We have previously reported that weight gain induced by high-fat diet (HFD) leads to an increase in mean arterial pressure (MAP, +14%) and heart rate (HR, +31%) in the adult rabbit. In the present study, we tested the hypothesis that an increased activity of the sympathetic nervous system may contribute to the development of obesity-induced hypertension. A combination of α- and β-adrenergic blockers (terazosin + propranolol) was chronically administered to rabbits housed in metabolic cages for continuous monitoring of arterial pressure by telemetry, 24 h a day. After 2 weeks of adrenergic blockade under control diet, animals were switched to HFD for the next 6 weeks. HFD induced a progressive increase in body weight, but no increase in mean arterial pressure (+0.2 ± 2.5%) and a slight increase in heart rate (+14 ± 3%). Time-control animals fed normal diet showed no changes in MAP or HR with long-term α- and β-adrenergic blockade. Our results indicate that the activation of the sympathetic nervous system may play an important role in the pathogenesis of obesity-induced hypertensio

Antic, Vladan

Kiener-Belforti, Francesca

Montani, Jean-Pierre

Tempini, Aldo

Van Vliet, Bruce N.

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Role of the Sympathetic Nervous SystemDuring the Development of Obesity-inducedHypertension in RabbitsVladan Antic, Francesca Kiener-Belforti, Aldo Tempini, Bruce N. Van Vliet, andJean-Pierre MontaniWe have previously reported that weight gaininduced by high-fat diet (HFD) leads to an increasein mean arterial pressure (MAP, 114%) and heartrate (HR, 131%) in the adult rabbit. In the presentstudy, we tested the hypothesis that an increasedactivity of the sympathetic nervous system maycontribute to the development of obesity-inducedhypertension. A combination of a- and b-adrenergic blockers (terazosin 1 propranolol) waschronically administered to rabbits housed inmetabolic cages for continuous monitoring ofarterial pressure by telemetry, 24 h a day. After 2weeks of adrenergic blockade under control diet,animals were switched to HFD for the next 6weeks. HFD induced a progressive increase inbody weight, but no increase in mean arterialpressure (10.2 6 2.5%) and a slight increase inheart rate (114 6 3%). Time-control animals fednormal diet showed no changes in MAP or HRwith long-term a- and b-adrenergic blockade. Ourresults indicate that the activation of thesympathetic nervous system may play an importantrole in the pathogenesis of obesity-inducedhypertension. Am J Hypertens 2000;13:556–559© 2000 American Journal of Hypertension, Ltd.KEY WORDS: Obesity, hypertension, sympatheticblockade, rabbits, high-fat diet.The association between obesity and hyper-tension has been recognized for many de-cades. However, the basic physiologic mech-anisms that link body weight and bloodpressure are still incompletely understood. Severallines of evidence indicate that the activity of the sym-pathetic nervous system may be elevated in obesity.First, a correlation between blood pressure and nor-epinephrine levels has been shown in borderline obesehypertensive subjects and during blood pressure re-duction induced by weight loss.1 Second, increasedcaloric intake activates the sympathetic nervous sys-tem, whereas fasting reduces sympathetic activity.2Third, in healthy humans, body fat is a major deter-minant of the resting rate of muscle sympathetic nervedischarge.3 Finally, studies in dogs4,5 support the im-portance of sympathetic activation during rapidweight gain as a plausible mechanism contributing tothe increased blood pressure.Adult rabbits fed an ad libitum high-fat diet (HFD)represent an attractive and promising model to studythe mechanisms of obesity-induced hypertension.These rabbits exhibit hemodynamic and neurohu-moral changes that mimic changes observed in humanobesity, including hypertension, a hyperdynamicReceived May 19, 1999. Accepted October 28, 1999.From the Institute of Physiology, University of Fribourg (VA,FK-B, AT, J-PM), Fribourg, Switzerland; Memorial University ofNewfoundland (BNVV), St. John’s, Canada.This work was supported in part by grants from the Swiss Na-tional Science Foundation (32-47329.96) and the Swiss Foundationin Cardiology.Address correspondence and reprint requests to Jean-Pierre Mon-tani, MD, Institute of Physiology, University of Fribourg, Rue duMuse´e 5, CH-1700 Fribourg, Switzerland; e-mail: jean-pierre.montani@unifr.chAJH 2000;13:556–559© 2000 by the American Journal of Hypertension, Ltd. 0895-7061/00/$20.00Published by Elsevier Science, Inc. PII S0895-7061(99)00267-8circulation with increased heart rate and cardiac out-put, elevations in plasma insulin and plasma reninactivity, cardiac hypertrophy, and impaired diastolicfunction, as reported previously.6,7Recently, we have studied the sequential cardiovas-cular and renal changes that occur in rabbits duringweight gain induced by a HFD.8 HFD induced a rapidincrease in mean arterial pressure, heart rate, andglomerular filtration rate that stabilized, respectively,at 14%, 31%, and 68% above control values. The modelwas also characterized by a net accumulation of so-dium, with significant sodium retention during thefirst 3 weeks of HFD. Time-course analysis of thechanges in blood pressure in this model suggests thatobesity-induced hypertension may consist of twophases: the early phase could be due to high-fat intakeor overfeeding, whereas the later phase seems to bestrongly related to weight gain and increased fat mass.To test the hypothesis that an increased activity ofthe sympathetic system may play a role in both theearly and later phases of obesity-induced hyperten-sion, we studied freely moving rabbits during thedevelopment of obesity while sympathetic activitywas blocked pharmacologically. To that purpose, weadministered a combination of a- and b-adrenergicantagonists, to block the peripheral vasoconstrictoractions and direct renal tubular effects of sympatheticactivation, and to prevent the sympathetically medi-ated stimulation of the heart and of renin release.MATERIALS AND METHODSAnimal Preparation Adult male lop-eared rabbits(body weight 4.33 6 0.10 kg) of the breed “Be´lierFranc¸ais” were used in this study. All protocols wereapproved by the State Animal Committee. Underhalothane anesthesia and aseptic techniques, the rab-bits were instrumented with an implantable pressuretransducer and radiotransmitter (model TA11PA-C40,Data Sciences International, St. Paul, MN) to monitorarterial pressure by telemetry, as described previous-ly.8 After surgery, the rabbits were housed in individ-ual cages, customized for urine collection, in a quietair-conditioned room with a 12-h light–dark cycle.The rabbits were allowed to recover for at least 10days before the start of the experiments. All animalshad free access to tap water and were fed 180 g ofstandard rabbit chow per day.Continuous Hemodynamic Monitoring by Teleme-try Each metabolic cage was equipped with receivers,connected by a multiplexer to a calibrated pressure an-alog adapter, as described previously.8 The analog pres-sure signal was then sent to an A/D converter andprocessed by a personal computer using customizedalgorithms9 to compute mean arterial pressure (MAP)and heart rate (HR) on a beat-to-beat basis. The signalwas sampled at 500 Hz, for 5-sec periods every 30 sec,from 10:00 am to 8:00 am the next morning. Weeklyresults are reported as the average of 7 consecutive days.Experimental Protocol After 1 week of control mea-surements rabbits were given a combination of a- andb-adrenergic blockers for the next 8 weeks. Terazosinmonohydrochloride (Abbott Laboratories, AbbottPark, IL) and dl-propranolol (Sigma, St. Louis, MO)were added to the drinking water and the concentra-tion was adjusted according to the average water in-take of the animals to assure a daily drug intake of’20 mg/kg of each substance. To test the adequacy ofthe sympathetic blockade, we analyzed the cardiovas-cular response to the intravenous injection (throughan ear vein) of an a-adrenergic agonist (phenylephrine16 mg/kg) or a b-adrenergic agonist (isoproterenol0.05 mg/kg) before and during a and b blockade.After 2 weeks of sympathetic blockade, the rabbits(n 5 5) were switched to a HFD ad libitum (standardrabbit chow with 10% added fat as soya oil-to-pork fat1:1) for another 6 weeks. Three additional rabbits weretreated with adrenergic blockers for 8 weeks, but werekept on the standard rabbit chow to serve as time-controls. Water intake, food intake, and 24-h urineoutput were determined daily at ’9:00 am. Bodyweight was measured twice a week. Blood sampleswere withdrawn weekly by arterial puncture of thecentral ear artery for various analytic measurements.Analytical Measurements Plasma and urine sodiumand potassium were determined by flame photometry(model IL 943, Instruments Laboratoires, Lexington,MA), and creatinine by the kinetics of Jaffe´ (Beckmancreatinine analyzer 2, Fullerton, CA). Glomerular filtra-tion rate (GFR) was assessed based on creatinine clear-ance. Sodium balance was calculated as the differencebetween sodium intake and urinary sodium excretion,taking into account an average of 20% nonrenal (fecal)loss of sodium (results from separate experiments), con-sistent with values reported by Grace et al.10Statistical Analysis Statistical analysis within groupwas performed by analysis of variance for repeated mea-surements. Because each rabbit within a group serves asits own control, experimental values were comparedwith control values in each group using Dunnett’s mul-tiple comparison procedure. Changes were consideredto be statistically significant if P , .05.RESULTSIn the five pre-HFD rabbits, combined a and b blockaderesulted in an immediate decrease in MAP from 66.1 62.1 mm Hg to 59.3 6 2.0 mm Hg (211.2 6 2.0%) on day1, but MAP increased slowly over the next few days toplateau at 63.9 6 1.9 mm Hg (23.3 6 2.0%) during thesecond week of pharmacologic blockade. SympatheticAJH–MAY 2000–VOL. 13, NO. 5, PART 1 SYMPATHETIC BLOCKADE AND OBESITY 557blockade induced the same changes in MAP in time-control rabbits (n 5 3). The adequacy of sympatheticblockade was assessed by pharmacologic tests. Beforeblockade, intravenous phenylephrine (16 mg/kg) in-creased MAP by 37.8 6 0.5 mm Hg, whereas intrave-nous isoproterenol (0.05 mg/kg) increased HR by 71.4 67.2 beats/min. During long-term blockade, the increasesin MAP and HR induced by phenylephrine and isopro-terenol were only 13.2 6 1.9 mm Hg and 8.8 6 3.1beats/min, respectively.Figure 1 illustrates the sequential changes in MAP,HR, and sodium balance during 6 weeks of HFD diet(n 5 5) or normal diet (n 5 3) during sympatheticblockade. In Figure 1, the control week (week 0, 100%)corresponds to the second week of pharmacologic block-ade, with values of MAP and HR of 63.9 6 1.9 mm Hgand 195 6 5 beats/min in the HFD group (n 5 5), and59.3 6 1.1 mm Hg and 182 6 6 beats/min in the time-control group (n 5 3). Despite a progressive increase inbody weight from 4.46 6 0.12 kg to 5.41 6 0.23 kg inHFD rabbits, MAP remained unchanged throughout thepharmacologic blockade (63.8 6 1.3 mm Hg at week 6 ofHFD, or 0.2 6 2.5% above control). In contrast, HRincreased immediately with HFD (214 6 4 beats/min or110 6 3%, week 1) and remained elevated throughoutHFD (222 6 8 beats/min or 114 6 3%, week 6). Intime-control rabbits fed a normal diet, MAP and HRremained stable throughout the experimental protocol(60.6 6 0.6 mm Hg and 182 6 8 beats/min, respectively,during the last experimental week). The changes inMAP, HR, and sodium balance from our previousstudy8 (intact rabbits without sympathetic blockade, fedan HFD) are included in Figure 1 for comparison.Two weeks of combined a and b blockade increasedGFR from 10.2 6 0.8 to 12.2 6 1.3 mL/min (118.4 64.1%), but this change did not reach statistical signifi-cance (n 5 5). Similar changes were observed in time-control rabbits, from 9.8 6 0.4 mLmin to 11.7 6 0.8mL/min (118.4 6 7.2%). However, when data of bothgroups were pooled (n 5 8), the increase in GFR wassignificant after 2 weeks of blockade. In the HFD group,a further increase of GFR to 13.7 6 0.8 mL/min wasobserved, but the change was only significant whencompared to the period before blockade. GFR remainedstable in our time-control rabbits (11.8 6 1.7 mL/min).Finally, analysis of sodium balance in HFD rabbitsshowed a slight but statistically nonsignificant tendencyfor sodium retention with the HFD. In contrast, potas-sium balance data in HFD rabbits (computed as potas-sium intake minus urinary potassium excretion) showedpotassium retention over the entire experimental period.Sodium and potassium balances remained stable intime-control rabbits.DISCUSSIONThe most significant finding of the present study is thatpharmacologic blockade of the sympathetic nervous sys-tem with a selective a1-antagonist (terazosin) and a non-specific b-receptor antagonist (propranolol) prevents theincrease in MAP induced by a high-fat, high-calorie dietin rabbits. In our previous study,8 we reported that rab-bits fed an ad libitum HFD showed a rapid increase inMAP already after 3 days of HFD (19%) that stabilizedat 14% above control over the next 7 weeks. Sympatheticblockade appeared to block both the early and late in-crease in blood pressure, suggesting that an activation ofthe sympathetic nervous system is involved in bothphases of obesity-induced hypertension.FIGURE 1. Percent changes in mean arterial pressure (MAP),heart rate (HR), and sodium balance in rabbits submitted to 6 weeksof high-fat diet (solid line, closed symbols) or in time-control rabbits(solid line, open symbols) during a 1 b-adrenergic blockade. Averagesodium balance during the control period was subtracted from thesubsequent weekly averages. Values are expressed as mean 6 SE. Thedotted line shows the changes observed in high-fat diet animalswithout sympathetic blockade (from our previous study8).AJH–MAY 2000–VOL. 13, NO. 5, PART 1558 ANTIC ET ALInterestingly, the increased HR (131%) induced byHFD alone8 was not completely suppressed by sympa-thetic blockade, but simply attenuated (114%). If oneassumes effective b blockade as evidenced by our iso-proterenol challenge tests, those data suggest that mech-anisms other than cardiac sympathetic activation arepartially responsible for the tachycardia observed in thismodel of hypertension. Possible mechanisms include ametabolically mediated increase in intrinsic HR or areduction in vagal tone as has been observed in obesedogs.11 Our renal data are also consistent with an overallsympathetic hyperactivity in obesity-induced hyperten-sion. In the present study, sympathetic blockade mark-edly attenuated the sodium retention observed in rabbitsduring weight gain.8 In the intact animals, an increase inplasma renin activity, as observed in obese dogs12 andrabbits,6 and direct tubular effects of sympathetic activa-tion,13 may both contribute to sodium retention. There-fore, inhibition of these mechanisms may explain theobserved attenuation of sodium retention.The marked increase in GFR by HFD alone8 was alsoattenuated in the present study. As in other studies12, wepostulated that the increase in GFR in intact obese ani-mal models could be related to an increased tubularreabsorption at a site proximal to the macula densa,resulting in a compensatory increase in GFR. Decreasedtubular reabsorption induced by sympathetic blockadewould thus minimize the increase in GFR. An alternateexplanation is that sympathetic blockade alone increasedGFR by 18%, which could have blunted a further in-crease in GFR with HFD.Our study in rabbits is also in accordance with obser-vations on the role of sympathetic nervous system inobese dogs. Combined adrenergic blockade for 7 daysdecreases blood pressure to a greater extent in obesedogs compared to lean dogs,4 and bilateral renal dener-vation attenuates the sodium retention and hypertensionassociated with obesity.14 Recently, Rocchini et al5 haveshown that clonidine, a central a2 agonist that inhibitscentral nervous sympathetic activity, prevents insulinresistance and hypertension in obese dogs.The mechanisms by which weight gain leads tosympathetic activation are not yet fully understood,but an interesting candidate is leptin. Leptin produc-tion correlates positively with body mass index andchronic leptin infusion increases both blood pressureand heart rate in rats,15 probably through sympatheticactivation.16 In addition, leptin is unable to increaseblood pressure and HR in rats during combined a andb blockade.17 In summary, our study suggests an im-portant role of the sympathetic nervous system duringthe development of obesity-induced hypertension.ACKNOWLEDGMENTSWe thank Dr. B. Tru¨mpi from Abbott AG, Baar, Switzerland,for the supply of Terazosin. We also thank M.F. Baeriswylfor analytical measurements, and L. Monney, A. Gaillard,and E. Regli for the general setup of the animal room.REFERENCES1. Sowers JR, Nyby M, Stern N, Beck F, Baron S, CataniaR, Vlachis N: Blood pressure and hormonal changesassociated with weight reduction in the obese. Hyper-tension 1982;4:686–691.2. Landsberg L, Young JB: Fasting, feeding and regulationof the sympathetic nervous system activity. N EnglJ Med 1978;298:1295–1301.3. Scherrer U, Randin D, Tappy L, Vollenweider P, JequierE, Nicod P: Body fat and sympathetic nerve activity inhealthy subjects. Circulation 1994;89:2634–2640.4. Hall JE, Van Vliet BN, Garrity CA, Connell RD, BrandsMW: Role of increased adrenergic activity in obesity-induced hypertension (abst). Circulation 1992;86(supplI):I–541.5. Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini AJ:Clonidine prevents insulin resistance and hypertensionin obese dogs. Hypertension 1999;33[part II]:548–553.6. Carroll JF, Dwyer TM, Grady AW, Reinhart GA, Mon-tani JP, Cockrell K, Meydrech EF, Mizelle HL: Hyper-tension, cardiac hypertrophy, and neurohumoral activ-ity in a new animal model of obesity. Am J Physiol1996;271:H373–378.7. Carroll JF, Summers RL, Dzielak DJ, Cockrell K, Mon-tani JP, Mizelle HL: Diastolic compliance is reduced inobese rabbits. Hypertension 1999;33:811–815.8. Antic V, Tempini A, Montani JP: Serial changes in cardio-vascular and renal function of rabbits ingesting a high-fat,high-calorie diet. Am J Hypertens 1999;12:826–829.9. Montani JP, Mizelle HL, Van Vliet BN, Adair TH: Ad-vantages of continuous measurement of cardiac output24 h a day. Am J Physiol 1995;269:H696–H703.10. Grace SA, Munday KA, Noble AR: Sodium, potassiumand water metabolism in the rabbit: the effect of sodiumdepletion and repletion. J Physiol 1979;292:407–420.11. Van Vliet BN, Hall JE, Mizelle HL, Montani JP, SmithMJ Jr: Reduced parasympathetic control of heart rate inobese dogs. Am J Physiol 1995;269:H629–H637.12. Hall JE, Brands MW, Dixon WN, Smith MJ: Obesity-induced hypertension: renal function and systemic he-modynamics. Hypertension 1993;22:292–299.13. Van Vliet BN, Lohmeier TE, Mizelle HL, Hall JE: Thekidney, in Bennet T, Gardiner S (eds): Nervous Control ofBlood Vessels. The Autonomic Nervous System, Vol 8.London, Harwood Academic Publishers, 1996, pp 371–433.14. Kassab S, Kato T, Wilkins FC, Chen R, Hall JE, GrangerJP: Renal denervation attenuates the sodium retentionand hypertension associated with obesity. Hyperten-sion 1995;25:893–897.15. Shek EW, Brands MW, Hall JE: Chronic leptin infusionincreases arterial pressure. Hypertension 1998;31:409–414.16. Haynes WG, Sivitz WI, Morgan DA, Walsh SA, MarkAL: Sympathetic and cardiorenal actions of leptin. Hy-pertension 1997;30:619–623.17. Shek EW, Kim PK, Hall JE: Adrenergic blockade pre-vents leptin-induced hypertension (abst). FASEB J1999;13:A456.AJH–MAY 2000–VOL. 13, NO. 5, PART 1 SYMPATHETIC BLOCKADE AND OBESITY 559

Role of the sympathetic nervous system during the development of obesity-induced hypertension in rabbits

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