(Hypertension. 1997;30:1560-1565.)
© 1997 American Heart Association, Inc.
Articles |
Antihypertensive Agent Moxonidine Enhances Muscle Glucose Transport in Insulin-Resistant Rats
From the Muscle Metabolism Laboratory, Department of Physiology, University of Arizona, Tucson (E.J.H., D.L.F., E.Y.B.); the Department of Endocrinology, Eberhard-Karls University, Tübingen, Germany (S.J.); and Lilly Deutschland, Bad Homburg, Germany (J.G.).
Correspondence to Erik J. Henriksen, Department of Physiology, Ina E. Gittings Bldg #93, University of Arizona, Tucson, AZ 85721-0093. E-mail ejhenrik{at}u.arizona.edu
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Abstract |
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Abstract The sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with insulin resistance. In the present study, the effects of chronic in vivo moxonidine treatment of obese Zucker rats—a model of severe glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia—on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal muscle glucose transport activity (2-deoxyglucose uptake) were investigated. Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg body weight. Body weights in control and moxonidine-treated groups were matched, except at the highest dose, at which final body weight was 17% lower in the moxonidine-treated animals compared with controls. The moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of insulin (17% and 19%, respectively) and free fatty acids (36% and 28%, respectively), whereas plasma glucose was not altered. During an oral glucose tolerance test, the glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest moxonidine-treated obese groups. Moreover, glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle glucose transport were elicited by 2 mg/kg moxonidine. These findings indicate that in the severely insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with moxonidine can significantly improve, in a dose-dependent manner, whole-body glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal muscle glucose transport activity and reduced circulating free fatty acids.
Key Words: sympatholytics • glucose tolerance test • imidazoline receptor modulation
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Introduction |
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Essential hypertension has been shown by several investigators to be associated frequently with a decreased insulin sensitivity of whole-body glucose disposal.1 2 3 The hypertensive patient often shows a clustering of atherogenic risk factors, referred to as the "metabolic syndrome" or "Syndrome X,"4 5 and insulin resistance and the accompanying hyperinsulinemia are thought to play major roles in the etiology of this condition.6 The treatment of hypertension with centrally acting, sympatholytic compounds has included moxonidine, a selective high-affinity imidazole I1-receptor modulator (putative agonist).7 8 Recently, antihypertensive treatment with moxonidine also was associated with a decrease in fasting plasma glucose levels in a group of human subjects with hyperglycemia.9 In addition, Ernsberger et al10 11 have demonstrated that glucose tolerance in the obese spontaneously hypertensive Koletsky rat is improved with chronic moxonidine administration. However, the cellular locus for the improvement in glucose control and the potential for moxonidine to be used as an intervention in treating Syndrome X have not been addressed.
In the present study, the obese Zucker (fa/fa) rat—an animal model of severe glucose intolerance, insulin resistance of skeletal muscle glucose metabolism, hyperinsulinemia, and dyslipidemia12 13 —was used to address the following questions. (1) Does chronic (21 days at 2, 6, or 10 mg/kg) treatment with the antihypertensive agent moxonidine improve oral glucose tolerance? (2) Are alterations in whole-body glucose disposal after chronic moxonidine treatment associated with an increase in insulin-stimulated skeletal muscle glucose transport? (3) Does moxonidine treatment elicit any beneficial adaptations in circulating insulin and free fatty acid levels?
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Methods |
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Animals
Female lean (Fa/?) and obese Zucker (fa/fa) rats were purchased at 7 to 8 weeks of age from Harlan. In the 10 mg/kg moxonidine study, animals were maintained on Purina chow and water ad libitum. In the 2 and 6 mg/kg moxonidine studies, all animals were provided with 20 g of chow (the average amount of chow consumed by the 6 mg/kg moxonidine–treated animals) and water ad libitum daily. Lights were on in the animal rooms from 6 AM to 6 PM. All procedures described below were reviewed and approved by the University of Arizona Animal Use and Care Committee.
Chronic Treatment Groups
Obese animals received one of the following treatments by gavage
for 21 consecutive days: vehicle (100 mmol/L Tris, pH 7.4)
or moxonidine (2, 6, or 10 mg/kg body weight; Lilly
Deutschland). Lean animals received either vehicle or 10 mg/kg
moxonidine for 21 days. Treatments were given between 10 AM
and 12 PM. All animals were food-restricted (restricted to
6 g chow at 5 PM) the evening before the experiment.
Twenty hours after the last treatment (beginning at 7 AM),
the animals underwent an OGTT using a 1 g/kg body weight glucose
feeding by gavage.14 Blood was drawn from a cut at the tip
of the tail at 0, 15, 30, and 60 minutes after the glucose feeding.
This whole blood was thoroughly mixed with EDTA (48.4
mmol/L final concentration) and centrifuged at
13 000g to separate the plasma. Moxonidine treatments then
resumed for another 2 days. Again, 20 hours after the final moxonidine
treatment, epitrochlearis muscles were removed and prepared for
incubation.
Glucose Transport Activity
Epitrochlearis muscles were initially incubated for 60 minutes
at 37°C in 3 mL of oxygenated KHB15
containing 8 mmol/L glucose, 32 mmol/L
mannitol, and 0.1% BSA (Sigma). The right muscle from each animal was
incubated in medium containing no insulin, whereas the contralateral
muscle was incubated in medium containing a maximally effective
concentration of insulin (13.3 nmol/L; Humulin, Lilly).
Thereafter, muscles were rinsed for 10 minutes at 37°C in 3 mL of
oxygenated KHB containing 40 mmol/L mannitol,
0.1% BSA and, if present previously, insulin. The muscles were
then transferred to flasks containing 2 mL of oxygenated
KHB, 0.1% BSA, 1 mmol/L
2-deoxy[1,2-3H]glucose (2-DG, 300 mCi/mol, Sigma) and
39 mmol/L [U-14C]mannitol (0.8 mCi/mol, ICN
Radiochemicals), and insulin, if present previously. After this
final 20-minute incubation at 37°C, muscles were trimmed of fat,
extraneous muscle tissue, and connective tissue, frozen in liquid
N2, weighed, and dissolved in 0.5 mL of 0.5 mol/L
NaOH. Glucose transport activity was then calculated as described by
Henriksen and Ritter.16 This method for assessing glucose
transport activity in epitrochlearis muscles of this size has been
thoroughly studied and validated.17 In addition, the heart
was isolated, frozen, and weighed.
Blood Analyses
Plasma samples were analyzed for glucose (Sigma),
insulin (Linco Research), and free fatty acids (Wako).
Statistical Analysis
All data are presented as mean±SE. The significance of
differences between multiple groups was assessed by ANOVA with a post
hoc Dunnett's test (Statview II, Abacus Concepts). When only two
groups were compared, Student's t test was used.
P<.05 were considered significant.
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Results |
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Study 1: 10 mg/kg Moxonidine and Ad Libitum Feeding
The initial study involved treatment of ad libitum–fed lean and obese Zucker rats with a dose of moxonidine known to elicit maximal reductions in blood pressure in insulin-resistant rat models.10 18 Chronic treatment with 10 mg/kg moxonidine of ad libitum–fed obese Zucker rats resulted in markedly less weight gain and a significantly lower (17%, P<.05) final body weight compared to obese vehicle-treated animals (Table 1
), likely due to reduced food
consumption at this high dose.10 In contrast, chronic
treatment with this dose of moxonidine did not significantly affect
body weight gain in ad libitum-fed lean Zucker rats. Heart weight was
significantly reduced by moxonidine treatment in both lean (11%,
P<.05) and obese (14%, P<.05) Zucker rats.
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Compared with obese controls, obese Zucker rats treated with 10
mg/kg moxonidine displayed significantly reduced
(P<.05) fasting plasma insulin (19%) and free fatty acids
(28%) levels, whereas fasting glucose levels were not altered (Table
).
Only fasting plasma insulin was greater (23%, P<.05) in
the lean animals because of the 10 mg/kg moxonidine
treatment.
During the OGTT, the glucose response (incremental area under the
curve) was 67% lower (98±27 versus 301±27
mmol/Lxminute, P<.05) in the 10 mg/kg
moxonidine–treated obese animals compared with the obese control group
(Fig 1). Plasma insulin was significantly
lower at the 30- and 60-minute time points of the OGTT in the
moxonidine-treated obese animals. Associated with this increased
glucose tolerance, insulin-mediated glucose transport in the
epitrochlearis muscle of the 10 mg/kg moxonidine-treated obese
animals was enhanced by 70% (P<.05) (Fig 2).
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Interestingly, chronic treatment of ad libitum–fed lean Zucker rats
with 10 mg/kg moxonidine led to a 40% reduction (106±29 versus
177±36 mmol/Lxminute) in the glucose response during the
OGTT (see Fig 1). This was associated with a 39% greater insulin
response (5436±1497 versus 3899±672 pmol/Lxminute).
Insulin-mediated skeletal muscle glucose transport activity was not
altered (Fig 2).
Study 2: 2 and 6 mg/kg Moxonidine and Pair Feeding
To avoid the confounding influence of altered body weight gain on
these metabolic parameters in the obese
animals, a subsequent study was conducted in which pair feeding of
obese Zucker rats was incorporated and two doses of moxonidine, one
with a more pronounced hypotensive effect (6 mg/kg) and another
with a marginal hypotensive effect (2 mg/kg),18 were
used. With pair feeding (20 g chow per day, the amount consumed by the
6 mg/kg moxonidine–treated obese group), the final body weights
of the 2 and 6 mg/kg moxonidine–treated obese groups were not
significantly different from those of the respective vehicle-treated
control groups (Table). Heart weights again were significantly reduced
in the 2 mg/kg (5%, P<.05) and 6 mg/kg
(13%, P<.05) moxonidine–treated obese groups compared
with their respective controls.
Compared with controls, obese Zucker rats treated with 6
mg/kg moxonidine displayed significantly (P<.05)
reduced fasting plasma insulin (17%) and free fatty acids (36%)
(Table). The glucose response during an OGTT was 47% lower (164±25
versus 311±28 mmol/Lxminute, P<.05), whereas
the insulin response tended to be lower (39830±3114 versus 54096±7379
pmol/Lxminute, 26%) (Fig 3).
Finally, insulin-mediated glucose transport activity in the isolated
epitrochlearis muscle was 39% greater (P<.05) than control
after the 6 mg/kg moxonidine treatment period (Fig 4).
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In contrast, the 2 mg/kg moxonidine treatment did not
significantly alter fasting plasma insulin or free fatty acid levels
(Table). Although the glucose response during the OGTT of these 2
mg/kg moxonidine–treated obese animals was 41% lower (143±14
versus 244±21 mmol/L per minute, P<.05) (Fig 3), this likely was not due to altered insulin action, because the
insulin response (Fig 3) and insulin-mediated muscle glucose transport
activity (Fig 4) were not changed significantly after treatment with 2
mg/kg moxonidine.
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Discussion |
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Moxonidine is a centrally acting, selective imidazoline I1-receptor modulator that reduces sympathetic outflow, thereby lowering blood pressure in a number of experimental animal models and human subjects.8 11 Because essential hypertension is often accompanied by insulin resistance,1 2 3 it is important to determine the effect of antihypertensive treatments on insulin action. In the present study, we have demonstrated that chronic treatment of the insulin-resistant, hyperinsulinemic, and dyslipidemic obese Zucker rat with moxonidine leads to improved whole-body glucose tolerance (Figs 1
and 3), likely resulting
from enhanced insulin-stimulated skeletal muscle glucose transport
activity (Figs 2 and 4) and possibly via reduced circulating free fatty
acid levels (Table).
The results of this study are essentially in agreement with those of
Ernsberger et al,10 11 who studied the
metabolic effects of moxonidine on the ad libitum–fed
obese spontaneously hypertensive Koletsky rat. These investigators
reported that chronic (90 days) oral administration of a high dose of
moxonidine (8 mg/kg per day) resulted in reductions in fasting
plasma insulin, triglycerides, and total
cholesterol,10 as well as in significantly
improved oral glucose tolerance.10 11 However, these
results are confounded by the large body-weight loss experienced by the
moxonidine-treated obese animals, likely due to the reduced food intake
of this group.10 We have demonstrated that chronic
administration of moxonidine can elicit beneficial
metabolic adaptations (Table, Fig 3) in the absence of
significant differences in body weight between the drug-treated and
control groups (Table). Moreover, we have significantly extended the
investigation of Ernsberger et al10 by demonstrating that
enhanced skeletal muscle glucose transport likely underlies the
increased glucose tolerance in the moxonidine-treated obese groups (Fig 3).
It is clear from the present results and those of Ernsberger et
al10 11 that the effects of chronic 10 mg/kg
moxonidine treatment are quite different in lean versus obese rats. In
the lean, insulin-sensitive, and normolipidemic animals, the primary
effect of moxonidine treatment was on improved glucose tolerance during
the OGTT, most likely as a result of enhanced insulin levels during the
test (Fig 1). This would suggest that moxonidine in these lean animals
acts primarily on the ß-cells of the pancreas to increase insulin
secretion.11 Whereas some previous in vitro studies have
indicated that, at high doses, moxonidine can inhibit basal insulin
secretion from isolated pancreatic islets,19 20 other
investigations indicate that lower doses of moxonidine actually can
potentiate the effect of glucose to stimulate insulin release from
isolated pancreatic islets.20 In the obese,
insulin-resistant, and dyslipidemic animals, the
enhanced glucose tolerance after moxonidine treatment was associated
with a lower plasma level of insulin during the OGTT (Fig 1), enhanced
insulin-stimulated muscle glucose transport activity (Fig 2), and lower
circulating free fatty acid levels (Table). This indicates that the
mode of action of this agent in the obese animal is much more complex
and includes central, sympatholytic actions of the drug, as well as
actions, directly or indirectly, on skeletal muscle and adipose
tissue.
It is of considerable interest that other central sympatholytic agents,
such as clonidine, produce a hyperglycemic response and worsen glucose
tolerance when administered in vivo in animals and in
humans.21 22 23 It is believed that these detrimental effects
of clonidine on glucose metabolism are mediated by the
activation of 
2-adrenergic receptors located in the
central nervous system23 and on the ß-cells of the
pancreas.22 Because moxonidine selectively
activates I1-imidazoline receptors and has
relatively minimal interaction with 2-adrenergic
receptors,11 this highlights the potential importance of
the involvement of I1-imidazoline receptors in the
beneficial effects of central sympatholytic agents in improving glucose
tolerance in conditions of insulin resistance.
Substantial evidence has accumulated indicating that, under certain
conditions, insulin resistance of skeletal muscle glucose disposal is
related to elevated circulating free fatty acid levels.24
In the present study, the obese control animals displayed markedly
elevated plasma-free fatty acid levels (Table) and insulin resistance
of skeletal muscle glucose transport (Fig 2) compared with age-matched
lean animals. Moreover, chronic treatment with the higher dose of
moxonidine (6 mg/kg) was associated with a substantial reduction
in free fatty acid levels (Table) and an increase in insulin-stimulated
muscle glucose transport activity (Fig 4), whereas after treatment with
a lower dose (2 mg/kg), neither variable was significantly
altered compared with the vehicle-treated control. The reduction in
free fatty acid levels may have resulted from decreased adipose tissue
lipolysis, because moxonidine is known to reduce circulating levels of
norepinephrine.18 It is possible that the
improvement in insulin action observed with chronic moxonidine
treatment was secondary to the reduction in plasma free fatty acids
elicited by this intervention.
Interestingly, Ishizuka et al25 recently reported that the level of IRS-1, an essential component of the intracellular insulin signaling pathway for activation of glucose transport,26 was reduced by 30% in skeletal muscle from the obese spontaneously hypertensive Koletsky rat compared with lean hypertensive littermates. Moreover, the IRS-1 level increased by 24% in the obese animals after chronic treatment with 8 mg/kg per day moxonidine. Although these data are consistent with a putative role of an enhanced IRS-1 level in the metabolic improvements associated with this moxonidine treatment, it is impossible to attribute the increase in IRS-1 solely to the effects of moxonidine, because these ad libitum–fed, moxonidine-treated animals also experienced a substantial reduction in body weight.10
Several other antihypertensive agents also elicit similar beneficial
metabolic adaptations in the animal model of insulin
resistance, hyperinsulinemia, and
dyslipidemia used in the present study. The
angiotensin-converting enzyme inhibitors
captopril27 and trandolapril28 and the
ß-adrenergeric receptor modulator
(ß1-antagonist/ß2-agonist)
celiprolol29 increase insulin-stimulated skeletal muscle
glucose transport and bring about a decline in circulating insulin and
free fatty acid levels when administered at doses known to reduce blood
pressure. The improvement in insulin action on skeletal muscle glucose
transport in this animal model of insulin resistance elicited by
moxonidine (70%) is very similar in magnitude to that brought about by
the ACE inhibitors (60% to 70%)27 28 or
celiprolol (68%).29 As with chronic ACE
inhibitor treatment,27 28 chronic moxonidine
also leads to small but significant reductions in cardiac mass, even in
lean animals (Table). This effect of moxonidine may be related to a
reduced sympathetic drive to the heart, or it may be related to its
ability to reduce peripheral vascular
resistance.8 Based on the results of the present study
and previous reports,10 11 it appears that moxonidine, a
sympatholytic compound, can be considered, with the previously
mentioned antihypertensive agents, to be a potentially useful
intervention in the overall treatment of individuals with Syndrome X.
Thus, with these types of compounds, one could treat not only
hypertension but also the other associated pathologies, primarily
insulin resistance, hyperinsulinemia, impaired
glucose tolerance, and dyslipidemia, thereby reducing
multiple cardiovascular disease risk factors.
It should be noted that additional mechanisms other than improved
skeletal muscle glucose transport may underlie some of the improvement
in glucose tolerance brought about by the lower dose of moxonidine (Fig 3). Although a portion of the enhanced glucose tolerance may be
attributed to the small (
20%), but statistically insignificant,
increase in insulin-mediated muscle glucose transport (Fig 4), it is
also possible that decreased hepatic glucose production may be
caused by moxonidine treatment at this dose. It is clear that further
investigations in this area are necessary to address this point.
In conclusion, the sympatholytic antihypertensive agent moxonidine, a centrally acting, selective I1-imidazoline receptor modulator (putative agonist), effectively and dose-dependently enhances whole-body glucose tolerance in the obese Zucker rat, an animal model of insulin resistance, hyperinsulinemia, glucose intolerance, and dyslipidemia. This effect likely is mediated by an increase in insulin action on skeletal muscle glucose transport and by a reduction in circulating free fatty acid levels. This compound appears to be useful in the treatment of obese hypertensive and insulin-resistant syndromes, such as Syndrome X. Future studies should investigate the potential cellular adaptations that may underlie the improvements of insulin-stimulated glucose transport activity after treatment with the antihypertensive agent moxonidine.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants from the Arizona Affiliate of the American Heart Association and Lilly Deutschland, Bad Homburg, Germany.
Received February 12, 1997; first decision March 18, 1997; accepted June 27, 1997.
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