Augmented Input From Cardiac Sympathetic Afferents Inhibits Baroreflex in Rats With Heart Failure

Augmented Input From Cardiac Sympathetic AfferentsInhibits Baroreflex in Rats With Heart Failure

Lie Gao, Harold D. Schultz, Kaushik P. Patel, Irving H. Zucker, Wei Wang

Abstract—It has been established that the baroreflex is markedly decreased in chronic heart failure (CHF). Our recent studyhas indicated that activation of the cardiac sympathetic afferent reflex (CSAR) inhibits the baroreflex in normal rats, andin the rats with CHF the CSAR is significantly enhanced, which is related to augmented central angiotensin II (Ang II)mechanism. Therefore, the hypothesis is that the augmented CSAR in the CHF state tonically inhibits the baroreflex viacentral AT1 receptor. To test the hypothesis, the rats with myocardial infarction-induced CHF or sham surgery wereanesthetized with �-chloralose and urethane, vagotomized, and recordings were made of the mean arterial pressure(MAP) and renal sympathetic nerve activity (RSNA). We found: (1) left ventricular epicardial application of capsaicinor electrical stimulation of the central end of the left cardiac sympathetic nerve blunted the baroreflex in both sham andCHF rats; (2) left ventricular epicardial application of lidocaine had no significant effects on the baroreflex in sham ratsbut improved the baroreflex in CHF rats (maximum slope, 1.7�0.3 to 2.9�0.2%/mm Hg; P�0.01); and (3) intracerebralventricular injection of losartan had no significant effect on baroreflex in sham rats but improved the baroreflex in CHFrats (maximum slope 1.9�0.2 to 3.1�0.2%/mm Hg; P�0.01). These results suggest that tonic cardiac sympatheticafferent input plays an important role in the blunted baroreflex associated with CHF, which is mediated by central AT1

receptors. (Hypertension. 2005;45:1173-1181.)

Key Words: baroreflex � cardiac function � heart failure � reflex � renal nerves � sympathetic nervous system

Chronic heart failure (CHF) has long been known to beassociated with a blunted arterial baroreflex sensitiv-

ity.1–5 This is a clinically important phenomenon not onlybecause it contributes to altered moment to momentcardiovascular homeostatic adjustments in the CHF patientbut also because it has been directly implicated in anenhanced risk of sudden cardiac death6 and total cardio-vascular mortality.7 However, the mechanisms by whichthe baroreflex is impaired in this disease remain incom-pletely understood.

In a previous study, we showed that in the CHF state, thecardiac sympathetic afferent reflex (CSAR) was aug-mented in dogs with CHF8 –10 and in rats with CHF.11 Thesites at which this reflex is enhanced reside at both theafferent endings10 and in the central nervous system.12

Evidence from this laboratory also suggests that theenhanced gain of the cardiac sympathetic afferent reflex inCHF is related to an enhanced central angiotensin II (AngII) mechanism.11,13 However, cardiac sympathetic afferentcan inhibit baroreflex sensitivity14 and our recent studyalso demonstrated that in normal rats, electrical andchemical stimulation of the CSAR inhibited the arterialbaroreflex control of renal sympathetic nerve activity(RSNA), and that central blockade of AT1 receptorsprevented this inhibition.15 We thus reasoned that in the

CHF state, the enhanced CSAR might contribute to im-pairment of arterial baroreceptor reflex function via centralAng II mechanism. In the present study, we examined theeffects of blocking CSAR on this reflex function in the ratswith chronic myocardial infarction-induced CHF and ex-plored the role of central Ang II mechanism in this process.

MethodsMale Sprague-Dawley rats weighing 180 to 200 grams were used inthese experiments. All experiments were approved by the Institu-tional Animal Care and Use Committee of the University ofNebraska Medical Center and were performed under the guidelinesof the American Physiological Society and the National Institutes ofHealth Guide for the Care and Use of Laboratory Animals.

Model of Chronic Heart FailureCHF was produced by coronary artery ligation as previously de-scribed.16,17 All rats were anesthetized with ketamine (100 mg/kg,intraperitoneally), intubated, and mechanically ventilated. A leftthoracotomy was performed through the fifth intercostal space, thepericardium was opened, the heart was exteriorized, and the leftanterior descending coronary artery was ligated. Sham-operated ratswere prepared in the same manner but did not undergo coronaryartery ligation. All the rats survived the sham surgery. However,�68% of rats survived coronary artery ligation surgery.

Received November 14, 2004; first decision December 7, 2004; revision accepted March 21, 2005.From the Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha.Correspondence to Wei Wang, MD, PhD, Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, 985850

Nebraska Medical Center, Omaha, NE 68198-5850. E-mail [email protected]© 2005 American Heart Association, Inc.

Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000168056.66981.c2

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Acute ExperimentsGeneral Animal Preparation

Seven to 9 weeks after coronary ligation, each rat was anesthetizedwith urethane (800 mg/kg intraperitoneally) and �-chloralose (40

mg/kg intraperitoneally). A midline incision in the neck was made,and the trachea was cannulated to facilitate mechanical ventilation.Each vagus was then identified, tied, and sectioned, and the rightcommon carotid artery was catheterized with a Millar transducer (modelSPR-524; Millar Instruments) for measurement of mean arterial pres-sure (MAP). Heart rate (HR) was derived from the arterial pressurepulse using the cardiotachometer function of the PowerLab (model 16S;ADInstruments). A femoral vein was cannulated with a polyethylenecatheter (PE20) for administration of drugs.

TABLE 1. Body Weight, Heart Weight, Lung Weight, InfarctSize, and Hemodynamics in the Anesthetized Rats Subjected toEither Coronary Ligation or Sham OperationMeasurements Sham CHF

No. 12 10Body weight, g 406.7�16.9 378.9�10.1Wet whole heart weight, g 1.9�0.2 2.7�0.2†Wet whole heart weight/body weight, mg/g 4.7�0.3 7.1�0.4‡Wet lung weight, g 2.2�0.1 4.1�0.3†Wet lung weight/body weight, mg/g 5.4�0.4 10.8�0.7‡IS, %LV area 0 47.3�5.4‡SAP, mm Hg 111.9�9.3 96.5�7.4*DAP, mm Hg 82.4�5.9 79.3�6.1MAP, mm Hg 89.5�4.4 85.9�7.6HR, bpm 322.8�10.9 347.6�17.3LVSP, mm Hg 119.5�6.6 99.7�10.1*LVEDP, mm Hg 0.2�0.5 13.9�2.6‡

DAP indicates diastolic arterial pressure; HR, heart rate; IS, infarct size;LVEDP, left ventricular end-diastolic pressure; LVSP, left ventricular peaksystolic pressure; MAP, mean arterial pressure; SAP, systolic pressure.

*P�0.05, †P�0.01, and ‡P�0.001 compared with sham group.

TABLE 2. Effects of Epicardial Application of Capsaicin andElectrical Stimulation of Cardiac Sympathetic Afferents onMAP, HR, and RSNA

Groups Treatment MAP, mm Hg HR, bpm RSNA, %

Sham(n�12)

Before cap 90.3�5.5 314.7�19.9 100

During cap 105.4�4.9* 392.5�23.7* 178.7�17.6†

Before ele sti 91.3�6.1 326.6�18.7 100

During ele sti 109.4�7.5‡ 414.4�31.8‡ 192.2�21.3§

CHF(n�10)

Before cap 85.3�6.6 339.6�21.4 100

During cap 116.1�9.3* 424.4�18.7* 251.9�19.6†

Before ele sti 84.9�8.8 341.5�27.6 100

During ele sti 116.6�7.9‡ 451.8�32.6‡ 227.7�21.3‡

Cap indicates capsaicin; ele sti, electrical stimulation; RSNA, renal sympa-thetic nerve activity.

*P�0.05 and †P�0.01 compared with before capsaicin.‡P�0.05 and §P�0.01 compared with before electrical stimulation.

Figure 1. Top panels show original recordings of arterial blood pressure changes induced by phenylephrine injection (10 �g intrave-nous; starting at the nadir of arterial pressure fall after administration of nitroglycerin) and attendant RSNA reflex responses in a CHFrat before (left) and during (right) epicardial application of capsaicin (A) and electrical stimulation of cardiac sympathetic afferents (C).Bottom panels show the composite arterial baroreflex curves from a group of CHF rats (*P�0.05, n�10).

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Recording of RSNAThe left renal sympathetic nerves were placed on a pair of

platinum–iridium recording electrodes and then were covered with afast-setting silicone (Kwik-Sil; World Precision Instruments). Theamplified discharge was monitored on a storage oscilloscope (model121 N; Tektronix), imported to a computer system with otherparameters, and then stored on disk until analyzed.

Epicardial Application of Capsaicin or LidocaineThe chest was opened through the fourth intercostal space. The

pericardium was removed to expose the left ventricle. A 2-mm piece

of filter paper containing capsaicin (0.4 �g in 2 �L) or lidocaine (2%in 20 �L) was applied to the anterior surface of the left ventricle.Each drug was applied for �2 minutes until the end of abaroreflex test.

Electrical Stimulation of Cardiac SympatheticAfferent Nerves

The chest was opened through the left second intercostal space.The left ventral ansa, which contains cardiac sympathetic afferentnerves, was identified, tied, and ligated. A pair of stainless steelstimulation electrodes was placed on the central end of this nerve.

Figure 2. Cardiac sympathetic afferent stimulation impairs baroreflex control of renal sympathetic nerve activity in both sham and CHFrats. Epicardial application of capsaicin (left panels) or electrical cardiac sympathetic afferent stimulation (right panels) reduced theaverage slope (A and E) and Gainmax (B and F), and increased the minimum RSNA (C and G). *P�0.05 and **P�0.01 compared withbefore capsaicin or electrical stimulation; †P�0.05 compared with sham group before capsaicin or electrical stimulation; ‡P�0.05 com-pared with sham group during capsaicin or electrical stimulation. Sham rats, n�12; CHF rats, n�10.

Gao et al Cardiac Sympathetic Afferent Blunts Baroreflex 1175



The stimulus (7 V, 1 ms, 20 Hz) was delivered with a stimulator(Grass S88; Astro-Med ) and a stimulus isolation unit.

Intracerebroventricular LosartanThe rats were placed in a stereotaxic head-holder (Stoelting) and

the skull was exposed through an incision on the midline of the scalp.An intracerebroventricular cannula (outer diameter 0.5 mm and innerdiameter 0.1 mm) connected to a microsyringe (model 7001 Ham-ilton) was implanted into the right cerebral ventricle. The coordinateswere determined from the Paxinos and Watson rat atlas,18 which are0.8 mm posterior, 1.4 mm lateral to the bregma, and 3.8 mm ventralto the zero level. Losartan was given as 500 nmol in 1 �L artificialcerebrospinal fluid (aCSF). At the end of the experiment, the cannulatip placement was confirmed by microinjection of Fast Green (1 �L).

Measurement of Left Ventricle End-Diastolic Pressure,Left Ventricle Systolic Pressure, and Cardiac Infarct Size,and the Verification of Central Microinjection Site

At the end of each experiment, the Millar catheter was advancedthrough the carotid artery into the left ventricle (LV) to determineLV end-diastolic pressure and LV systolic pressure, which wereobtained from a 7- to 9-beat average. The rats were then euthanizedwith an overdose of anesthetic (pentobarbital sodium 100 mg/kg,intravenous). The hearts were removed from the chests, sectioned,photographed with a digital camera, and the ratio of the infarct areato whole LV minus septum was measured using SigmaScan Pro 5software. The brains were removed from the skull, placed in 10%formalin, and sectioned, and the microinjection site was verified.

Construction of Arterial Baroreflex Curves andStatistical Analysis

Baroreflex curves were generated by measuring the RSNA re-sponses to decreases and then increases in arterial pressure byintravenous administration of nitroglycerin (25 �g) followed byphenylephrine (10 �g). The RSNA response was normalized aspercentile of baseline. A sigmoid logistic function was fit to the datausing a nonlinear regression program (Sigma Plot; SPSS). Fourparameters were derived from the equation: % RSNA�A/{1 � exp[B (MAP � C)]} � D, in which A is percent RSNA range, B is theslope coefficient, C is the pressure at the midpoint of the RSNArange (BP50), and D is minimum RSNA.19 The peak slope (ormaximum gain) was determined by taking the first derivative of thebaroreflex curve described by the equation.

The sympathetic afferent stimulation induced increases in RSNAand arterial pressure reached their maximal responses at 5 to 10seconds and then gradually declined to the baseline, which lasted �3to 4 minutes. Baroreflex function was tested when the RSNA andarterial pressure reached their peak (during 5 to 10 seconds afterstimulation of cardiac sympathetic afferents), and the testing lasted�20 to 30 seconds. In CHF rats, epicardial application of lidocaineor intracerebroventricular losartan induced a decrease in RSNA. Inthis case, the baroreflex function testing was performed when theRSNA reached its nadir (�40 to 60 seconds after the treatment oflidocaine or losartan).

The baseline MAP and RSNA were averaged over a 20-secondperiod before any treatment. The maximum MAP and RSNAresponses to the sympathetic afferent stimulation, lidocaine, orlosartan were measured over 10 seconds. However, the change of

Figure 3. A, Original recording of arterialblood pressure changes induced byphenylephrine injection (10 �g intrave-nous; starting at the nadir of arterialpressure decline after administration ofnitroglycerin) and attendant RSNA reflexresponses in a CHF rat before (left) andduring (right) epicardial application oflidocaine. B, Composite arterial barore-flex curves from a group of CHF rats(*P�0.05, n�10).




MAP and RSNA during baroreflex testing was averaged for each for1 second to obtain smooth baroreflex function curves, which weregenerated from data collected as pressure increased on administra-tion of phenylephrine beginning at the nadir of arterial pressure afternitroglycerin administration.

All values are expressed as mean�SE. We constructed compositebaroreflex curves by averaging the 4 parameters of the logisticequation for all curves and using the mean parameters to construct asingle curve. A 1-way analysis of variance followed with theNewman-Keuls test for post-hoc analysis was used when multiplecomparisons were made. A value of P�0.05 was considered statis-tically significant.

ResultsBody Weight, Heart Weight, Lung Weight, andBaseline HemodynamicsTable 1 summarizes the hemodynamic characteristics ofsham and CHF rats. In the rats with CHF, gross examinationrevealed a dense scar in the anterior ventricular wall and themean infarct area was 47.3�5.4% of the LV area. No infarctswere evident in sham-operated rats. The body weight wassimilar in the 2 groups. However, both the heart weight andheart-to-body weight ratio were higher in CHF rats comparedwith sham-operated rats. Both the lung weight and thelung-to-body weight ratio were higher in CHF rats comparedwith sham-operated rats, thus documenting the occurrence of

substantial pulmonary congestion. Pleural fluid and asciteswere found in the 10 CHF rats compared with none in the 12sham-operated rats.

There were no statistically significant differences in base-line MAP, diastolic arterial pressure, and HR between thesham-operated rats and CHF rats. However, the systolicarterial pressure and peak LV systolic pressure were de-creased, and the LV end-diastolic pressure was significantlyincreased in CHF rats compared with sham-operated rats.

Effects of Chemical and Electrical Stimulation ofCardiac Sympathetic Afferents on ArterialBaroreflex FunctionIn both sham and CHF rats, HR, MAP, and RSNA weresignificantly higher during epicardial application of cap-saicin or electrical stimulation of cardiac sympatheticafferents compared with those before treatment (Table 2).Figure 1 (upper panels) show original recordings of arterialblood pressure changes induced by phenylephrine andattendant RSNA reflex responses before and during epicardialapplication of capsaicin (Figure 1A) and electrical stimulation ofcardiac sympathetic afferents (Figure 1C) in 1 CHF rat. Thereduced reflex sympatho-inhibition to phenylephrine in CHFrats was further impaired by these treatments. These patterns

Figure 4. Blockade of cardiac sympathetic afferent input normalized the impaired baroreflex function in CHF rats. Epicardial applicationof lidocaine increased the average slope (A) and Gainmax (B), and decreased the minimum RSNA (C) only in CHF rats. *P�0.05 com-pared with before lidocaine; †P�0.05 compared with sham rats. Sham rats, n�12; CHF rats, n�10.




were confirmed by the average group data shown in Figure 1(bottom panels). Both chemical and electrical stimulation signif-icantly reduced the average slope and Gainmax and increased theminimum RSNA of baroreflex curve in both sham and CHFgroups (Figure 2).

Effects of Epicardial Application of Lidocaine onArterial Baroreflex FunctionIn the rats with CHF, the baseline RSNA was significantlylower during epicardial application of lidocaine (from 100 to81.8�6.5%; P�0.05). In addition, lidocaine significantlyincreased the average slope and Gainmax, and decreased theminimum RSNA of baroreflex curve (Figures 3 and 4).

In contrast to the CHF rats, lidocaine had no significanteffects on baseline RSNA, or on the average slope, Gainmax,and minimum RSNA of the arterial baroreflex curve in shamrats (Figure 4).

Effects of Intracerebroventricular Losartan onArterial Baroreflex FunctionFigure 5A shows an original recording of arterial bloodpressure changes induced by phenylephrine treatment startingat the nadir of arterial pressure decline after administration ofnitroglycerin and attendant RSNA reflex responses beforeand after intracerebroventricular losartan in a CHF rat. Thereflex RSNA response to phenylephrine is enhanced afterintracerebroventricular losartan. This pattern was confirmedby the average group data reported in Figure 5B. Figure 6A

shows an original recording of arterial blood pressurechanges induced by phenylephrine and attendant RSNAreflex responses before and during electrical stimulation ofcardiac sympathetic afferents after intracerebroventricularlosartan in rats with CHF. In this setting, electrical cardiacsympathetic afferent stimulation failed to blunt the reflexRSNA response to phenylephrine after intracerebroventricu-lar losartan. This pattern was confirmed by the average groupdata shown in Figure 6B. Although there were no significantdifferences in HR and MAP, baseline RSNA was signifi-cantly lower after intracerebroventricular losartan (from 100to 76.8�9.5%; P�0.01). In addition, losartan significantlyincreased the average slope, Gainmax and range of the RSNAresponse (Figure 7), and decreased the minimum RSNA. Itcan be seen from the Figure 7 that intracerebroventricularlosartan prevented the electrical stimulation of cardiac sym-pathetic afferents from lowering the average slope, Gainmax,and range of the RSNA response of the arterial baroreflexcurve in both sham and CHF rats.

In sham-operated rats, however, intracerebroventricularlosartan had no significant effects on the average slope,Gainmax, and range of the RSNA responses of the arterialbaroreflex curve (Figure 7).

DiscussionIt has been well established that arterial baroreceptor reflexfunction is markedly decreased20–22 and the cardiac sympa-

Figure 5. A, Original recording of arterialblood pressure changes induced byphenylephrine injection (10 �g intrave-nous; starting at the nadir of arterialpressure decline after administration ofnitroglycerin) and attendant RSNA reflexresponses in a CHF rat before (left) andafter (right) intracerebroventricular losar-tan. B, Composite arterial baroreflexcurves from a group of CHF rats(*P�0.05, n�10).




thetic afferent reflex is augmented8–10 in chronic heart failure.However, it is not clear what relationship exists between theaforementioned 2 cardiovascular reflexes in this state. Thecardiac sympathetic afferent reflex is a sympatho-excitatoryreflex23 and contributes to the elevation in sympathetic tone.24

Increases in sympathetic nerve activity can antagonizebaroreflex function25–27 in the heart failure state. Therefore, itis possible that the augmented cardiac sympathetic afferentreflex might impair arterial baroreflex function via itssympatho-excitatory effects. In the present study, we foundthat in anesthetized rats with CHF, LV epicardial applicationof lidocaine decreased the baseline RSNA and improved theimpaired baroreflex control of RSNA (see Figures 3 and 4),suggesting that blockade of cardiac sympathetic afferentinput partially normalized the impaired baroreflex functionseen in the heart failure state. To our knowledge, this is firstdemonstration that tonic cardiac sympathetic afferent inputplays an important role in blunting the baroreflex in CHF.This phenomenon appears to be specific to heart failure statesbecause in sham-operated rats, we failed to find any changeof RSNA and baroreflex parameters during epicardial appli-cation of lidocaine, indicating that there is little, if any, toniccardiac sympathetic afferent input in the regulation of sym-pathetic nerve activity in the normal rats. However, in thenormal cats, Gnecchi-Ruscone et al demonstrated that tonicsympathetic afferent activity inhibited baroreflex function,14

which differs from our findings in the current study. Thedifferent anesthetics, species, and the methods to blocksympathetic afferent nerves used in the 2 experiments mightaccount for this inconsistency. In addition, the potentialdifferences in baroreflex control of RSNA and HR also mightplay some role in the contravention.

The exact mechanisms by which arterial baroreflex func-tion is impaired by tonic cardiac sympathetic afferent input inrats with CHF are not completely clear. Our previous studiesshowed that the Ang II concentration in the cerebrospinalfluid was increased in the dogs with pacing induced heartfailure,24 and Wang et al demonstrated the prevention ofsympathetic and cardiac dysfunction induced by myocardialinfarction in transgenic rats deficient in brain angioten-sinogen.28 Evidence from our laboratory also suggests that theaugmented central Ang II mechanism was involved in theenhanced CSAR in the heart failure state. For instance,central administration of losartan normalized the enhancedCSAR in the dogs with pacing-induced heart failure,12 andintracerebroventricular administration of losartan normalizedthe enhanced CSAR evoked by epicardial application of bothbradykinin and capsaicin in rats with CHF.11 In a recent studyin normal rats,15 we found that intracerebroventricular admin-istration of losartan normalized the enhanced RSNA inducedby electrical stimulation of cardiac sympathetic afferents. Inaddition, losartan also prevented this electrical stimulation

Figure 6. A, Original recording of arterialblood pressure changes induced byphenylephrine injection (10 �g intrave-nous; starting at the nadir of arterialpressure decline after administration ofnitroglycerin) and attendant RSNA reflexresponses in a CHF rat before (left) andduring (right) electrical stimulation of car-diac sympathetic afferents after pretreat-ment with intracerebroventricular losar-tan. B, Composite arterial baroreflexcurves from a group of CHF rats(*P�0.05, n�10).




from impairing arterial baroreflex function. These resultssuggested that central Ang II is the key mediator in theinhibitory effect of CSAR evoked by the electrical stimula-tion on the arterial baroreflex function in normal state. In thepresent study, we confirmed that central administration oflosartan normalized the enhanced RSNA and improved theimpaired arterial baroreflex control of RSNA in rats withCHF (Figures 5 and 6), a result similar to that found byDiBona et al.29 These results imply elevated central Ang II asplaying an important role in the inhibitory effects of toniccardiac sympathetic afferent input on arterial baroreflexcontrol of RSNA in the heart failure state. In contrast, in thesham-operated rats, we failed to find any change in RSNA

and baroreflex parameters after intracerebroventricular ad-ministration of losartan, indicating that in the normal state,central Ang II does not tonically inhibit arterial baroreflexfunction.

In the present study, we noticed that intracerebroventricu-lar losartan improved the blunted arterial baroreflex sensitiv-ity of CHF via increasing both the average slope and range ofRSNA response of the arterial baroreflex curve, but leftepicardial application of lidocaine partially improved theimpaired arterial baroreflex function of CHF only via chang-ing the average slope. This difference implies that increasedcentral Ang II level mediates not only the responses toaugmented input from cardiac sympathetic afferents but alsosome other yet unknown pathways to impair the arterialbaroreflex function in heart failure state.

As expected, in the sham-operated rats of the present study,we confirmed that both epicardial application of capsaicinand electrical stimulation of cardiac sympathetic afferentsinhibited the arterial baroreflex control of RSNA, and thatintracerebroventricular losartan attenuated the inhibitory ef-fect of electrical stimulation of cardiac sympathetic afferentson arterial baroreflex function.15 However, in the presentstudy, we also found that in the rats with CHF, both epicardialapplication of capsaicin and electrical stimulation of cardiacsympathetic afferents increased MAP and RSNA and furtherreduced the average slope and Gainmax of the arterial barore-flex. These results suggest that in this heart failure model, theaugmented cardiac sympathetic afferent reflex was not max-imal and could still be enhanced. However, these results alsoimply that at least in the present CHF model, the arterialbaroreceptor reflex, even though blunted, can still controlRSNA over a limited range and could be further impairedwhen the cardiac sympathetic afferents were chemically andelectrically stimulated.

In conclusion, the results of the present study suggest thattonic cardiac sympathetic afferent input plays an importantrole in the blunted baroreflex associated with CHF, which ismediated by central AT1 receptors.

PerspectivesIn this study, we found that blockade of cardiac sympatheticafferents partially normalized the decreased arterial barore-flex in the rats with chronic myocardial infarction-inducedCHF. Consequently, these findings indicate that in the heartfailure state, the tonic cardiac sympathetic afferent inputplays an important role in impairing arterial baroreflexfunction. These results suggest a new mechanism by whicharterial baroreflex function is impaired in the heart failurestate and provide a new potential therapy to this disease. Forinstance, blockade of the cardiac sympathetic afferent reflexmight benefit the CHF patient via improvement of theimpaired arterial baroreflex function.

AcknowledgmentsThis study was supported by grant-in-aid from the American HeartAssociation and National Institutes of Health grants RO-1 HL077691 and PO-1 HL62222. Dr Gao was supported by a postdoctoralfellowship from the American Heart Association, Heartland Affili-ate, award number 0425680Z.

Figure 7. Blockade of central AT1 receptors normalized theimpaired baroreflex function in CHF rats. Intracerebroventricularlosartan increased the average slope (A), Gainmax (B), and rangeof RSNA response (C) only in CHF rats. *P�0.05 compared withbefore losartan; #P�0.05 compared with sham rats. Sham rats,n�12; CHF rats, n�10.




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In an article by L. Gao et al in the June 2005 issue of Hypertension (Gao L, Schultz HD, PatelKP, Zucker IH, Wang W. Augmented input from cardiac sympathetic afferents inhibits baroreflexin rats with heart failure. Hypertension. 2005;45:1173–1181), the authors mistakenly omitted arelevant reference. In a study by L Mircoli et al (Mircoli L, Fedele L, Benetti M, Bolla GB,Radaelli A, Perlini S, Ferrari AU. Preservation of the baroreceptor heart rate reflex by chemicalsympathectomy in experimental heart failure. Circulation. 2002;106:866–872) these authorsshowed that chronic chemical sympathectomy normalized arterial baroreflex function in rats withmyocardial infarctions. Whereas the authors’ study focused on cardiac sympathetic afferentfunction in chronic heart failure, the study by Mircoli et al clearly suggests that interruption ofsympathetic function may be a novel strategy for normalization of baroreflex function and perhapsmyocardial function in an early stage of myocardial infarction. The authors apologize for thisoversight.

e25

Correction

Lie Gao, Harold D. Schultz, Kaushik P. Patel, Irving H. Zucker and Wei WangHeart Failure

Augmented Input From Cardiac Sympathetic Afferents Inhibits Baroreflex in Rats With

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Augmented Input From Cardiac Sympathetic Afferents Inhibits Baroreflex in Rats With Heart Failure