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Mar 29, 2014 - Abstract The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective a1- adrenoceptor antagonist, on ...
Mol Cell Biochem (2014) 392:205–211 DOI 10.1007/s11010-014-2031-5

Selective alpha1-adrenoceptor blockade prevents fructose-induced hypertension Linda T. Tran • Kathleen M. MacLeod John H. McNeill



Received: 13 September 2013 / Accepted: 14 March 2014 / Published online: 29 March 2014 Ó Springer Science+Business Media New York 2014

Abstract The purpose of this study was to investigate the effect of chronic treatment with prazosin, a selective a1adrenoceptor antagonist, on the development of hypertension in fructose-fed rats (FFR). High-fructose feeding and treatment with prazosin (1 mg/kg/day via drinking water) were initiated simultaneously in male Wistar rats. Systolic blood pressure, fasted plasma parameters, insulin sensitivity, plasma norepinephrine (NE), uric acid, and angiotensin II (Ang II) were determined following 9 weeks of treatment. FFR exhibited insulin resistance, hyperinsulinemia, hypertriglyceridemia, and hypertension, as well as elevations in plasma NE and Ang II levels. Treatment with prazosin prevented the rise in blood pressure without affecting insulin levels, insulin sensitivity, uric acid, or Ang II levels, while normalizing plasma NE levels in FFR. These data suggest that over-activation of the sympathetic nervous system, specifically a1-adrenoceptors, contributes to the development of fructose-induced hypertension, however, this over-activation does not appear to an initial, precipitating event in FFR. Keywords Insulin resistance  Hypertension  Fructose-fed rat  Prazosin  a1-Adrenoceptors

Introduction The metabolic syndrome is a clustering of cardiovascular risk factors that include abdominal obesity, dyslipidemia, insulin resistance, and hypertension. Insulin resistance has

L. T. Tran  K. M. MacLeod  J. H. McNeill (&) Faculty of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada e-mail: [email protected]

been implicated as a causal factor in the pathogenesis of the metabolic syndrome [1, 2]. Insulin-induced stimulation of the sympathetic nervous system is a proposed mechanism that links insulin resistance to hypertension. In the setting of hyperinsulinemia, insulin may chronically activate the sympathetic nervous system, resulting in increased peripheral vascular tone and elevated blood pressure. In support of this hypothesis, plasma norepinephrine (NE) levels and sympathetic nerve activity are increased in response to insulin infusion [3–6]. As a consequence of continued a1-adrenoceptor activation, an increase in the activity of the sympathetic nervous system may contribute to insulin resistance through enhanced vasoconstriction, reducing blood flow and glucose delivery to insulin-sensitive tissues [7]. The compensatory hyperinsulinemia in response to insulin resistance can then act as a continued stimulus to activate the sympathetic nervous system. The issue of which abnormality occurs first has been raised. Specifically, do elevated levels of insulin activate the sympathetic nervous system or does activation of the sympathetic nervous system exacerbate insulin resistance? As a result of the cyclical relationship between insulin resistance and elevated sympathetic activity, determining the primary event has been a difficult task. Chronic activation of the sympathetic nervous system has been suggested as an initial, precipitating event in the development of hypertension [8]. It has been demonstrated that sympathetic nerve hyperactivity preceded hyperinsulinemia and subsequent elevations in blood pressure in a population of young, nonobese Japanese individuals [9]. In fructose-fed rats (FFR), chemical sympathectomy prevented the development of hyperinsulinemia and hypertension, demonstrating that a functional sympathetic nervous system is necessary for the development of hyperinsulinemia and hypertension in this animal model

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[8]. Treatment with moxonidine [10] or rilmenidine [11], imidazoline receptor agonists that centrally reduce sympathetic outflow, also prevented the development of insulin resistance and hypertension in FFR. Vessels from FFR exhibited decreased vascular responses to NE, suggesting an impaired sensitivity to NE [12]. This effect may have occurred as a compensatory change following increased activity of the sympathetic nervous system, which can lead to receptor down-regulation or desensitization [13, 14]. Since blockade of the sympathetic nervous system prevented both insulin resistance/hyperinsulinemia and hypertension, it has been suggested that chronic over-activation of the sympathetic nervous system is an early precipitating event in the pathogenesis of fructose-induced hypertension [8]. There has not been a study reporting the effect of chronic blockade of the sympathetic nervous system on other proposed mediators of fructose-induced hypertension, such as the renin angiotensin system. The aim of this study was to determine whether chronic over-activation of the sympathetic nervous system is an initial defect that contributes to the development of hypertension in FFR. We determined the effects of prazosin, a peripheral a1-adrenoceptor antagonist, on plasma levels of insulin, glucose, triglycerides and NE, systolic blood pressure (SBP), and insulin sensitivity. To determine whether chronic activation of the sympathetic nervous system is an initial event that affects the renin angiotensin system, we assessed the effect of chronic prazosin treatment on plasma levels of angiotensin II (Ang II). We hypothesized that the development of hypertension in FFR is dependent on chronic activation of peripheral a1adrenoceptors that acts as a precipitating event, which contributes to an increase in Ang II and is involved in the development of fructose-induced hypertension. In a previous study, Zhou et al. [15] treated fructose-fed rats with the nonspecific a-blocking agent, phentolamine. Norepinephrine levels did not increase when measured 13 weeks after the onset of fructose feeding. Phentolamine did prevent the increase in blood pressure found in fructose-fed rats. Other goals of the present study were to determine: (1) if there were differences between the a-1 specific antagonist, prasozin, and phentolamine and (2) to determine if norepinephrine did increase at a time earlier than 13 weeks. Plasma uric acid levels were also determined since recent evidence suggests that elevations of blood uric acid are involved in fructose-induced hypertension.

Materials and methods Animals and experimental design Male Wistar rats were obtained from Charles River Laboratories (St-Constant, Quebec) at 5 weeks of age and

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randomly divided into four experimental groups: control (C, n = 8), control prazosin-treated (CP, n = 8), fructose (F, n = 8), and fructose prazosin-treated (FP, n = 8). At 6 weeks of age, fasted (5 h) plasma parameters (glucose, insulin and triglycerides) and SBP were measured in all groups. At 7 weeks of age, rats in fructose-fed groups (F and FP) were started on a 60 % fructose diet (Teklad Laboratory Diets, Madison, WI, USA) for 9 weeks, whereas rats in control groups (C and CP) were maintained on standard laboratory rat chow containing 30 % carbohydrate in the form of starch for the same period. Prazosin (CP and FP) treatment was initiated concurrently at a dose of 1 mg/kg administered via drinking water for the duration of the study. Rats were housed on a 12 h light–dark cycle and received food and water ad libitum. At the end of the study, rats from all groups were euthanized with an overdose of pentobarbital (65 mg/kg, i.p.). This investigation conforms to the Canadian Council on Animal Care Guidelines on the Care and use of Experimental Animals. All protocols were approved by the University of British Columbia Animal Care Committee. SBP measurements The FFR has been used extensively in our laboratory and is known to develop an elevation in blood pressure within six weeks of initiation of fructose feeding [16–18], therefore only basal and pre-termination blood pressure measurements were done in this study. Prior to obtaining blood pressure measurements, rats were preconditioned to the procedure. SBP was measured in conscious rats before the start of treatment and immediately prior to termination using the indirect non-invasive tail-cuff method without external preheating as previously described [19, 20]. Oral glucose tolerance test and insulin sensitivity index At the end of the study, all rats were fasted overnight (15 h) and subjected to an oral glucose tolerance test (OGTT). A 40 % glucose solution was prepared and administered by oral gavage (1 g/kg) to conscious animals. Blood samples were obtained immediately prior to glucose administration (time 0) and at 10, 20, 30, 60, and 90 min following the glucose challenge. Plasma was separated and stored at -20 °C until further analysis. The insulin sensitivity index was calculated for each animal using data obtained from the OGTT and applied to the formula of Matsuda and DeFronzo [21] where insulin sensitivity index = 100/square root [(mean plasma glucose 9 mean plasma insulin) 9 (fasting plasma glucose 9 fasting plasma insulin)]. Values obtained with this methodology correlate highly with results obtained from the euglycemic hyperinsulinemic clamp technique [21].

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Blood collection Blood samples were collected from the tail vein for determination of fasted plasma glucose, insulin, uric acid, and triglyceride levels. Plasma samples were separated, aliquoted, and stored at -20 °C until further analysis. At termination, blood was collected via cardiac puncture. For determination of plasma NE levels, blood was aliquoted into heparinized tubes. For determination of plasma Ang II levels, blood was placed into plastic tubes containing 0.44 mM o-phenanthroline, 25 mM ethylenediaminetetraacetic acid (EDTA), 1 mM q-hydroxymercuribenzoic acid, and 0.12 mM pepstatin A. Plasma samples were separated and stored at -20 °C until analysis. Biochemical measurements Plasma glucose levels were determined through a Beckman Glucose Analyzer II (Beckman, Fullerton, CA, USA). Plasma triglycerides were measured using an enzymatic colourimetric assay from Boehringer Mannheim (Germany). Plasma insulin levels were determined using a radioimmunoassay kit from Linco Research (St. Charles, MO, USA). Plasma uric acid levels were measured using an ELISA kit from Cedarlane (Hornby, Toronto, ON, Canada). Plasma NE and Ang II levels were measured using an enzyme immunoassay kit from Cedarlane (Hornby, Toronto, ON, Canada) and IBL Hamburg (Toronto, ON, Canada), respectively. Reagents All chemicals were reagent grade and purchased from Sigma (St. Louis, MO, USA). Prazosin was a generous gift from Apotex Inc. (Toronto, ON, Canada).

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among any of the treatment groups prior to the start of fructose feeding (data not shown). General characteristics of rats following 9 weeks of prazosin treatment are summarized in Table 1. Body weight and food intake did not differ among the experimental groups. Plasma insulin and plasma uric acid levels were significantly elevated in animals from the F and FP groups. Plasma triglycerides were significantly elevated in FFR and chronic prazosin treatment significantly exacerbated the hypertriglyceridemia in FFR. Treatment with prazosin had no effect on any parameters measured in control rats. SBP and insulin sensitivity index There was no difference in SBP between groups at the start of treatment. SBP was significantly elevated in the F group following 9 weeks of high-fructose feeding (Fig. 1). Chronic prazosin treatment attenuated the increase in blood pressure in FFR, while treatment with prazosin had no effect on SBP in control rats. Comparisons of the insulin sensitivity index demonstrated that high-fructose feeding significantly impaired insulin sensitivity (Fig. 2). Chronic treatment with prazosin did not alter insulin sensitivity in either control or FFR. Plasma NE and Ang II levels High-fructose feeding significantly increased plasma NE (Fig. 3a) in FFR. Chronic prazosin treatment normalized plasma NE in FFR, while it increased levels of plasma NE in control rats. High-fructose feeding also significantly increased plasma Ang II levels (Fig. 3b). Prazosin treatment also elevated levels of plasma Ang II in FFR, and did not alter plasma Ang II levels in control rats.

Statistical analysis All data are expressed as mean ± SEM. Statistical analysis of all data was performed using the Number Cruncher Statistical Software 2000 (NCSS, Kaysville, UT, USA). Data with multiple time points were analyzed by General Linear Model ANOVA, and inter-group comparisons of dependent variables were analyzed by one-way ANOVA. For all results, the Newman–Keuls test for post hoc analysis was applied. A value of p \ 0.05 was taken as the level of significance.

Results General characteristics of rats following 9 weeks of prazosin treatment There were no differences in body weight, food intake, and plasma levels of glucose, insulin, triglycerides, or uric acid

Discussion In FFR, treatment with prazosin, an a1-adrenoceptor antagonist, prevented the development of hypertension without affecting insulin levels, insulin sensitivity, or elevated Ang II levels. Surprisingly, chronic prazosin treatment normalized plasma NE levels while exacerbating hypertriglyceridemia in FFR. These data suggest the involvement of the sympathetic nervous system, specifically peripheral a1-adrenoceptors, in the development of fructose-induced hypertension. Using plasma NE levels as a marker of adrenergic function, we observed that FFR had elevated adrenergic function as reflected by an increase in plasma NE. This finding is in agreement with a meta-analysis that determined circulating levels of plasma NE were significantly increased in hypertensive individuals as compared to age-matched

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Table 1 General characteristics and fasted plasma parameters of control and fructose-fed rats following 9 weeks of prazosin treatment C

CP

F

FP

Body weight (g)

478 ± 14

511 ± 15

498 ± 11

507 ± 18

Food intake (g/day)

29.5 ± 1.3

31.4 ± 0.9

27.3 ± 0.5

27.9 ± 1.5

Plasma insulin (ng/mL)

1.46 ± 0.15

1.31 ± 0.18

2.29 ± 0.30a

2.24 ± 0.24a 8.92 ± 0.34

Plasma glucose (mmol/L)

7.89 ± 0.19

8.61 ± 0.22

8.07 ± 0.20

Plasma triglycerides (mmol/L)

0.93 ± 0.15

0.74 ± 0.13

1.69 ± 0.19a

2.67 ± 0.36b

0.27 ± 0.02

a

0.57 ± 0.04a

Plasma uric acid

0.23 ± 0.01

0.56 ± 0.02

Values expressed as mean ± SEM a p \ 0.05, versus C, CP p \ 0.05, versus all other groups

INSULIN SENSITIVITY INDEX

b

160 140

Pre-treatment Treatment Week 9

b

SBP (mmHg)

120 100 80 60 40 20

15

c

10

C

CP

F

FP

Treatment Groups Fig. 1 Systolic blood pressure (SBP) in control and fructose-fed rats immediately prior to the start of treatment and following 9 weeks of chronic prazosin treatment. The four experimental groups were C, CP, F, and FP. Statistical analysis was done by GLM-ANOVA followed by Newman–Keuls post hoc test. Values expressed as mean ± SEM, n = 8/group. b versus all other groups, p \ 0.05

normotensive individuals [22]. Numerous animal models of hypertension have been reported to exhibit increased sympathetic nerve activity, including the SHR [23], sucrose-fed rat [24], Dahl salt-sensitive rat [25], and DOCA salt hypertensive rat [26]. These observations provide evidence that an over-activated sympathetic nervous system may contribute to the development of hypertension. The study by Zhou et al. [15] did not find an increase in NE but the measurement was made at 13 weeks. Our results indicate an increase in plasma NE does occur at an earlier time. Insulin-induced stimulation of the sympathetic nervous system has been suggested to link hyperinsulinemia and hypertension [27]. Insulin can induce sympathetic nervous system activity through direct or indirect mechanisms. Insulin can directly stimulate NE release from adrenergic nerve endings [28], which in the vasculature of skeletal muscle may result in vasoconstriction, reducing glucose delivery and contributing to insulin resistance. Indirectly,

c

5

0 C

0

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20

CP

F

FP

Fig. 2 Insulin sensitivity index values obtained from OGTT data in control and fructose-fed rats following 9 weeks of prazosin treatment. The four experimental groups were C, CP, F, and FP. Statistical analysis was done by GLM-ANOVA followed by Newman–Keuls post hoc test. Values expressed as mean ± SEM, n = 8/group. c versus C, p \ 0.05

insulin can increase sympathetic nervous system activity by stimulating carbohydrate metabolism and oxidation [29] or by inducing baroreceptor-mediated increases in sympathetic activity following insulin-induced vasodilation [27]. Hyperinsulinemia may excessively stimulate the sympathetic nervous system or increase catecholamine release from sympathetic nerve endings in the kidney, heart, or vasculature, which can elevate blood pressure by stimulating sodium and water reabsorption, increasing cardiac output or increasing peripheral vascular resistance [30]. In support of an insulin-stimulated sympathetic nervous system, both animals [5, 31] and humans [3, 4, 6, 32] exhibited increased plasma NE levels following insulin infusion. Previous studies have demonstrated that central blockade of the sympathetic nervous system with imidazole receptor agonists [10, 11] or by using chemical sympathectomy [8] prevented the development of insulin resistance/hyperinsulinemia and hypertension in FFR. The results of this study support the concept that an over-activated sympathetic nervous system may contribute to the development of hypertension as it is in agreement with

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PLASMA NE (ng/mL)

20

209

A

15

c,d c,d

10

5

0 C

PLASMA ANG II (pg/mL)

400

CP

F

FP

B a

300

c

200

100

0 C

CP

F

FP

Fig. 3 Effect of chronic prazosin treatment on plasma a norepinephrine (NE) and b angiotensin II (Ang II) levels in control and fructose-fed rats following 9 weeks of study. The four experimental groups were C, CP, F, and FP. Statistical analysis was done by GLM-ANOVA followed by Newman–Keuls post hoc test. Values expressed as mean ± SEM, n = 8/group. a versus C, CP; c versus C; d versus FP, p \ 0.05

studies that demonstrated no increase in blood pressure during a1-adrenoceptor antagonism in FFR [33]. Although consistent with results reported by Kamide et al. [33] who reported that bunazosin, an a1-adrenoceptor antagonist, had no effect on the elevated levels of insulin following an OGTT, the lack of effect of prazosin on insulin sensitivity in FFR is puzzling given that central blockade of the sympathetic nervous system prevented insulin resistance [8, 10, 11]. These findings differ from those reported in hypertensive individuals, in which insulin sensitivity was improved following treatment with an a1-adrenoceptor antagonist [34–36]. The reason for this inconsistency is unclear, but may have occurred as a result of the mechanism used to inhibit the sympathetic nervous system, the type and/or dose of a1-adrenoceptor antagonist or the treatment regimen that was followed. In contrast to a report that demonstrated unchanged urinary epinephrine excretion following bunazosin treatment in FFR (Kamide et al. [33]), we observed normalized plasma NE levels in FFR treated with prazosin. Since prazosin selectively antagonizes a1-adrenoceptors, and a2-adrenoceptors function as autoreceptors to mop up excess NE from the circulation, it is possible that a2-adrenoceptors are upregulated to compensate for the increase in NE. This effect appears to occur in the setting of insulin resistance and/or

hypertension since control animals treated with prazosin exhibited elevated levels of NE. We believe that the increase in plasma NE that occurred in the CP and F group occurred through different mechanisms. We propose that the elevated levels of NE in FFR resulted from adrenergic overdrive while prazosin treated control animals exhibited increased NE levels due to a compensatory increase in catecholamine following receptor blockade. One effect of a1-adrenoceptor blockade is the ability to lower triglyceride levels through changes in lipoprotein lipase activity. Lipoprotein lipase is the major enzyme responsible for hydrolyzing triglycerides [37]. Stimulation of a1-adrenoceptors decreases lipoprotein lipase activity [38], while a1-adrenoceptor antagonists appear to increase lipoprotein lipase activity [39]. An increase in the activity of lipoprotein lipase hydrolyzes triglycerides into glycerol and free-fatty acids, which can be resynthesized and stored in adipose tissue. Previous studies have demonstrated that chronic treatment with an a1-adrenoceptor antagonist decreased triglyceride levels in sucrose-fed rats [40, 41] and hypertensive individuals [16, 42], although no difference was also observed in hypertensive humans [39]. Surprisingly, our study showed that prazosin treatment exacerbated hypertriglyceridemia in FFR. This observation is inconsistent with previously published reports and may have occurred as a result of a dysfunction between the a1-adrenoceptors and lipoprotein lipase that results in the setting of fructoseinduced insulin resistance and hypertension. There is considerable evidence that uric acid levels are increased in the FFR [15, 17, 18] found that uric acid levels were increased in fructose-fed rats. In their study, phentolamine did not prevent the increase in uric acid but did prevent the increase in blood pressure. In the present study, we obtained a similar result with an increase in uric acid levels in FFR that was non-responsive to prazosin treatment. We have now looked at uric acid levels in blood samples from a number of earlier studies and found that fructose feeding increased plasma uric acid from as early as 6 weeks after the initiation of fructose feeding (C = 0.36 ± 0.04 vs. F = 0.79 ± 0.02, p \ 0.05) through to 52 weeks of fructose feeding (C = 0.26 ± 0.03 vs. F = 0.52 ± 0.01, p \ 0.05) (unpublished data). Various drug interventions have shown that drugs that prevent the increase in uric acid levels also blocked the increase in blood pressure. Etanercept, a TNF inhibitor [43], bosentan, an endothelin receptor antagonist [44] and L158,809, an AngII receptor antagonist [45] have all been shown to decrease both blood pressure and uric acid levels without affecting the changes in insulin sensitivity and triglyceride levels associated with fructose feeding. However, while metformin, a biguanide used in the treatment of diabetes, also demonstrated a decrease in blood pressure and uric acid levels in fructose-fed rats, there was also a restoration of insulin sensitivity and triglyceride levels to normal

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values [46]. These results indicate that the system is complex and further studies are needed to elucidate the mechanisms and interconnections that occur in the fructose-induced model of the metabolic syndrome.

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Conclusion 8.

In conclusion, over-activation of the sympathetic nervous appears to contribute to the development of fructoseinduced hypertension; however, it does not appear to be the initial, precipitating event as previously proposed [8]. If over-activation of the sympathetic nervous system occurred as an initial event following fructose feeding and this disturbance contributed to the over-activation of the renin angiotensin system, then reduced or normalized Ang II levels following prazosin treatment would be expected. However, we did not observe changes to plasma Ang II levels following chronic prazosin treatment. Several mechanisms are involved in this form of hypertension, and although blocking a specific pathway prevents the development of hypertension, it does not necessarily normalize all abnormalities present in this animal model. Given that there is considerable evidence for a bi-directional interaction between the sympathetic nervous system and the renin angiotensin system [47]; determining the nature of this relationship remains a difficult task due to potential compensatory mechanisms that may exist between them. Acknowledgments This work was supported by the Heart and Stroke Foundation of British Columbia and Yukon. Thank you to Dr. M. Spiro from Apotex Inc. for the generous gift of prazosin. LTT was the recipient of a Graduate Research Scholarship in Pharmacy from the Health Research Foundation of Canada’s Research-Based Pharmaceutical Companies and the Canadian Institute for Health Research and a Pacific Century Graduate Scholarship from the University of British Columbia. This work was funded by the Heart and Stroke Foundation of British Columbia and Yukon.

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The authors have no conflict of interest. 20.

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