To explore the mechanisms of obesity-induced hypertension we analyzed the sequential changes in cardiovascular and renal function in adult rabbits switched to high-fat diet (HFD) for 8 weeks. Animals were housed in metabolic cages for continuous 24-h recording of arterial pressure by telemetry and daily urine collection. High-fat diet induced a progressive increase in body weight (+47%) and a rapid rise in mean arterial pressure, heart rate, and glomerular filtration rate that stabilized, respectively, at 14%, 31% and 68% greater than control values. Time-course analysis of changes in blood pressure may reveal two components of obesity-induced hypertension, an early phase related to HFD itself and a later phase related to weight gain. Am J Hypertens 1999;12:826-829 © 1999 American Journal of Hypertension, Lt

Antic, Vladan

Montani, Jean-Pierre

Tempini, Aldo

To explore the mechanisms of obesity-induced hypertension we analyzed the sequential changes in cardiovascular and renal function in adult rabbits switched to high-fat diet (HFD) for 8 weeks. Animals were housed in metabolic cages for continuous 24-h recording of arterial pressure by telemetry and daily urine collection. High-fat diet induced a progressive increase in body weight (147%) and a rapid rise in mean arterial pressure, heart rate, and glomerular filtration rate that stabilized, respectively, at 14%, 31 % and 68% greater than control values. Time-course analysis of changes in blood pressure may reveal two components of obesity-induced hypertension, an early phase related to HFD itself and a later phase related to weight gain. Am J Hypertens 1999

Vladan Antic

Aldo Tempini

Jean-pierre Montani

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Serial Changes in Cardiovascular and Renal Function of Rabbits Ingesting a High-Fat, High-Calorie Diet

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Serial Changes in Cardiovascular and RenalFunction of Rabbits Ingesting a High-Fat,High-Calorie DietVladan Antic, Aldo Tempini, and Jean-Pierre MontaniTo explore the mechanisms of obesity-inducedhypertension we analyzed the sequential changesin cardiovascular and renal function in adultrabbits switched to high-fat diet (HFD) for 8weeks. Animals were housed in metabolic cagesfor continuous 24-h recording of arterial pressureby telemetry and daily urine collection. High-fatdiet induced a progressive increase in body weight(147%) and a rapid rise in mean arterial pressure,heart rate, and glomerular filtration rate thatstabilized, respectively, at 14%, 31% and 68%greater than control values. Time-course analysis ofchanges in blood pressure may reveal twocomponents of obesity-induced hypertension, anearly phase related to HFD itself and a later phaserelated to weight gain. Am J Hypertens 1999;12:826–829 © 1999 American Journal ofHypertension, Ltd.KEY WORDS: Obesity, hypertension, rabbits, high-fatdiet, telemetry.Numerous epidemiologic and clinical stud-ies have reported a strong correlation be-tween body weight and blood pressure.1,2However, these studies are mainly correl-ative in nature, and the basic mechanisms relating obe-sity to hypertension are not clear. To elucidate thesemechanisms, many experimental models of obesity havebeen developed. In most models the obesity is alreadyestablished by the time of adult age (genetic models) oroccurs in small animals (mice and rats) in which exten-sive sequential endocrine and cardiovascular studies arenot feasible. Models with dogs fed a high-fat diet havebeen used successfully by us3 and others.4,5 However,the dog model is expensive, extremely labor-intensive,and may require force-feeding to obtain a suitableweight gain.An interesting alternate model developed recently6uses adult rabbits fed an ad libitum high-fat diet(HFD). These rabbits become spontaneously obeseand exhibit hemodynamic and neurohumoral changesthat mimic changes observed in human obesity. In thisearly study,6 the rabbits were studied only afterweight gain had occurred. Yet, sequential humoraland hemodynamic measurements are often helpful todetermine the mechanisms of certain forms of hyper-tension, as early changes of relevant parameters mayhelp establish a causal relationship and reveal thelogical sequence of events. To further characterize thismodel, we studied freely moving rabbits during thedevelopment of obesity, with special emphasis onmonitoring renal function and blood pressure by te-lemetry 24 h a day.MATERIALS AND METHODSAnimal Preparation Adult male lop-eared rabbits(26.3 6 1.6 week old; body weight, 4.04 6 0.11 kg) ofReceived May 13, 1998. Accepted September 15, 1998.From the Institute of Physiology, University of Fribourg, Fri-bourg, SwitzerlandAddress reprint requests and correspondence to Jean-PierreMontani, MD, Institute of Physiology, University of Fribourg,Rue du Muse´e 5, CH-1700, Fribourg, Switzerland; e-mail: jean-pierre.montani@unifr.chAJH 1999;12:826–829© 1999 by the American Journal of Hypertension, Ltd. 0895-7061/99/$20.00Published by Elsevier Science, Inc. PII S0895-7061(98)00231-3the breed “Be´lier Franc¸ais” were used in this study.All protocols were approved by the State AnimalCommittee. Using halothane anesthesia and aseptictechniques, the rabbits were instrumented with anarterial catheter connected to an implantable trans-ducer (model TA11PA-C40, Data Sciences Interna-tional, St. Paul, MN) and radio transmitter to monitorarterial pressure by telemetry. Through a groin inci-sion, the arterial pressure cannula was inserted intothe femoral artery, and the body of the implant wasattached to the abdominal wall. After surgery, therabbits were housed in individual cages, customizedfor urine collection, in a quiet air-conditioned roomwith a 12-h light-dark cycle. The rabbits were allowedto recover for at least 10 days before the start of theexperiments. All animals had free access to tap waterand were fed 150 g of standard rabbit chow per day.Continuous Hemodynamic Monitoring by Teleme-try Each cage (65 cm 3 70 cm 3 60 cm, W3D3H)was equipped with three RLA-2000 receivers, con-nected through a multiplexer (RMX-10) to a calibratedpressure analog adapter (R11CPA), allowing continu-ous recording of the analog pulsatile arterial pressuresignal. Corrections for changes in barometric pressurewere done through the APR-1 pressure reference de-vice. All devices are manufactured by Data SciencesInternational, St. Paul, MN. The analog pressure signalwas then sent to an A/D converter (CIO-DAS08, Com-puterBoards, Mansfield, MA) and processed by a per-sonal computer using customized algorithms for beat-to-beat analysis.7 The signal was sampled at 500 Hzfor 5-s periods every 30 s, from 10:00 am to 8:00 am thenext morning.Experimental Protocol After a first week of controlmeasurements with standard rabbit chow (150 g/day),the rabbits (n 5 8) were fed ad libitum a high-fat diet(standard rabbit chow with 10% added fat as soya oil:pork fat, 1:1) for 8 weeks. Another four rabbits were fedthe standard rabbit chow and served as time-controls.Water and food intake, and 24-h urine output, weredetermined daily at approximately 9:00 am. Bodyweight was measured twice a week. Blood samples werewithdrawn weekly by arterial puncture of the central earartery for various analytic measurements (see below).Analytical Measurements Sodium and potassiumwere determined by flame photometry (model IL 943,Instruments Laboratories, Lexington, MA), glucose bythe glucose oxidase method (Beckman glucose ana-lyzer 2, Beckman, Fullerton, CA), and creatinine by thekinetics of Jaffe´ (Beckman creatinine analyzer 2). Glo-merular filtration rate (GFR) was assessed based oncreatinine clearance.Statistical Analysis Statistical analysis within groupwas performed by analysis of variance for repeatedmeasurements and multiple comparison procedures.Because each rabbit within a group serves as its owncontrol, experimental values were compared with con-trol values in each group using Dunnett’s multiplecomparison procedure. Changes were considered tobe statistically significant if P , .05.RESULTSFigure 1 illustrates the percent changes in bodyweight, mean arterial pressure, heart rate, and glomer-ular filtration during 8 weeks of high-fat diet. Therewas a progressive increase in body weight, from4.05 6 0.15 kg to 5.91 6 0.09 kg (147 6 5%), (n 5 8,P , .05). Mean arterial pressure rose rapidly from acontrol value of 65.4 6 2.9 mm Hg to 73.8 6 3.2 mmHg (112.9 6 1.2%) after 2 weeks of HFD (n 5 8, P ,.05). Surprisingly, the increase in MAP was significantalready after three days of the high-fat diet (18.9 61.5%) and attained plateau values by the end of thefirst week. After eight weeks of HFD, mean arterialpressure was 14.1 6 2.5% (P , .05) above controlFIGURE 1. Percent changes in body weight, mean arterialpressure, heart rate, and glomerular filtration rate in rabbits given8 weeks of high-fat diet (solid line, closed symbols) or in time-control rabbits (dotted line, open symbols). Values are expressed asmean 6 SE. All changes in high-fat diet animals, compared withthe control week (week 0), were significant (P , .05).AJH–AUGUST 1999–VOL. 12, NO. 8, PART 1 OBESITY-INDUCED HYPERTENSION 827values (n reduced to 4 due to implant failure). Heartrate rose significantly from a control value of 164 6 3bpm to 217 6 4 beats/min (132.2 6 1.7%, n 5 8)during the first week of HFD. This increase was al-ready present at the very first day after diet switch,and remained elevated over the rest of the experiment(131.3 6 2.0%, week 8, P , .05). Glomerular filtrationrate rose significantly from 8.9 6 0.4 to 13.9 6 0.8mL/min (157 6 8%, week 1) and, as shown in Figure1, remained elevated throughout the remaining weeks(168 6 15%, week 8, n 5 8).The rabbits showed a significant positive daily so-dium balance (sodium intake minus urinary sodiumexcretion) during the first 3 weeks of HFD, comparedwith the control week. In the following weeks, dailysodium balance returned gradually toward controllevels. This resulted in a net accumulation of sodiumover the whole experimental period. Potassium bal-ance data showed a sustained potassium retention.Rabbits fed the high-fat diet tended to show a slightelevation in plasma glucose (17 6 2% at weeks 7 to 8,compared with a control value of 7.4 6 0.2 mmol/L),but this increase was not significant. At the end of 8weeks of HFD, fat intake was limited for the next 10days to avoid further weight gain. Mean arterial pres-sure and heart rate remained elevated (76.4 6 6.8 mmHg and 213 6 7 beats/min, respectively, during thelast 7 days of the 10-day period , versus 76.0 6 6.6 and216 6 6 during the eighth week of ad libitum HFDintake; n 5 4). As shown in Figure 1, animals fed thecontrol diet throughout the experiment showed aslight but significant increase in body weight, from4.02 6 0.19 kg to 4.46 6 0.14 (111.3 6 2.9%), and nochanges in any of the other parameters. There were noimplant failures in the control group.DISCUSSIONObesity is one of the most serious health problems inindustrialized societies, with a rapidly increasingprevalence in the United States8 and in Europe.9 Theassociation between obesity and hypertension hasbeen recognized for many decades10 and epidemio-logic studies show a good correlation between bodyweight and blood pressure both in normotensive andin hypertensive individuals.1,2 Numerous mecha-nisms have been postulated to explain obesity-in-duced hypertension. However, much of our knowl-edge is based on correlations between body weightand various factors thought to increase blood pressure(such as insulin levels, plasma renin, or sympatheticactivity), and the basic physiologic mechanisms thatlink body weight and blood pressure are not yet fullyelucidated.The present study is consistent with previous re-ports in rabbits6,11 that demonstrate that female NewZealand White rabbits fed an ad libitum high-fat dietbecome obese and develop mild hypertension andtachycardia. In our strain of male rabbits, 8 weeks ofHFD induced a 47% increase in body weight, a 14%increase in mean arterial pressure, and a 31% increasein heart rate. Obese rabbits also exhibited changes inrenal function, with increased glomerular filtrationrate and a net accumulation of sodium. These findingsare consistent with observations in the dog model ofobesity-induced hypertension.5 These changes may bedue to an increased tubular sodium reabsorption at asite before macula densa (by sympathetic activation,hyperinsulinemia, or renal tubular compression), re-sulting in a compensatory increase in GFR, as previ-ously hypothesized.5 These mechanisms could alsoexplain the increased plasma renin activity in obesedogs5 and rabbits,6 despite volume retention and in-creased blood pressure.A major finding of our study is that the high-fat dietinduced a rapid increase in daily mean arterial pres-sure and heart rate, which occurred in the very firstdays after a switch from the control to the high-fatdiet. Clearly, these early changes cannot be attributedto weight gain. More likely, metabolic changes in-duced by the high-fat diet and/or overfeeding, such ashyperinsulinemia and sympathetic nervous system ac-tivation, may mediate the initial hemodynamic re-sponse to the high-fat diet.12 Impaired flow-mediatedvasodilation could also play a role, as it has beenreported to occur after a single high-fat meal.13 In fact,blood pressure returns rapidly to control values whenrabbits are switched back to maintenance diet after asingle week of HFD (pilot studies, data not shown).On the other hand, the long-term increase in bloodpressure seems to be related more to increased fatmass than to fat intake per se. Indeed, when fat intakewas substantially reduced in obese rabbits after 8weeks of HFD to avoid any further weight gain, bloodpressure and heart rate remained elevated. An inter-esting observation is that the moderate but significantincrease (111%) in body weight of time-control rab-bits was not associated with an increase in bloodpressure. Based only on gross examination at the au-topsy, which revealed massive visceral fat accumula-tion in HFD rabbits as compared with control animals,we hypothesize that accumulation of fat rather thanlean mass might be necessary for hypertension to de-velop. Although hyperinsulinemia, elevated plasmarenin, or tubular physical factors may all play a role inobesity-induced hypertension, an interesting candi-date is leptin, the peptide product of the so-calledobese gene. Leptin production correlates positivelywith body mass index14 and chronic leptin infusionincreases both blood pressure and heart rate in rats,15probably through sympathetic activation.16In summary, a time-course analysis of the changesin blood pressure during a high-fat diet in rabbits mayAJH–AUGUST 1999–VOL. 12, NO. 8, PART 1828 ANTIC ET ALreveal two components of obesity-induced hyperten-sion, an early phase that could be due to high-fatintake and/or overfeeding, and a later phase thatseems to be strongly related to weight gain and in-creased fat mass. This rabbit model of obesity-inducedhypertension is an attractive and promising system forfurther studies to elucidate the mechanisms that linkweight gain and blood pressure.ACKNOWLEDGMENTSThis work was supported in part by grants from the SwissNational Science Foundation (32-47329.96) and the SwissFoundation in Cardiology. We thank M. F. Baeriswyl foranalytical measurements, and L. Monney, A. Gaillard, andE. Regli for the general setup of the animal room.REFERENCES1. Stamler RA, Stamler J, Riedlinger WF, et al: Weight andblood pressure findings in hypertension screening of 1million Americans. JAMA 1978;240:1607–1610.2. Jones DW: Body weight and blood pressure: effects ofweight reduction on hypertension. Am J Hypertens1996;9:50S–54S.3. Mizelle HL, Edwards TC, Montani JP: Abnormal car-diovascular responses to exercise during the develop-ment of obesity in dogs. Am J Hypertens 1994;7:374–378.4. Rocchini AP, Moorehead C, Wentz E, Deremer S: Obe-sity-induced hypertension in the dog. Hypertension1987;9(suppl III):III-64–III-68.5. Hall JE, Brands MW, Dixon WN, Smith MJ: Obesity-induced hypertension: renal function and systemic he-modynamics. Hypertension 1993;22:292–299.6. Carroll JF, Dwyer TM, Grady AW, et al: Hypertension,cardiac hypertrophy, and neurohumoral activity in anew animal model of obesity. Am J Physiol 1996;271:H373–378.7. Montani JP, Mizelle HL, Van Vliet BN, TH Adair: Ad-vantages of continuous measurement of cardiac output24 h a day. Am J Physiol 1995;269:H696–H703.8. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL:Increasing prevalence of overweight among US adults.The National Health and Nutrition Examination Sur-veys, 1960 to 1991. JAMA 1994;272:205–211.9. Bjo¨rntorp P: Obesity. Lancet 1997;350:423–426.10. Dustan HP: Mechanisms of hypertension associatedwith obesity. Ann Intern Med 1983;98:860–864.11. Carroll JF, Huang M, Hester RL, et al: Hemodynamicalterations in hypertensive obese rabbits. Hypertension1995;26:465–470.12. Schwartz JH, Young JB, Landsberg L: Effect of dietaryfat on sympathetic nervous system activity in the rat.J Clin Invest 1983;72:361–370.13. Vogel RA, Corretti MC, Plotnick GD: Effect of a singlehigh-fat meal on endothelial function in healthy sub-jects. Am J Cardiol 1997;79:350–354.14. Considine RV, Sinha MK, Heiman ML, et al: Serumimmunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292–295.15. Shek EW, Brands MW, Hall JE: Chronic leptin infusionincreases arterial pressure. Hypertension 1998;32:409–414.16. Haynes WG, Sivitz WI, Morgan DA, et al: Sympatheticand cardiorenal actions of leptin. Hypertension 1997;30:619–623.AJH–AUGUST 1999–VOL. 12, NO. 8, PART 1 OBESITY-INDUCED HYPERTENSION 829

Serial changes in cardiovascular and renal function of rabbits ingesting a high-fat, high-calorie diet

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Serial changes in cardiovascular and renal function of rabbits ingesting a high-fat, high-calorie diet

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