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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 examined skeletal
muscle microvessel reactivity to constrictor stimuli in obese (OZR)
versus lean Zucker rats (LZR). Gracilis arteries from both rat groups
were isolated, cannulated with glass micropipettes, and viewed via
television microscopy. Changes in vessel diameter were measured with a
video micrometer. Arterial constriction to norepinephrine was elevated
in OZR versus LZR, although vasoconstrictor reactivity to endothelin
and angiotensin II was unaltered. Differences in reactivity between
vessels of LZR and OZR were not explained by the loss of either
endothelial nitric oxide synthase or 
-adrenergic receptor function.
Reactivity of in situ cremasteric arterioles of OZR to norepinephrine
was elevated versus LZR. Treatment with prazosin increased the diameter of in vivo gracilis arteries of OZR to levels determined in LZR and
also normalized blood pressure in OZR. These results suggest that the
constrictor reactivity of skeletal muscle microvessels in OZR is
heightened in response to 
-adrenergic stimuli and that development
of diabetes in OZR may be associated with impaired skeletal muscle
perfusion and hypertension due to microvessel hyperreactivity in
response to sympathetic stimulation.
skeletal muscle microcirculation; hypertension; norepinephrine
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TYPE 2 DIABETES MELLITUS impacts ~11 million Americans and is a potent risk factor for the development of peripheral vascular disease, a debilitating condition impacting nearly 60 million Americans. The effects of diabetes may be exacerbated when combined with hypertension and obesity, a condition known as Syndrome X. Despite this correlation, the pathophysiological processes linking Syndrome X and impaired limb perfusion remain unclear. We hypothesize that a contributing factor to poor muscle perfusion in patients with Syndrome X is altered reactivity of skeletal muscle microvessels to vasoconstrictor stimuli.
The obese Zucker rat (OZR) has been chosen as a model of Syndrome X
because it has been previously reported to demonstrate concomitant
development of hypertension, type 2 diabetes mellitus, and obesity
(9, 18). We examined the constrictor reactivity of
skeletal muscle resistance arteries (gracilis muscle) and distal arterioles (cremaster muscle) to norepinephrine of obese Zucker rats
compared with their lean counterparts (LZR). The specificity of altered
adrenergic reactivity was assessed by comparing skeletal muscle
microvessel responses to norepinephrine, endothelin, and angiotensin
II. The role of nitric oxide was probed via inhibition of nitric oxide
synthase with NG-nitro-L-arginine
methyl ester (L-NAME), and the role of -adrenoreceptors was examined with the specific antagonist propranolol. The data obtained in these studies suggest that increased microvascular sensitivity to adrenergic stimulation may be associated with
hypertension and reduced hindlimb perfusion in the OZR.
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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 13- to 15-wk-old male LZR and OZR (Harlan) fed standard rat chow and tap water ad libitum. Rats were housed in an American Association for Accreditation of Laboratory Animal Care-accredited animal care facility at the Medical College of Wisconsin, and all protocols were approved by the Institutional Animal Care and Use Committee. For all experiments, rats were anesthetized with an injection of pentobarbital sodium (60 mg/kg ip), and a carotid artery was cannulated for determination of arterial pressure. Supplemental injections of anesthetic were given via intraperitoneal injection as needed.
Preparation of isolated vessels. Gracilis arteries were surgically dissected from the anesthetized rat, as described previously (5, 6). Arteries were placed in a heated (37°C) chamber that allowed the lumen and exterior of the vessel to be perfused and superfused, respectively, with physiological salt solution (PSS) from separate reservoirs. The PSS used in these experiments was equilibrated with 21% O2-5% CO2-74% N2 and had the following composition (mM): 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.6 CaCl2, 1.18 NaH2PO4, 24 NaHCO3, 0.026 EDTA, and 5.5 glucose. Vessels 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 intraluminal pressure and luminal gas concentrations to be controlled. Vessel diameter was measured using television microscopy and an on-screen video micrometer.
Arteries were extended to their in vivo length (determined before removal of the vessel from the anesthetized rat) and equilibrated at 80% of the mean arterial pressure of the animal to approximate the perfusion pressure encountered in vivo (LZR = 95 ± 5.4 mmHg; OZR = 118 ± 4.1 mmHg; Ref. 6). Any vessel that did not demonstrate active tone at rest was discarded. 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.
Measurement of cremaster arteriolar diameter. For each experiment, a cremaster muscle in each rat was prepared for television microscopy, as described previously (4). After completion of the muscle preparation, the tissue was continuously superfused with PSS, equilibrated with a gas mixture containing 5% CO2-95% N2, and maintained at 35°C as it flowed over the muscle. Arteriolar diameter was determined with a video micrometer, accurate to ±1 µm.
Measurement of gracilis artery diameter in vivo. In vivo determination of gracilis artery diameter was accomplished using a modification of stroboscopic microscopy techniques described previously for the in vivo beating heart (14). For each experiment, the skin was removed over the ventral surface of the thigh, and subcutaneous fat was gently removed. The animal was placed under a stroboscopic microscope (magnification ×100, Leitz), and the surfaces of the femoralis and gracilis muscles were illuminated by a strobed light source (Chadwick-Helmuth) flashed at 120 Hz. Images were acquired, stored, and analyzed using Scion Image Software for the MacIntosh.
Constrictor agonists.
The constrictor reactivity of isolated and in situ skeletal muscle
microvessels from LZR and OZR was assessed in response to 1)
norepinephrine (10
10 -106 M),
2) angiotensin (1010-107
M), and 3) endothelin
(1012-109 M). To determine the role of
nitric oxide as a contributor to the vascular constrictor reactivity,
the concentration versus response curves in response to norepinephrine
were also performed in the presence of 104 M
L-NAME. Finally, to determine the contribution of
individual adrenergic receptors to the constrictor reactivity of
vessels to norepinephrine, concentration versus response curves were
also evaluated in the presence of 105 M propranolol
(-adrenergic receptor antagonist) or 105 M
phentolamine (-adrenergic receptor antagonist).
Mathematical and statistical analyses. All data are presented as means ± SE. Significant differences between experimental conditions for all data were determined using analysis of variance, repeated measures analysis of variance, or Student's t-test, where appropriate. All post hoc analyses were done using Fisher's probable least significant difference test. In all cases, a probability level of P < 0.05 was considered to be 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 presents data describing the
resting diameter of in vitro gracilis arteries from LZR and OZR under
the experimental conditions of the present study. There was no
difference in resting diameter of skeletal muscle arterioles of LZR and
OZR under control conditions. Treatment with L-NAME reduced
arteriolar diameter in LZR only. Application of either propranolol or
phentolamine had no effect on basal arterial tone.
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Table 2 presents baseline hemodynamic
data from LZR and OZR under the experimental conditions of the study.
OZR were heavier and were hypertensive relative to LZR, but heart rate
was not different. Left ventricular mass, expressed as a percentage of total heart weight, was modestly increased, further substantiating the
presence of hypertension.
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Data describing the norepinephrine-induced constriction of isolated
gracilis arteries from LZR and OZR are presented in Fig. 1. In OZR, constriction of skeletal
muscle resistance arteries following application of norepinephrine was
markedly increased across the agonist concentration range compared with
responses determined in LZR. This difference is reflected in a 15-fold
leftward shift in the ED50 concentration for the
-adrenergic agonist (LZR = 6.4 ± 2.4 × 108 M vs. OZR = 4.3 ± 0.7 × 109 M; P < 0.01).
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Figure 2 presents data describing the
constriction of isolated gracilis arteries in response to challenge
with angiotensin II (Fig. 2A) or endothelin (Fig.
2B). In contrast to the shift in the constrictor reactivity
of vessels from OZR in response to -adrenergic stimulation, the
vascular response of vessels to either endothelin or angiotensin II was
similar in OZR versus to LZR.
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Figure 3 presents data describing the
effects of treatment of isolated gracilis arteries from LZR with the
nitric oxide synthase inhibitor L-NAME, the -adrenergic
antagonist phentolamine, or the -adrenergic antagonist propranolol
on the constriction of these vessels in response to challenge with
norepinephrine. Treatment of vessels with L-NAME had no
effect on arterial constriction in response to norepinephrine (Fig.
3A), suggesting that loss of endothelial nitric oxide cannot
explain the increased adrenergic reactivity observed in Fig. 1.
Propranolol (Fig. 3B) was also without effect, suggesting
that the loss of -adrenergic receptor function also could not
explain the observed hyperresponsiveness of vessels from OZR to
norepinephrine. Treatment of isolated gracilis arteries of LZR with
phentolamine nearly abolished vascular reactivity to norepinephrine
(Fig. 3B), demonstrating the predominance of -adrenergic
receptors in mediating norepinephrine-induced contraction of these
microvessels.
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Data describing the effects of blockade of -adrenergic receptors
following intravenous infusion of prazosin (50 µg/kg) on the resting
tone of in vivo gracilis arteries of LZR and OZR are presented in Fig.
4. After an intravenous infusion of a
bolus of prazosin, the diameter of gracilis arteries in LZR was not altered from their control value. In contrast, blockade of
-adrenergic receptors in OZR caused a significant dilation of
gracilis arteries, such that arterial diameter was not different from
that determined in LZR under control conditions.
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In Fig. 5, data are presented that
describe the reactivity of in situ cremasteric arterioles from LZR and
OZR in response to application of norepinephrine (Fig. 5A)
or angiotensin II (Fig. 5B). Although somewhat less
pronounced than upstream effects, cremasteric arterioles from OZR
demonstrated a significantly greater reactivity in response to
norepinephrine versus responses in distal arterioles from LZR (LZR
ED50 = 5.8 ± 2.2 × 109 M;
OZR ED50 = 5.7 ± 1.1 × 1010
M). Responses of cremasteric arterioles to following challenge with angiotensin II were not different between LZR and OZR (Fig. 5B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The principle new finding in this study is that -adrenergic
reactivity in the microvasculature of the hindlimb is markedly augmented in the OZR, a model of type 2 diabetes and Syndrome X. Whereas altered reactivity to vasodilators is the OZR is well established (10, 12), the effects of this condition on
vasoconstrictor reactivity are less clear, because studies reporting
increased vascular reactivity to constrictor stimuli (8, 13,
17) have been countered by studies to the contrary (3, 11,
15). Within studies reporting augmented constriction,
controversy exists regarding which constrictor stimuli are affected and
which stimuli are unaltered (8, 13, 16). Many of these
studies are further confounded by restriction of observations to
conduit arteries or by competing effects in in vivo systems. To address
this final issue, the present study focused primarily on the
investigation of isolated skeletal muscle resistance arteries, although
we also included additional experiments to examine microvessel
constrictor reactivity in both in vivo skeletal muscle resistance
arteries and in situ skeletal muscle arterioles.
One significant advantage of collecting data regarding the reactivity
of isolated skeletal muscle microvessels is that it allows for the
determination of vascular responses, and any alteration therein that
may develop in response to an experimental condition or pathology
without the potentially confounding effects of the specific agonists on
hemodynamic characteristics or nonvascular tissues. Thus the dramatic
increase in -adrenergic reactivity in the isolated skeletal muscle
resistance artery observed in OZR (Fig. 1) indicates a fundamental
alteration in vascular responsiveness to norepinephrine. Furthermore,
the additional experiments performed in the present study demonstrating
an increased -adrenergic sensitivity of in vivo gracilis arteries
and in situ cremasteric arterioles provide important information in
that these results demonstrate that observations using isolated
resistance arteries are also manifested under in vivo conditions and at
multiple levels in the skeletal muscle microvascular network. The
reduced diameter of in vivo gracilis arteries of OZR versus LZR under
control conditions (Fig. 4), as assessed by stroboscopic
epiillumination, was restored following administration of the
-adrenergic antagonist prazosin. In addition, under these same
conditions, the elevated blood pressure present in OZR was normalized
to levels seen in LZR, providing further evidence that that vascular
-adrenergic sensitivity is elevated in OZR versus LZR. Finally, the
reactivity of distal arterioles of in situ cremaster muscles in
response to adrenergic stimulation with norepinephrine was also
significantly increased in OZR relative to LZR. When taken together,
these data indicate that the development of obesity, type 2 diabetes
mellitus, and hypertension, as manifested in OZR, results in marked
changes in the contractile behavior of resistance arteries with direct consequences on in vivo microvascular resistance.
The mechanism by which -adrenergic microvessel reactivity is
increased in OZR is presently unknown, although the results of the
present study suggest that this altered reactivity is specific to
-adrenergic responses, because microvessel responses following challenge with angiotensin II and endothelin were unaltered in OZR
versus LZR (Figs. 2 and 5). This finding is in agreement with the
recent study by Carlson et al. (2) in which the authors demonstrated that sympathetic blockade, but not inhibition of angiotensin-converting enzyme, reduced blood pressure in OZR. The
results of the present study also suggest that the previously reported
loss of endothelial nitric oxide efficacy (7) was not a
contributor to the augmented -adrenergic reactivity of skeletal
muscle microvessels of OZR, because this response was unaltered
following inhibition of nitric oxide synthase activity with
L-NAME. Finally, our data indicate that blockade of
-adrenergic receptors (propranolol) had no effect on skeletal muscle
microvessel reactivity in response to norepinephrine, whereas
application of the -adrenergic receptor antagonist phentolamine
abolished all responses to norepinephrine. These data suggest that
there may be a fundamental alteration in the signaling pathways of
-adrenergic receptor stimulation that accounts for the exaggerated
contractile response of skeletal muscle microvessels observed in the
present studies. The results of the present study warrant future
investigation into potential factors that might alter the sensitivity
of -adrenoceptor behavior in skeletal muscle microvessels of OZR,
alterations to the plasma membrane lipid profile (1), or
the tonic effects of elevated blood glucose or insulin levels present
in Syndrome X (17).
The results of the present study describe a marked alteration to
the reactivity of skeletal muscle microvessels in OZR, a model of
Syndrome X. Microvessel constrictor responses following -adrenergic
stimulation were significantly enhanced in OZR versus LZR, although
reactivity in response to challenge with angiotensin II and endothelin
were not altered. In an in vivo setting, pharmacological blockade of
-adrenoceptors normalized both skeletal muscle microvessel diameter
and blood pressure in OZR to levels determined in LZR control animals.
The data suggest that a fundamental alteration to the behavior of
skeletal muscle microvessels develops in the OZR with the progression
of type 2 diabetes mellitus, and hypertension that may shift the
balance of constrictor and dilator influences to favor compromised
skeletal muscle perfusion.
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ACKNOWLEDGEMENTS |
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The authors thank Deron Jones for expert technical assistance during these studies and to Drs. W. M. Chilian and J. H. Lombard for helpful suggestions during the preparation of this manuscript.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-65289 and HL-29587, an American Heart Association Scientist Development Grant (to D. W. Stepp), and a Medical College of Wisconsin Faculty Development Grant (to J. C. Frisbee).
Address for reprint requests and other correspondence: D. W. Stepp, Vascular Biology Center, CB-3212A, Medical College of Georgia, Augusta, GA 30912 (E-mail: dstepp{at}mail.mcg.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.
10.1152/ajpheart.00695.2001
Received 3 August 2001; accepted in final form 2 November 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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P > 0.05 vs. OZR control diameter.
