Elsevier

Autonomic Neuroscience

Volume 130, Issues 1–2, 30 December 2006, Pages 41-50
Autonomic Neuroscience

Nocturnal hypertension in mice consuming a high fructose diet

https://doi.org/10.1016/j.autneu.2006.05.006Get rights and content

Abstract

Objective

To investigate the effect of fructose consumption on the light/dark pattern of blood pressure, heart rate and autonomic neural function in mice.

Background

Insulin resistant diabetes is associated with hypertension and autonomic dysfunction. There is evidence that the increasing incidence of diabetes may be related to dietary changes, including consumption of high levels of fructose.

Design/methods

C57/BL mice, instrumented with radiotelemetric arterial catheters, were fed a control or high fructose diet (60%). Cardiovascular parameters measured were light/dark pattern of mean arterial pressure (MAP), heart rate (HR) and variability (time and frequency domain). We also measured plasma insulin, glucose, lipids and angiotensin II (Ang II) as well as glucose tolerance. In situ hybridization was used to measure brainstem expression of tyrosine hydroxylase (TH) and Ang AT1a mRNA.

Results

Fructose diet (8 weeks) produced an increase in MAP, variance and low frequency domain (14 ± 3 vs. 33 ± 4 mm Hg2, variance and 10 ± 2 vs. 26 ± 4 mm Hg2, LF, control vs. fructose, P < 0.01). The changes occurred only at night, a period of activity for mice. Glucose tolerance was attenuated in the fructose group. Fructose also increased plasma cholesterol (80 ± 1 vs. 126 ± 2 mg/dl, control vs. fructose, P < 0.05) and plasma Ang II (18 ± 5 vs.65 ± 12 pg/ml, control vs. fructose, P < 0.05). Depressor responses to α1-adrenergic blockade with prasozin were augmented in fructose-fed mice. Using quantitative in situ hybridization, we found that Ang AT1a receptor and TH mRNA expression were significantly increased in the brainstem locus coeruleus.

Conclusion

A high fructose diet in mice produced nocturnal hypertension and autonomic imbalance which may be related to activation of sympathetic and angiotensin systems.

Introduction

Consumption of high levels of fructose in humans and animals leads to insulin resistance, obesity, hypertension and lipid abnormalities (Basciano et al., 2005). These symptoms are characteristic of type 2 diabetes, which has reached epidemic levels in western societies. It is the cardiovascular pathologies, associated with diabetes, which are closely tied to the mortality and morbidity. Diabetics commonly have hypertension along with a nighttime, non-dipper pattern in blood pressure (BP) levels, a condition which is associated with end organ damage (Nielsen et al., 1995, Nakano et al., 1998).

There is much information on the cardiovascular and metabolic effects of a high fructose diet in animal models. Fructose-fed rats show a moderate hypertension and glucose intolerance, associated with high levels of plasma insulin, glucose, cholesterol and triglycerides (Dai and McNeill, 1995, Katovich et al., 2001, Kamide et al., 2002, Hsieh, 2005). In mice, there is evidence that fructose alters glucose metabolism and lipid levels (Nagata et al., 2004). However, there is no information on the effects of fructose consumption on the circadian pattern of blood pressure and heart rate or on autonomic function. This is an important gap in view of clinical data in diabetics which document autonomic dysfunction and attenuation of day/night BP ratio (Nielsen et al., 1995, Nakano et al., 1998).

Our study used radiotelemetry which allows for long term measurement of BP under low stress conditions. It is particularly useful for the measurement of day/night cardiovascular rhythms (Chen et al., 2006). The telemetric method is combined with autoregressive spectral analysis which is a non-invasive, statistical means for studying autonomic function in freely moving animals (Farah et al., 2004, Joaquim et al., 2004). Heart rate and blood pressure variability (HRV and BPV), estimated in time or frequency (spectral analysis) domain, are used to detect early abnormalities in autonomic modulation of the cardiovascular system (Pagani et al., 1988, Spallone et al., 1997, Fazan et al., 1999). Changes often occur before or without alterations in BP and HR. For example, reduced HRV is associated with an increased risk for sudden death in patients with chronic heart failure (Galinier et al., 2000, La Rovere et al., 2003). Moreover, in humans with diabetes mellitus, spectral analysis of HR disclosed a significant decrease in variability, which was apparent even before any changes in other cardiovascular parameters (Pagani et al., 1988). The importance of BPV in clinical pathologies was established with reports that increased BPV was associated with end-organ damage (Zanchetti and Mancia, 1987, Parati et al., 1987, Mancia et al., 1988).

In terms of the mechanisms behind the fructose-induced cardiovascular changes, there is evidence for a role of the sympathetic nervous and renin angiotensin system (RAS). Sympathectomy (adrenal medullectomy coupled with neurotoxin exposure) attenuated the development of hypertension in rats fed a high fructose diet, suggesting a role for the sympathetic nervous system (Verma et al., 1999). Fructose feeding also increased urinary catecholamine excretion and adrenergic receptor expression (Kamide et al., 2002). Evidence for a role for the RAS in fructose-induced cardiovascular changes was seen by the increased expression of Ang receptors in the vasculature and depressor effect of Ang receptor antagonists (Katovich et al., 2001, Hsieh, 2005). In mice, there is data which show that a high fructose diet caused activation of the vascular RAS (Shinozaki et al., 2004).

The purpose of this study was to explore the consequences of long-term fructose consumption on cardiovascular and metabolic parameters in mice. Using radiotelemetry for chronic cardiovascular measurements and the autoregressive spectral method for blood pressure and heart rate analysis, we tested the hypothesis that a high fructose diet causes changes in the light/dark blood pressure pattern and changes in autonomic function. We further evaluated the possible role of the sympathetic and renin angiotensin systems in the cardiovascular changes: measuring plasma Ang II, testing the effect of adrenergic blockade and quantifying brainstem tyrosine hydroxylase (TH) and Ang receptor mRNA levels.

Section snippets

General procedures

Experiments were performed in male C57BL/6 mice (Harlan Inc, Indianapolis, Ind), 24–29 g. Mice were housed individually at 22 °C with a 12:12-h light/dark cycle (0500 h–1700 h, lights on). After an acclimatization period, mice were given ad libitum access to tap water and randomly assigned to either standard pellet diet (30% protein, 58% carbohydrate and 12% fat) or a diet containing high fructose (67% carbohydrate—98% of which is fructose, 13% fat and 20% protein). After 7 weeks on the dietary

Results

Body weight, non-fasting blood glucose and plasma insulin were not different between the groups (Table 1). There were increases in plasma cholesterol and Ang II (almost four-fold), but no change in triglycerides in the fructose group (Table 1).

Glucose tolerance was attenuated as shown in the time course of the GTT and the area under the curve (AUC) (Fig. 1). For the GTT, there were significant main effects of group (con vs. fructose) [F(1.16) = 8.89, P < 0.01], time (time after glucose) [F(4.64) = 

Discussion

The key findings of the present study were that a dietary model of glucose intolerance in mice was associated with nocturnal hypertension, sympathetic activation and increased plasma Ang II levels. There were also central nervous system changes, seen as increased mRNA expression of brainstem Ang AT1a receptor and TH. A mere eight weeks of consumption of a fructose-enriched diet was sufficient to induce prominent metabolic and cardiovascular changes. The fructose feeding model in mice may be

Acknowledgements

The authors acknowledge the financial support of NIH R01HL69319 (MM) and AHA Scientist Development Grant 0535201N (YC). They express thanks to the University of Cincinnati Mouse Metabolic Phenotyping Center (DK59630) and to J. Aguiar and M. Pazinne (undergraduate Brazilian research fellows supported by the Foundation for the Improvement of Postsecondary Education and Coordenação Aperfeiçoamento de Pessoal de Nível Superior- FIPSE/CAPES.

References (60)

  • J. Luo et al.

    Nongenetic mouse models of non-insulin-dependent diabetes mellitus

    Metabolism

    (1998)
  • R. Nagata et al.

    Single nucleotide polymorphism (− 468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis [corrected]

    J. Biol. Chem.

    (2004)
  • T. Orban et al.

    High-fructose diet preserves beta-cell mass and prevents diabetes in nonobese diabetic mice: a potential role for increased insulin receptor substrate-2 expression

    Metabolism

    (2001)
  • M.A. Ostos et al.

    Fructose intake increases hyperlipidemia and modifies apolipoprotein expression in apolipoprotein AI-CIII-AIV transgenic mice

    J. Nutr.

    (2002)
  • M. Pagani et al.

    Spectral analysis of heart rate variability in the assessment of autonomic diabetic neuropathy

    J. Auton. Nerv. Syst.

    (1988)
  • A. Seltzer et al.

    Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats

    Brain Res.

    (2004)
  • V. Spallone et al.

    Autonomic neuropathy and cardiovascular risk factors in insulin-dependent and non insulin-dependent diabetes

    Diabetes Res. Clin. Pract.

    (1997)
  • S. Verma et al.

    Sympathectomy prevents fructose-induced hyperinsulinemia and hypertension

    Eur. J. Pharmacol.

    (1999)
  • H. Basciano et al.

    Fructose, insulin resistance, and metabolic dyslipidemia

    Nutr. Metab. (Lond.)

    (2005)
  • D.R. Blake et al.

    Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors: results from the Baltimore Longitudinal Study on Aging

    Diabetes

    (2004)
  • P. Bressler et al.

    Insulin resistance and coronary artery disease

    Diabetologia

    (1996)
  • Y. Chen et al.

    Differentiation of brain angiotensin type 1a and 1b receptor mRNAs: a specific effect of dehydration

    Hypertension

    (2001)
  • Y. Chen et al.

    Cardiovascular autonomic control in mice lacking angiotensin AT1a receptors

    Am. J. Physiol., Regul. Integr. Comp. Physiol.

    (2005)
  • Y. Chen et al.

    Adenovirus-mediated small-interference RNA for in vivo silencing of angiotensin AT1a receptors in mouse brain

    Hypertension

    (2006)
  • J.P. Despres et al.

    Hyperinsulinemia as an independent risk factor for ischemic heart disease

    N. Engl. J. Med.

    (1996)
  • V. Dias da Silva et al.

    Antihypertensive action of amiodarone in spontaneously hypertensive rats

    Hypertension

    (2001)
  • V. Farah et al.

    Cholinergic input is critical in the regulation of heart rate variability and stress reactivity in mice

    Hypertension

    (2003)
  • R. Fazan et al.

    Power spectra of arterial pressure and heart rate in streptozotocin-induced diabetes in rats

    J. Hypertens.

    (1999)
  • A. Frattola et al.

    Prognostic value of 24-hour blood pressure variability

    J. Hypertens.

    (1993)
  • I. Gabriely et al.

    Fructose amplifies counterregulatory responses to hypoglycemia in humans

    Diabetes

    (2002)
  • Cited by (0)

    View full text