Articles

Antihypertensive Agent Moxonidine Enhances Muscle Glucose Transport in Insulin-Resistant Rats

Erik J. Henriksen, Stephan Jacob, Donovan L. Fogt, Erik B. Youngblood, Jochen Gödicke
https://doi.org/10.1161/01.HYP.30.6.1560
Hypertension. 1997;30:1560-1565
Originally published December 1, 1997

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Abstract

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.

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?

Methods

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.

Results

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.

View this table:
Table 1.

Effects of Chronic Moxonidine Treatment on Body Weight, Heart Wet Weight, and Fasting Plasma Glucose, Insulin, and Free Fatty Acids in Zucker Rats

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/L×minute, 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⇓).

Figure 1.
Figure 1.

Effects of chronic treatment with 10 mg/kg moxonidine and ad libitum feeding on glucose tolerance in lean and obese Zucker rats. Animals were treated for 21 days with either vehicle or moxonidine and the glucose and insulin responses to a 1 g/kg OGTT were determined. Data are mean±SE for 8 to 10 animals per group. *P<.05 versus vehicle-treated group at same time point.

Figure 2.
Figure 2.

Effect of chronic treatment with 10 mg/kg moxonidine and ad libitum feeding on insulin-mediated skeletal muscle glucose transport activity in lean and obese Zucker rats. Animals were treated for 21 days with either vehicle or moxonidine (MOX). 2-Deoxyglucose uptake in the absence of insulin (open bars) and in the presence of insulin (filled bars), as well as the net increase in 2-deoxyglucose uptake due to insulin (shaded bars), were assessed in the isolated epitrochlearis muscles. Data are mean±SE for 8 to 10 animals per group. *P<.05 versus vehicle-treated group at same time point.

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/L×minute) 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/L×minute). 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/L×minute, P<.05), whereas the insulin response tended to be lower (39830±3114 versus 54096±7379 pmol/L×minute, 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⇓).

Figure 3.
Figure 3.

Effects of chronic treatment with 2 or 6 mg/kg moxonidine on glucose tolerance in pair-fed obese Zucker rats. Animals were treated for 21 days with either vehicle or moxonidine, and the glucose and insulin responses to a 1 g/kg OGTT were determined. All animals consumed 20 g of chow per day. Data are mean±SE for 8 to 10 animals per group. *P<.05 versus vehicle-treated group at same time point.

Figure 4.
Figure 4.

Effect of chronic treatment with 2 or 6 mg/kg moxonidine on insulin-mediated skeletal muscle glucose transport activity in pair-fed obese Zucker rats. Animals were treated for 21 days with either vehicle or moxonidine (MOX). 2-Deoxyglucose uptake in the absence of insulin (open bars) and in the presence of insulin (filled bars), as well as the net increase in 2-deoxyglucose uptake due to insulin (shaded bars), were assessed in the isolated epitrochlearis muscles. All animals consumed 20 g of chow per day. Data are mean±SE for 8 to 10 animals per group. *P<.05 versus vehicle-treated group at same time point.

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.

Discussion

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 β-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 α2-adrenergic receptors located in the central nervous system23 and on the β-cells of the pancreas.22 Because moxonidine selectively activates I1-imidazoline receptors and has relatively minimal interaction with α2-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 β-adrenergeric receptor modulator (β1-antagonist/β2-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.

Selected Abbreviations and Acronyms

ACE=angiotensin-converting enzyme
IRS-1=insulin receptor substrate-1
KHB=Krebs-Henseleit buffer
OGTT=oral glucose tolerance test

Acknowledgments

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.
  • Revision received March 18, 1997.
  • Accepted June 27, 1997.

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  • Antihypertensive Agent Moxonidine Enhances Muscle Glucose Transport in Insulin-Resistant Rats
    Erik J. Henriksen, Stephan Jacob, Donovan L. Fogt, Erik B. Youngblood and Jochen Gödicke
    Hypertension. 1997;30:1560-1565, originally published December 1, 1997
    https://doi.org/10.1161/01.HYP.30.6.1560
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