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2-adrenoceptors are not
present in proximal arterioles of rat intestine
Department of Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9229
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The purpose of
this study was to evaluate two potential stimuli for nitric oxide (NO)
release in rat intestinal arterioles during sympathetic nerve
activation. To determine whether these vessels contain endothelial
2-adrenoceptors linked to the
L-arginine-NO pathway,
intravital microscopy was used to study the response of first-order
arterioles (1As, 20-40 µm ID) to direct application of
1) the selective
2-agonist BHT-933 and
2) norepinephrine (NE) or
sympathetic nerve stimulation before and after
1- or
2-receptor blockade. The effect
of sympathetic nerve stimulation on 1A wall shear rate (WSR) was also
determined to evaluate the possibility of hemodynamic shear stress as a
stimulus for NO release. BHT-933 had no effect on 1A diameter, whereas
NE produced dose-dependent constrictions of 5 ± 3 to 15 ± 3 µm, which were usually abolished by the
1-antagonist prazosin but
unaffected by the 2-antagonist idazoxan. Sympathetic nerve stimulation at 3, 8, and 16 Hz induced constrictions of 4 ± 1, 8 ± 2, and 17 ± 4 µm,
respectively, and these constrictions were also usually abolished by
prazosin but unaffected by idazoxan. Resting WSR averaged 1,997 ± 163 s
1 and decreased to
1,587 ± 209, 1,087 ± 195, and 537 ± 99 s1 during 3-, 8-, and 16-Hz
nerve stimulation. These results suggest that
2-adrenoceptor-dependent
pathways do not influence either resting tone or sympathetic
constriction of proximal arterioles in the intestinal submucosa and
that luminal shear stress in these vessels significantly decreases with
sympathetic constriction. It therefore appears unlikely that either
2-receptor activation or
changes in hemodynamic shear serve as stimuli for arteriolar NO release
during periods of increased sympathetic nerve activity.
microcirculation; adrenergic receptors; endothelium-derived relaxing factor; nitric oxide; sympathetic nerves
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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WE HAVE RECENTLY REPORTED that arteriolar responses to sympathetic nerve stimulation are increased after inhibition of nitric oxide (NO) synthase with NG-monomethyl-L-arginine (L-NMMA) and that excess L-arginine completely reverses this effect (28). In a subsequent study (29), we found that arteriolar sympathetic constriction is similarly increased after disruption of endothelial function and that L-NMMA has no effect on this response after endothelial disruption. These findings indicate that the activity of endothelium-derived NO attenuates sympathetic neurogenic constriction in the intestinal arteriolar network.
Although the above studies afford no insight into the stimulus for
arteriolar NO release during increased sympathetic nerve activity, the
triggering event could be the activation of endothelial 2-adrenoceptors by neurally
released norepinephrine (NE). These receptors have been identified in
cultured arterial endothelial cells from a number of species (5, 12,
24) and in cultured microvascular endothelial cells from rat cerebral
cortex (21) and epididymal fat (39). Pharmacological evidence of
endothelial 2-adrenoceptors
that mediate vascular relaxation has been obtained from various conduit
arteries in the rat (4, 11, 25), dog (2, 14, 18, 25, 26), and pig (3,
5, 14, 34), and the role of NO in this relaxation is supported by
findings in both conduit and resistance arteries of the pig coronary
vasculature (5, 18, 34, 38), rat mesenteric artery (4), and arterioles of the rat spinotrapezius muscle (27). However, there can be considerable heterogeneity in adrenoceptor populations among and within
different vascular beds (17, 23, 30, 31); e.g., there appear to be no
endothelial 2-receptors in
arterioles of the rat cremaster muscle (31). To our knowledge, there
have been no investigations concerning the possible existence of
arteriolar 2-receptors linked
to NO release in the rat intestine.
The luminal shear stress associated with blood flow represents another possible stimulus for arteriolar NO release during periods of increased sympathetic nerve activity. Hemodynamic shear stress is considered to be an important stimulus for sustained microvascular NO release under resting conditions (6, 19), and this influence can attenuate the constriction of rat mesenteric artery segments during adrenergic nerve stimulation in vitro (37). Although we recently observed that wall shear rate actually falls in rat mesenteric arteries during sympathetic nerve stimulation in vivo (28), shear stress could remain unchanged or even increase in downstream intestinal arterioles if the effect of local diameter reduction is greater than the effect of decreased flow velocity.
To gain a better understanding of the interplay between the endothelium
and sympathetic nerves in the arteriolar network, we set out to
evaluate the possible contribution of
2-adrenoceptors and hemodynamic
shear stress to NO release during sympathetic constriction. We
evaluated the effect of sympathetic nerve stimulation on arteriolar
wall shear rate in the superfused rat intestine and also attempted to
determine whether these microvessels contain functional
2-adrenoceptors capable of
promoting vascular smooth muscle relaxation. Intravital microscopy was
used to assess arteriolar diameter and hemodynamic responses to
1) the selective
2-receptor agonist BHT-933 and
2) NE and perivascular nerve
stimulation before and then after
2- or
1-adrenoceptor blockade.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Surgery and intravital microscopy Male Sprague-Dawley rats aged 7-8 wk (Harlan Sprague Dawley, Indianapolis, IN) were anesthetized with thiopental sodium (100 mg/kg ip) and placed on a heating mat to maintain a 37°C rectal temperature. The trachea was intubated to ensure a patent airway, and the rat was allowed to breathe spontaneously. In thiopental-anesthetized rats, arterial blood gases are maintained within normal ranges during unaided breathing through a trachea tube (8), indicating uncompromised ventilation. The right carotid artery was cannulated for direct measurement of arterial blood pressure with a Gould P23 ID pressure transducer. Experiments were conducted only if mean arterial pressure was >90 mmHg.
The small intestine was prepared for observation using a technique developed by Bohlen and Lash (10). A midline abdominal incision was used to expose the terminal portion of the small intestine (ileum), and a 14- to 16-cm loop of ileum was gently exteriorized without disturbing any of its feed vessels or neural inputs. The loop of ileum was initially bathed in a warm electrolyte solution (Normosol, Abbott Laboratories, Chicago, IL) and then continuously superfused with a physiological electrolyte solution (119 mM NaCl, 25 mM NaHCO3, 6 mM KCl, and 3.6 mM CaCl2) warmed to 37°C and equilibrated with a mixture of 5% O2-5% CO2-90% N2 (pH 7.35-7.40). Isoproterenol (10 mg/l; Sigma, St. Louis, MO) and phenytoin (20 mg/l; Parke-Davis, Morris Plains, NJ) were added to the superfusate to suppress intestinal motility. At these concentrations, isoproterenol and phenytoin have no effect on resting arteriolar tone in this vascular bed (9, 28). After exteriorization of the ileum, chyme was flushed from the lumen through two small incisions made 6 cm apart along the antimesenteric border. Four sutures were then tied to this border at 1-cm intervals, and the bowel was draped over a transparent pedestal. Finally, as much of the preparation as possible was covered with polyvinyl film, with the continuous superfusate flow directed beneath the film to prevent its equilibration with atmospheric O2. Arteriolar responses to the2-adrenoceptor agonist BHT-933
(see below) were also evaluated in rat spinotrapezius muscle. For these
experiments, the rats were anesthetized, intubated, and cannulated as
described above, and the right spinotrapezius muscle was surgically
exteriorized as previously described (6). With this approach, the
muscle is gently drawn away from the body wall without disturbing any
of its feed vessels or neural inputs and secured with silk ligatures
over a transparent pedestal. A three-sided superfusion chamber is then
placed around the muscle and in contact with the animal's back to form
an enclosed reservoir, and the muscle is continuously superfused with
the physiological electrolyte solution warmed to 35°C and
equilibrated with a mixture of 5%
CO2-95%
N2 (pH 7.35-7.40).
After exteriorization of either the intestine or spinotrapezius muscle,
the rat was transferred to the stage of an Olympus BHMJ intravital
microscope (Hyde Park, NY) that was coupled to a charge-coupled device
videocamera (Dage-MTI, Michigan City, IN). Video images were displayed
on a Panasonic high-resolution video monitor and stored on videotape
for off-line analysis. Observations were made with a ×10 eyepiece
and Nikon ×10 or ×20 water-immersion objectives (final
video magnification ×730 or ×1,460). Arteriolar inner
diameters were measured off-line during videotape replay with a video
image shearing monitor (IPM, San Diego, CA), and center-line red cell
velocities were measured on-line with an optical Doppler velocimeter
(Microcirculation Research Institute, Texas A & M University).
Experimental protocols.
The first series of experiments was designed to determine whether
intestinal arterioles are capable of
2-receptor-mediated dilation by
evaluating the effect of BHT-933, a selective
2-agonist (32), on first-order
arterioles (1As) before and then during exposure to the selective
2-antagonist idazoxan (16). For
application of BHT-933, glass micropipettes beveled to an outer tip
diameter of 6-8 µm were filled with
105 or
108 M BHT-933 dissolved in
superfusate and connected to a Picospritzer II pressure ejection system
(General Valve, Fairfield, NJ). A micromanipulator was used to position
the pipette tip in light contact with the outer vessel wall, and
BHT-933 was ejected at a pressure of 5, 15, or 30 psi for 1 min. The
105 and
108 M pipette
concentrations of BHT-933 were chosen based on an earlier assessment of
arteriolar responsiveness to BHT-933 in superfused rat striated muscle
(17). After a 2-min recovery period, this sequence was repeated two
more times so that responses to all three levels of the agonist
(applied in random order) could be evaluated in the same vessel. Next,
a 1-ml bolus of either 105
or 108 M BHT-933 was added
directly to the tissue bath (final superfusate concn of 3 × 107 or 3 × 1010 M, respectively), and
the 1A response was measured for 3 min. After agonist washout and
measurement of the arteriolar response to the remaining bolus of
BHT-933, the series of pipette and bolus applications was repeated
using only the BHT-933 vehicle.
5 M in the solution
bathing the intestine. Idazoxan at a local concentration of
106 M maximally inhibits
2-mediated responses in a
variety of arteries (2, 11, 14), but we used a superfusate
concentration of 105 M to
ensure an effective concentration within the arteriolar wall, where
nearby blood flow acts as a diffusive sink (17). Finally, adenosine was
added to the superfusate (final concn
103 M), and passive
arteriolar diameter was measured.
In a second series of experiments, the efficacy and selectivity of
BHT-933 as an 2-agonist was
verified by evaluating its effect on spinotrapezius muscle arterioles,
which have previously been shown to possess vascular smooth muscle
2-adrenoceptors (27). BHT-933
was applied to spinotrapezius muscle arcade arterioles before and then
during idazoxan exposure using the protocol described above, except
that BHT-933 ejection at 30 psi could not be used because of
significant vessel movement in response to the pressure pulse.
A third and fourth series of experiments were designed to directly
explore the possibility that sympathetic adrenergic constriction of
intestinal arterioles is accompanied (and therefore modulated) by the
activation of 2-adrenoceptors.
In the third series of experiments, NE was delivered directly to the
arteriolar wall via pressure ejection, and the response was measured
before and then during exposure to either idazoxan or the selective
1-antagonist prazosin. For NE
application, glass micropipettes (2-3 µm outer tip diam) were
filled with 106 M NE, and
NE was ejected at 5, 10, and 15 psi (randomized) for 1 min. After two
additional NE applications at the remaining ejection pressures
(separated by a minimum 3-min recovery period), the series of NE
ejections was repeated in the presence of either prazosin (superfusate
concn 106 M) or idazoxan
(105 M). After superfusion
of the first inhibitor for 20 min, the series of NE applications was
repeated. Then, after a 30-min washout period, a final series of NE
applications was made in the presence of the second inhibitor. The two
inhibitors were used in random order. Finally, adenosine
(103 M) was added to the
superfusate for measurement of passive arteriolar diameter.
In the fourth series of experiments, a bipolar platinum electrode was
secured in a micromanipulator and used to stimulate the sympathetic
postganglionic efferents traveling along an upstream mesenteric
artery-vein pair. For stimulation, the electrode and artery-vein pair
were raised slightly above the superfusate, and the nerves were
stimulated with square-wave pulses from a Grass SD-9 stimulator at
supramaximal voltage (7-10 V) and 3-ms duration. Stimulation did
not alter mean arterial pressure. For these experiments, a 1A was
selected for study, and after a 1-min control period, the nerves were
stimulated for 1 min at a frequency of 3, 8, or 16 Hz (randomized).
After a recovery period to allow a complete return to control diameter,
this sequence was repeated two more times for stimulation at the two
remaining frequencies. This perivascular nerve stimulation induces a
widespread frequency-dependent constriction that is completely blocked
at all levels of the arteriolar network by the nonselective
-adrenoceptor antagonist phentolamine (20, 28), verifying that these
responses are due to sympathetic nerve activation. After sympathetic
nerve stimulation under the normal superfusate, either prazosin or
idazoxan (randomized) was added to the superfusate as described above,
and the series of nerve stimulations was repeated after exposure to the
inhibitor for 20 min. Then, after a 30-min washout period, the final
series of nerve stimulations was repeated in the presence of the second inhibitor. Finally, adenosine
(103 M) was added to the
superfusate for measurement of passive arteriolar diameter.
For the third and fourth series of experiments, a 30-min washout period
between application of the first and second blockers was used because
in experiments in which we applied prazosin first and subsequently
observed complete inhibition of responses to NE or sympathetic nerve
stimulation (see RESULTS), these
responses were fully restored by the time idazoxan was added after 30 min of washout. Because idazoxan had no effect on responses to NE or
sympathetic nerve stimulation, it was not possible to directly verify
the completeness of its washout. Instead, we relied on the findings of
other investigators, who have reported that idazoxan's effects are
completely reversed after a 30-min washout period (11).
Data and statistical analysis. The effect of BHT-933, NE, or sympathetic nerve stimulation on arteriolar diameter was quantified as the absolute difference between the diameter at maximal response (averaged over at least 15 s) and that during the preceding control period. In all cases, the maximal response was attained within the 1-min stimulation or ejection period.
In the fourth series of experiments, arteriolar diameter (D) and center-line red cell velocity (VRBC) were measured and used for calculation of mean red cell velocity (VM, mm/s), volume flow (Q, nl/s), and wall shear rate (WSR, s1) as follows
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Effect of an 2-receptor
agonist on intestinal and spinotrapezius muscle arterioles.
A total of four rats (204 ± 9 g body wt) were used to evaluate the
effect of BHT-933 on intestinal 1A diameter. The mean resting diameter
of arterioles studied here (n = 7) was
21 ± 3 µm, and mean passive diameter measured at the end of the
experiment was significantly greater, averaging 38 ± 4 µm. Figure 1 shows that neither direct
application of BHT-933 to the arteriolar wall nor addition of BHT-933
to the superfusate had any effect on 1A diameter. In the presence of
idazoxan, which had no effect by itself on resting diameter (20 ± 2 µm under 105 M idazoxan),
there was also no observable vasodilation or vasoconstriction during
application of BHT-933. Vehicle application had no effect on arteriolar
diameter.
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2-mediated response when
2-receptors are present, three
rats (196 ± 4 g body wt) were used to evaluate the effect
of BHT-933 on spinotrapezius muscle arcade arterioles. The mean resting
diameter of the arterioles studied here
(n = 6) was 13 ± 1 µm, and mean
passive diameter was significantly greater, averaging 20 ± 3 µm.
Figure 2 shows that direct application of
BHT-933 to the arteriolar wall and bolus addition of BHT-933 to the
superfusate caused significant dose-dependent constrictions from
control. Constrictions to 5 and 15 psi and bolus application averaged 2 ± 1, 3 ± 1, and 5 ± 2 µm, respectively, with
108 M BHT-933 (Fig.
2A) and 3 ± 1, 6 ± 2, and 5 ± 2 µm, respectively, with
105 M BHT-933 (Fig.
2B). All constrictions to BHT-933
were completely blocked by
105 M idazoxan, except at
the highest agonist bath concentration, where a slight but significant
constriction remained (Fig. 2B).
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Effect of NE on intestinal arterioles.
A total of four rats (211 ± 6 g body wt) were used in these
experiments. The mean resting diameter of the arterioles studied here
(n = 7) was 20 ± 3 µm, and mean
passive diameter was significantly greater, averaging 35 ± 2 µm.
Figure 3 shows that direct application of
NE (pipette concn of 106 M)
to the arteriolar wall at pressures of 5, 10, and 15 psi induced constrictions of 5 ± 3, 10 ± 3, and 15 ± 3 µm,
respectively, and that these constrictions were unaffected by
105 M idazoxan
(constrictions of 6 ± 3, 9 ± 3, and 13 ± 4 µm from control). In contrast, responses to NE were abolished or greatly reduced in the presence of
106 M prazosin.
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Effect of sympathetic nerve stimulation on arteriolar diameter and
wall shear rate.
A total of three rats (203 ± 4 g body wt) were used to
determine the effect of perivascular nerve stimulation on 1A diameter. The mean resting diameter of the arterioles studied here
(n = 6) was 40 ± 5 µm,
and mean passive diameter was significantly greater, averaging 62 ± 4 µm. Figure 4 shows that perivascular nerve stimulation at 3, 8, and 16 Hz induced constrictions of 4 ± 1, 8 ± 2, and 17 ± 4 µm, respectively, and that addition of idazoxan to the superfusate had no significant effect on the
constrictions at 3- or 16-Hz stimulation (5 ± 2 and 21 ± 4 µm, respectively). In contrast, idazoxan significantly enhanced the
arteriolar response to 8-Hz stimulation (12 ± 2 µm). As
with NE application, responses to nerve stimulation were abolished or
greatly reduced in the presence of
106 M prazosin.
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1
and that during perivascular nerve stimulation at 3, 8, and 16 Hz WSR
dropped significantly to 1,587 ± 209, 1,087 ± 195, and 537 ± 99 s1, respectively.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We have recently reported that, in rat intestine, the magnitude and rate of arteriolar responses to sympathetic nerve stimulation are significantly increased after exposure to the NO synthase inhibitor L-NMMA (28). In that study, L-NMMA also caused a modest increase in resting arteriolar tone, but a similar augmentation of resting tone by another method did not enhance sympathetic constriction, ruling out a nonspecific effect of L-NMMA. Finally, L-NMMA's effect on sympathetic constriction could be completely reversed by excess L-arginine (28). In a second study, the sympathetic constriction of intestinal arterioles was similarly increased after inactivation of the arteriolar endothelium with CO2 embolization, and L-NMMA had no effect on sympathetic constriction after this procedure (29). Taken together, these findings indicate that endothelium-derived NO is an important modulator of sympathetic neurogenic constriction in the arteriolar network of rat intestine.
The current study focused on the possibility that endothelial
2-adrenoceptors and/or
hemodynamic shear stress could play pivotal roles in the release of NO
during sympathetic constriction in the rat intestine. The salient
findings of this study are that potential
2-receptor stimuli such as
1) the agonist BHT-933 and 2) NE or sympathetic nerve
stimulation after 1-blockade
have no effect on proximal arteriolar tone in this vascular bed and that 2-blockade has no effect
on the response of these arterioles to directly applied NE or
sympathetic nerve stimulation. These findings argue against the
existence of functional
2-adrenoceptors in this segment
of the intestinal microvasculature and therefore against their
postulated involvement in the NO-dependent attenuation of sympathetic
constriction (28, 29). In addition, the marked reduction in arteriolar
wall shear rate that we observed during sympathetic nerve stimulation
is not consistent with an important role for hemodynamic shear stress
as a continuing stimulus for NO release under these conditions.
Vascular smooth muscle adrenoceptors.
In rat striated muscle, the constriction of proximal arterioles to
exogenously applied NE is mediated jointly by smooth muscle 1- and
2-adrenoceptors (17, 27, 31).
In contrast, the constriction of these arterioles in response to
increased sympathetic nerve activity is mediated solely by
1-receptors (30). Our finding
that 1-receptor blockade
virtually abolishes both NE- and sympathetic nerve-induced constriction
of proximal arterioles in the rat intestine (Figs. 3 and 4) highlights
the difference in functional adrenoceptor populations that can exist
among different microvascular beds within the same species. Others have
reported that adrenergic constriction of arterioles and small arteries is mediated entirely by
1-adrenoceptors in rat
mesentery (1, 22, 35), and our current findings extend these
observations into the intestinal arteriolar network downstream from
these mesenteric vessels.
Endothelial adrenoceptors.
There is indirect evidence for endothelial
2-receptors in a number of
conduit arteries. In the endothelium-intact state only, the application
of selective 2-agonists or NE
in the presence of 1- and
-blockers causes relaxation of coronary, carotid, and femoral
arteries of the dog (2, 14, 18, 25, 26), coronary, carotid, femoral,
renal, and mesenteric arteries of the pig (3, 5, 14, 34), and the
aorta, mesenteric, and tail arteries of the rat (4, 11, 25). There is
mounting evidence from the rat and other species that, where present,
this 2-dependent relaxation is
mediated by endothelial NO release (4, 18, 27, 34, 38). For example,
the 2-dependent relaxation of
rat mesenteric artery rings is abolished not only by endothelial
removal but also by NO synthase inhibition (4). However, endothelial
2-receptors are apparently not
present in all arterial vessels. Selective
2-agonists have no significant vasoactive effect on canine mesenteric arteries (13), and receptor autoradiography has not provided direct evidence of these receptors in
some other conduit arteries, including two of the vessels mentioned above (dog coronary artery and rat aorta; Ref. 36). This could reflect
a true absence of receptors or, in some cases, receptor concentrations
below detection levels for this technique (36).
2-receptors are not present in
all microvascular networks. There is evidence for such receptors in rat
spinotrapezius muscle, where L-NMMA has been found to
potentiate arteriolar responses to NE before but not after
2-blockade (27). In rat
cremaster muscle arterioles,
L-NMMA augments
2-adrenergic tone to a greater
extent than 1-adrenergic tone,
raising the possibility of enhanced NO release during
2-receptor activation (31).
However, additional findings from this latter study support a different
interpretation that does not involve endothelial
2-receptors, i.e., that basally released NO interferes with
2-adrenergic tone more than
1-adrenergic tone. In addition
to the findings detailed above, we also observed that
1-receptor blockade with
prazosin did not uncover a dilator response to sympathetic nerve
stimulation or NE application (Figs. 3 and 4), as would be expected if
there were an 2-mediated
relaxing influence that was normally masked by
1-mediated constriction.
Hemodynamic shear. The shear stress associated with luminal blood flow is considered to be an important stimulus for endothelial NO release (6, 19), and the establishment of luminal flow through isolated rat mesenteric arteries leads to an endothelium-dependent attenuation of the response to sympathetic nerve stimulation (37). In light of these findings, we also evaluated the possibility that basally released NO could be responsible for the attenuation of sympathetic arteriolar constriction due to a preservation of normal hemodynamic shear stress. However, we found that sympathetic nerve stimulation at 3, 8, and 16 Hz reduced the average 1A wall shear rate by 20, 45, and 73%, respectively (Table 1), apparently due to a predominant effect of reduced flow velocity. This finding argues against the importance of hemodynamic shear as a stimulus for continued NO release under these conditions.
Although the current findings discount two potential stimuli for endothelial NO release in intestinal arterioles during increased sympathetic activity, other possibilities remain unexplored. For example, recent evidence suggesting that high O2 levels can inhibit arteriolar NO release (33) raises the possibility that the flow-related decrease in arteriolar wall PO2 during sympathetic nerve stimulation (7) could lead to increased endothelial NO release. Additional studies are necessary to evaluate this and other potential mechanisms of arteriolar NO release during periods of increased sympathetic activity. Further studies are also necessary to determine whether NO limits arteriolar sympathetic constriction via the direct interruption of smooth muscle transduction events or via prejunctional inhibition of NE release. There is evidence of both mechanisms in large arteries (15), but this issue has not been investigated at the microvascular level.| |
ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the expert technical assistance of Kim Wix in this study.
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FOOTNOTES |
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This investigation was supported by National Heart, Lung, and Blood Institute Grants HL-44012 and HL-52019.
Address for reprint requests: M. A. Boegehold, Dept. of Physiology, PO Box 9229, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9229.
Received 9 December 1996; accepted in final form 11 September 1997.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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