS used in these experiments had the following composition (in mM): 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.6 CaCl2, 1.18 NaH2PO4, 24 NaHCO3, 0.026 EDTA, and 5.5 glucose.
After isolation, vessels were prepared for in vitro microscopy as described previously (5). Vessels were placed in a heated (37°C) chamber that allowed the vessel lumen and exterior to be perfused and superfused, respectively, with PSS from separate reservoirs. Gracilis arteries were cannulated at both ends with glass micropipettes (~100 µm tip diameter) and secured to the inflow and outflow pipettes using 10-0 nylon suture. Any side branches were ligated with a single strand teased from 6-0 silk suture. The inflow pipette was connected to a reservoir perfusion system that allowed the intralumenal pressure and lumenal gas concentrations to be controlled. Vessel diameter was measured using television microscopy and an on-screen video micrometer. Arteries were extended to their approximate in situ length and equilibrated at 80% of the animal's MAP, to approximate the perfusion pressure encountered in vivo (14). Any vessel that did not demonstrate active tone at rest (assessed by dilation in response to 10
6 M sodium nitroprusside in the vessel chamber) was not
used in the study. Active tone at the equilibration pressure was
calculated as
(
D/Dmax) · 100, where
D is the diameter increase from rest in response to
Ca2+-free PSS and Dmax is the
maximum diameter measured at the equilibration pressure in
Ca2+-free PSS. Active tone for vessels used in this study
was not different between normotensive rats either on a LS diet
(38.3 ± 2.2%) or a HS diet (36.7 ± 3.0%).
Determination of vascular reactivity.
After the equilibration period, arterial diameter and VSM transmembrane
potential (Em) of isolated vessels were measured
before and after challenge with 1) the physiological dilator
stimulus of hypoxia (reduction in superfusate and perfusate
PO2 from ~140 mmHg, under conditions of 21%
O2, to ~35 mmHg, under conditions of 0% O2;
Ref. 5); 2) the stable PGI2 analog
iloprost (109 g/ml); 3) the Gs
protein activator cholera toxin (109 g/ml); 4)
the adenylyl cyclase activator forskolin (107 M); and
5) the ATP-sensitive K+ channel
(KATP) channel agonist aprikalim (106 M). In
an additional series of experiments, the dilation of isolated gracilis
arteries in response to reduced PO2 was
assessed after inhibition of cytochrome P-450 4A-derived
metabolites of arachidonic acid with 105 M
17-octadecynoic acid (17-ODYA; Ref. 9). Maximum diameter of all vessels was determined by measuring the dilator response to
perfusion and superfusion with Ca2+-free PSS containing
103 M adenosine. In all cases, arterial diameter and VSM
Em were measured after the vascular response to an
individual agonist or to hypoxia had stabilized.
Measurement of VSM Em.
VSM Em was measured with a high-impedance
amplifier and glass microelectrodes (40-80 M
impedance) filled
with 3 M KCl. Criteria for successful impalement included an abrupt
drop to a steady level of Em for a minimum of
5 s and an abrupt return to baseline on exit of the electrode from
the cell. Five measurements were made under each condition (in response
to each challenge), and the results were averaged to obtain the final
value of Em for that vessel under each
experimental condition (15).
Blockade of prostaglandin
H2-thromboxane A2
receptors.
Previous studies (2, 23) have suggested that
overproduction of vasoconstrictor factors such as prostaglandin
H2 (PGH2) and thromboxane A2
(TxA2) via cyclooxygenases can contribute to an impaired
dilation in response to endothelium-dependent stimuli in spontaneously
hypertensive rats. In addition, Mayhan (16) determined
that an inappropriate activation of the
PGH2-TxA2 receptor could underlie the impaired
dilator responses of cerebral arterioles to acetylcholine in
spontaneously hypertensive rats. More recently, Suzuki et al.
(27) demonstrated that blockade of the
PGH2-TxA2 receptor could restore dilator
reactivity of cheek pouch microvessels to acetylcholine and vasoactive
intestinal peptide in spontaneously hypertensive hamsters. Given these
previous observations, it is possible that overproduction of
constrictor factors or inappropriate activation of the
PGH2-TxA2 receptor may occur in skeletal muscle microvessels of normotensive rats on a HS diet. These processes, in
turn, could contribute to the impaired hypoxic dilation of the vessels,
which is an endothelium- and cyclooxygenase-dependent response in
animals on a normal salt diet (5, 9, 17). To evaluate this
hypothesis, dilator responses of isolated gracilis arteries from
normotensive rats on either a LS or HS diet were assessed during
exposure to hypoxia and after challenge with iloprost (109 g/ml). Vessel responses to dilator stimuli were
assessed before and after application of the selective
PGH2-TxA2 receptor antagonist SQ-29548
(BioMol), as described previously (12). Briefly, SQ-29548 was added to the superfusate and perfusate PSS to a concentration of
105 M and allowed to incubate with the isolated vessels
for 30 min, after which the dilator responses to hypoxia and iloprost
were reassessed.
Determination of intracellular cAMP levels.
Previous studies have demonstrated that challenge with PGI2
causes an increase in cellular levels of cAMP during the subsequent signal transduction cascade, ultimately leading to relaxation of VSM
cells (1, 11, 18, 22, 26). As such, the impaired hypoxic
dilation of skeletal muscle resistance arteries in animals on a HS diet
could be due to an impaired production of cAMP in response to exposure
of the vessel to PGI2. In a separate series of experiments,
gracilis arteries from normotensive rats on either a LS or HS diet were
surgically isolated and placed in PSS containing IBMX
(103 M), a nonspecific inhibitor of cellular
phosphodiesterases, to minimize the degradation of produced cAMP
(24). The PSS for these experiments was equilibrated with
a 21% O2-5% CO2-balance N2 gas
mixture. After a 60-min equilibration period, vessels from rats on a LS
or HS diet (n = 12 arteries from 6 rats for all
challenges) were then either exposed to 30 min of hypoxia (0%
O2) or were challenged with 109 g/ml
iloprost, 109 g/ml cholera toxin, or 107 M
forskolin or maintained under the control condition (normoxia). After
imposition of the different challenges, vessels were immediately frozen
in liquid N2. Subsequently, the frozen vessels were
homogenized to a powder and resuspended in 0.1 M hydrochloric acid.
After centrifugation, the supernatant was removed and cAMP
concentration in the supernatant was determined using a commercially
available competitive binding immunoassay kit (Assay Designs, Ann
Arbor, MI). The resulting values of cAMP concentration in the
supernatant were corrected for dilution effects and normalized to
protein content using the Bradford method for protein determination
(25).
Data and statistical analyses. All data are presented as means ± SE. Differences in baseline animal and vessel characteristics, dilator responses, VSM hyperpolarization, or cAMP production between gracilis arteries from rats on a LS or HS diet were evaluated using either Student's t-test, ANOVA, or Tukey's test post hoc where appropriate. Throughout all analyses, P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Table 1 summarizes data from the
present studies describing the basic characteristics of isolated
gracilis arteries from normotensive rats on either a LS or HS
diet. Throughout the study, resting diameter of these vessels
was not different between the two groups of rats, indicating that the
level of basal vascular tone in skeletal muscle resistance arteries was
not altered by the HS diet. The maximum diameter of vessels (determined
using Ca2+-free PSS containing 103 M
adenosine) was also not different between gracilis arteries of
normotensive rats on either diet, indicating that short-term elevations
in dietary salt intake do not cause a significant remodeling of
skeletal muscle resistance arteries, resulting in a reduced passive
diameter. Under control conditions (21% O2), resting VSM Em and vascular cAMP production in isolated
gracilis arteries was not different between vessels of rats on either
the LS or the HS diet.
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Responses of isolated skeletal muscle resistance arteries to
vasodilator stimuli.
The responses of isolated gracilis arteries from normotensive rats on a
LS and a HS diet to acute reductions in superfusate PO2 are summarized in Fig.
1. After hypoxia, isolated vessels from
rats on a LS diet demonstrated a significant dilation (Fig. 1A) associated with hyperpolarization of the VSM cell
membrane (Fig. 1B). In contrast, vessels from rats on a HS
diet failed to dilate and exhibited no change in VSM
Em during exposure to reduced
PO2.
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9 g/ml) in isolated gracilis arteries from rats on LS
and HS diets. Comparable to observations described above for vessel
responses to hypoxia, challenge with iloprost resulted in a significant dilation (Fig. 2A) and VSM cell membrane hyperpolarization
(Fig. 2B) in arteries from rats on a LS diet; these
responses were significantly reduced in gracilis arteries from rats fed
a HS diet.
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7 M),
isolated vessels from rats on both HS and LS diets exhibited significant dilation (Fig. 4A) and VSM hyperpolarization
(Fig. 4B), and these responses were not different between
the two animal groups.
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6 M), a KATP channel
opener. These data were similar to those determined using forskolin, in
that isolated vessels from rats on both diets exhibited a strong
dilation (Fig. 5A) and a significant hyperpolarization of
the VSM (Fig. 5B) in response to aprikalim. Neither the
dilation nor the VSM hyperpolarization in response to application
of aprikalim was different in vessels from rats on the HS or LS
diet.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Although physiological consequences associated with the development of salt-sensitive hypertension remain an active area of ongoing investigation, recent studies have demonstrated that HS diet per se can have significant consequences for microvessel structure and function, independent of any alteration in MAP. For example, dilator responses of skeletal muscle arterioles to endothelium-derived, nitric oxide-dependent stimuli are impaired during chronic ingestion of a HS diet (3, 4, 13), and recent studies in our laboratory (14, 28) have indicated that hypoxic dilation of rat skeletal muscle resistance arteries is severely impaired by exposure to elevated dietary salt intake, without a change in arterial blood pressure. This impaired dilation to the physiological stimulus of reduced PO2 may result from reduced VSM responsiveness to PGI2 (the predominant mediator of hypoxic dilation in the gracilis artery; Refs. 5, 9, and 17) because HS diet also attenuates the dilation of these vessels in response to iloprost. The results of the present study provide novel information about several aspects of altered vascular control in resistance vessels of animals on a HS diet. For example, these experiments demonstrate that changes in VSM Em in response to reduced PO2 and iloprost in vessels of animals on a HS diet are altered in a manner that parallels the impaired relaxation of the vessels in response to these vasodilator stimuli. Thus it appears that that exposure to a HS diet leads to alterations in electromechanical coupling in skeletal muscle resistance arteries that results in an impaired relaxation of the vessels in response to the physiological stimulus of reduced PO2. Results of this study also indicate that the impaired dilation and smooth muscle hyperpolarization during exposure to hypoxia in resistance vessels of animals on a HS diet may be due to a compromised ability of PGI2 to cause the intracellular generation of cAMP via adenylyl cyclase, and that the site of this impairment in the signal transduction pathway appears to be at the level of the Gs protein linking PGI2 receptors to adenylyl cyclase. Finally, this study also provides evidence against a contribution of PGH2-TxA2 receptors or altered cytochrome P-450 metabolism to the impaired hypoxia-induced dilation of skeletal muscle resistance arteries from normotensive rats on a HS diet.
In agreement with previous studies in our laboratory (6-8, 14, 28), vascular relaxation in response to reduced PO2 and iloprost was impaired in skeletal muscle resistance arteries from normotensive rats on a HS diet compared with responses in vessels from rats on a LS diet. A primary goal of the present study was to determine whether the impaired relaxation of vessels of animals on a HS diet in response to hypoxia and iloprost could be due to changes in the electrophysiological response of VSM cells to these vasodilator stimuli. As presented in Figs. 1B, 2B, 3B, and 4B, this pattern was evident, as hyperpolarization of the VSM during challenge with hypoxia or iloprost was attenuated in vessels from rats on a HS diet compared with responses in vessels from rats on a LS diet. However, the hyperpolarization of the VSM cell membrane in response to challenge with forskolin and aprikalim were comparable between the two animal groups. These observations indicate reduced relaxation of resistance arteries in response to reduced PO2 and PGI2 involves alterations in the electrophysiological response of the VSM cells to these stimuli, but function of membrane potassium channels and the immediate cellular signaling pathways leading to VSM hyperpolarization and vasodilation is unaltered with elevated salt intake. These results are highly significant in that they indicate impaired vasodilation and altered electromechanical coupling in VSM cells during exposure of resistance arteries to hypoxia in animals on a HS diet reflect alterations to specific sites within the signaling pathways of VSM relaxation. These data also demonstrate that alterations of vessel wall structure and mechanics (e.g., reduced vessel distensibility) developing in response to elevated dietary salt intake (10) do not play a significant role in contributing to the initial development of impaired dilator responses in animals on a HS diet. However, it is important to emphasize that this apparent lack of a contribution of altered microvessel structure and vessel wall distensibility to the impaired relaxation of vessels from animals on a HS diet is relevant for short-term elevations in dietary salt intake only. As the duration of the elevated dietary salt intake increases, in addition to impaired cellular signaling, the contribution of structural alterations to the microvessel wall may play a greater role in determining the net dilator responses to agonists and stimuli (8, 10, 11).
Previous studies (5, 9, 17) have demonstrated that hypoxic dilation of skeletal muscle resistance arteries and arterioles largely depends on the production and release of PGI2 from the vascular endothelium. We have previously demonstrated endothelial production and/or release of PGI2 by skeletal muscle resistance arteries is not impaired with elevated dietary salt intake (14), and dilator reactivity of skeletal muscle resistance arteries and arterioles of normotensive rats on a HS diet is impaired in response to challenge with iloprost (6-8, 14, 28). One possible explanation for an impaired hypoxic dilation of microvessels of normotensive rats on a HS diet, despite normal PGI2 release by the endothelium, could be that exposure to reduced PO2 also leads to the production of additional vasoconstrictor products of the cyclooxygenase pathway of arachidonic acid metabolism (PGH2 and TxA2) in vessels of animals on a HS diet, overwhelming the dilator effects of PGI2. This possibility has previously been proposed to cause the impaired endothelium-dependent dilator responses in vessels of spontaneously hypertensive rats (2, 23). It is also possible that PGI2 released by the endothelium in response to hypoxia could be activating an inappropriate receptor (the PGH2-TxA2 receptor), thus preventing the full manifestation of its dilator effects, as previously demonstrated by Mayhan (16) in cerebral arterioles of spontaneously hypertensive rats. Furthermore, the recent study by Suzuki et al. (27) demonstrated that blockade of PHG2-TxA2 receptors in the cheek pouch of spontaneously hypertensive hamsters restores microvessel dilator reactivity to acetylcholine and vasoactive intestinal peptide. In the present study, we used the selective PGH2-TxA2 receptor blocker SQ-29548 to evaluate the potential contribution of PGI2-induced activation of PGH2-TxA2 receptors or inappropriate production of PGH2 or TxA2 to the impaired relaxation of the vessels to reduced PO2 in animals on the HS diet. If blockade of these receptors restores the normal vasodilator response to hypoxia or iloprost in gracilis arteries from rats on a HS diet, it would suggest that the above described processes may mask the normal dilator pathways that contribute to the relaxation of these vessels in response to reduced PO2. However, as presented in Fig. 5, application of the PGH2-TxA2 receptor antagonist had no effect on hypoxia- or iloprost-induced dilation of skeletal muscle resistance arteries of normotensive rats on either diet. Therefore, it appears unlikely that HS diet either causes a significant alteration in the profile of vasoactive arachidonic acid metabolites released in response to hypoxia or results in the inappropriate binding of endothelium-derived PGI2 to the PGH2-TxA2 receptor on the VSM cells.
It has previously been demonstrated that challenge with PGI2 triggers a sharp increase in the levels of cAMP in VSM cells, ultimately leading to the opening of K+ channels in the cell membrane, hyperpolarization of the cell, and vascular relaxation (1, 11, 18, 26). In the present experiments, skeletal muscle resistance arteries from normotensive rats on a LS diet exhibited a significant increase in cAMP production during exposure to reduced PO2 and after challenge with either the PGI2 analog iloprost or the adenylyl cyclase activator forskolin (Fig. 6A). In contrast, there was no measurable increase in cAMP in response to either hypoxia or iloprost in vessels from normotensive rats on a HS diet (Fig. 6B). However, direct activation of adenylyl cyclase in vessels from animals on a HS diet resulted in a significant increase in cAMP production comparable to that demonstrated in vessels from rats on a LS diet. These data suggest that an inability of the cell to produce cAMP in response to the binding of endothelium-derived PGI2 to its membrane receptor is a major contributing factor to the impaired relaxation of skeletal muscle resistance arteries in response to reduced PO2 in animals exposed to an elevated dietary salt intake. However, the ability of the cell to produce cAMP in response to activation of adenylyl cyclase or for downstream effector sites (e.g., KATP channels) to respond to activation does not appear to be impaired because arterial dilation and VSM hyperpolarization in response to challenge with forskolin and aprikalim and forskolin-induced cAMP production by the vessels are not compromised by exposure to elevated dietary salt intake.
Results of this study indicate that dilation and VSM hyperpolarization in response to reduced PO2 are impaired in skeletal muscle resistance arteries of rats subjected to an increase in dietary salt intake. Our data also suggest that this impaired relaxation is not due to an alteration in the profile of dilator agents released by the endothelium in response to reduced PO2 or inappropriate effects of endothelium-derived PGI2 on the VSM cell membrane. Rather, it appears that exposure to HS diet leads to a disruption of intracellular signaling pathways that impairs the ability of the cell to produce cAMP after exposure to PGI2. This disruption in the signal transduction pathway appears to occur at the coupling of the PGI2 receptor-G protein complex to adenylyl cyclase because activation of the Gs protein with cholera toxin is impaired in animals on a HS diet, whereas direct activation of adenylyl cyclase with forskolin or direct activation of KATP channels with aprikalim results in normal dilation and smooth muscle hyperpolarization in vessels from rats on a HS diet.
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ACKNOWLEDGEMENTS |
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The authors acknowledge the excellent technical assistance of Luanne Kelly for measurements of cAMP and Tianjian Huang for construction and use of the microelectrodes for determining Em. The authors thank the Berlex Laboratories for the generous donation of the iloprost used in these experiments.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-29587, HL-37374, HL-65289, and F32-HL-09994 and a Faculty Development Grant from the Medical College of Wisconsin.
Address for reprint requests and other correspondence: J. C. Frisbee, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (E-mail: jfrisbee{at}mcw.edu).
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.
Received 21 March 2001; accepted in final form 6 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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