(Hypertension. 1997;29:564-569.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Enhances Baroreflex Control of Sympathetic Outflow in Heart Failure
the Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha.
Correspondence to Irving H. Zucker, PhD, Department of Physiology and Biophysics, University of Nebraska College of Medicine, 600 S 42nd St, Omaha, NE 68198-4575. E-mail izucker@mail.unmc.edu
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Abstract |
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Enhanced sympathetic outflow is seen in both patients with congestive heart failure and animals with experimental heart failure. In a previous study, we demonstrated that the baroreflex control of heart rate was impaired in conscious rabbits with pacing-induced heart failure and that this impairment was partially restored by blockade of angiotensin II type 1 (AT1) receptors. In the present study, we determined the interaction between the renin-angiotensin system and baroreflex control of renal sympathetic nerve activity in normal conscious rabbits and conscious rabbits with pacing-induced heart failure before and after AT1 receptor blockade. Heart failure was induced by rapid ventricular pacing at a rate of 360 to 380 beats per minute for an average of 16.7±0.6 days. To generate baroreflex curves, we altered arterial pressure by administering phenylephrine and sodium nitroprusside. A sigmoidal logistic function was fit to renal sympathetic nerve activity–mean arterial pressure relationships for analysis of several components of baroreflex function. AT1 receptors were blocked by intravenous administration of the specific antagonist L-158,809. In normal rabbits, there was no significant difference in any parameter of baroreflex function before and after blockade of AT1 receptors. In contrast, blockade of AT1 receptors enhanced baroreflex sensitivity in heart failure rabbits. The maximal gain increased to 5.0±0.7% renal sympathetic nerve activity/mm Hg from 2.6±0.3 (P<.05). Although L-158,809 had no effect on baseline renal sympathetic nerve activity in normal rabbits, analysis of the data in the heart failure rabbits indicated that baseline renal sympathetic nerve activity was reduced from 33±5% to 17±4% after L-158,809 administration after adjustment for changes in arterial pressure. These data suggest that angiotensin II plays a role in baroreflex impairment in this model of heart failure and may be in part responsible for the depressed baroreflex sensitivity observed in heart failure.
Key Words: sympathetic nervous system • arterial pressure • receptors, angiotensin • heart failure
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Introduction |
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Sympathoexcitation in congestive HF is well documented in both patients with congestive HF and animals with experimental HF.1 2 Plasma norepinephrine and muscle sympathetic nerve activity are increased in HF.3 4 It is well accepted that the renin–Ang II system is activated in human5 6 and experimental7 HF. The interaction between the sympathetic nervous and renin–Ang II systems is also well known. Sympathoexcitation by Ang II occurs at several loci in the sympathetic nervous system. These include sympathetic ganglia, postganglionic synapses, and the central nervous system.8 It has also been well established that administration of angiotensin-converting enzyme inhibitors to patients with HF reduces myocardial sympathetic outflow as assessed by coronary sinus norepinephrine.9 10 Because of this close and well-known interaction of the two systems, we hypothesized that Ang II plays an important role in sympathoexcitation in the HF state. In a previous study,11 we demonstrated that the baroreflex control of HR is impaired in conscious rabbits with pacing-induced HF and that this impairment was partially restored by blockade of AT1 receptors. The evaluation of baroreflex control of HR is complicated by the dual innervation of the sinoatrial node. In our previous study, we had to use pharmacological tools to assess the relative roles of the vagus versus the sympathetic innervation of the sinoatrial node in the HF state before and after AT1 receptor blockade. Therefore, in the present study, we aimed to extend our previous observations by investigating the interaction between the renin–Ang II and sympathetic nervous systems in conscious rabbits with pacing-induced HF. In the present study, we directly measured RSNA to determine the effect of Ang II on baroreflex control of RSNA in both normal rabbits and rabbits with pacing-induced HF.
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Methods |
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Fourteen male New Zealand White rabbits weighing between 2.5 and 3.5 kg were used in the present study. The rabbits were divided into two groups: a normal (sham) group and an HF group. All rabbits were fed and housed according to institutional guidelines at the University of Nebraska Medical Center. These studies were approved by the University of Nebraska Medical Center Institutional Animal Care and Use Committee and conformed to the Guiding Principles for the Use and Care of Laboratory Animals of the National Institutes of Health and American Physiological Society.
Surgical Procedures
Rabbits were anesthetized with an anesthetic cocktail consisting of ketamine hydrochloride (Ketaset, Fort Dodge Laboratories Inc; 58.8 mg/kg), acepromazine maleate (Fermenta Animal Health Co; 1.2 mg/kg), and xylazine (Rompun, Miles Inc; 5.9 mg/kg) in lactated Ringer's solution given by intramuscular injection (1 mL/kg). Supplemental anesthesia was provided by pentobarbital sodium (Abbott Laboratories; 0.3 to 0.35 mg/kg) injected intravenously via a marginal ear vein.
After the rabbit was intubated and placed on positive-pressure ventilation, a left thoracotomy was performed through the fifth intercostal space. A pacing electrode was secured to the apex of the left ventricle. The lead was brought out of the chest and connected to a pacemaker (model 5985, Medtronic Inc) implanted subcutaneously in the back. The chest was closed in layers and evacuated. Postoperatively, the rabbits were placed on an antibiotic regimen for 3 to 5 days (Tylosin, Elano Animal Health; 5 mg/kg IM).
At least 1 week after the thoracotomy, the rabbit was anesthetized as described above, and Micro-Renathane catheters (Braintree Scientific Inc) were inserted into the left common carotid artery and jugular vein. The catheters were flushed daily with heparin sodium (Elkins-Sinn, Inc; 1000 U/mL). During the recovery period, the rabbits were brought to the laboratory and trained to sit quietly in a plastic box of our own design. At least 3 days after the second surgery, control measurements were taken, and the pacemaker was programmed to 360 to 380 beats per minute. The rabbits were paced continuously for an average of 16.7±0.6 days. At periodic intervals, the pacemaker was turned off so that resting hemodynamics could be monitored.
Renal Nerve Recording and Implantation
After approximately 2 weeks of pacing, a renal nerve electrode was implanted with the use of the same anesthetic regimen described above. The pacemaker was turned off until 1 day after this surgery. The left renal sympathetic nerves were exposed through a flank incision with the use of a retroperitoneal approach. The renal nerves were dissected from the surrounding tissue and renal artery. A pair of polytetrafluoroethylene-coated stainless steel wire electrodes (A-M Systems Inc, 0.125 mm OD) were placed around the dissected renal nerves. To insulate the electrodes and nerve from the surrounding tissue and protect the nerves from desiccation, we covered the electrodes and nerve assembly with a two-component silicone gel (Wacker Sil-Gel). A ground lead was sutured to the muscle close to the electrodes. The electrodes and ground lead were tunneled beneath the skin to the back and fixed between the shoulder blades. The flank incision was closed. The day after surgery, the pacemaker was programmed to the rate used before the surgery.
The normal rabbits were treated in a similar fashion except they were not paced. During recovery, the normal rabbits were also brought to the laboratory several times a week and trained to sit quietly in the plastic box.
After rabbits had recovered from the surgeries and at least 2 to 3 days after implantation of the renal nerve electrode, baroreflex experiments were performed. On the day of the experiment, the rabbit was placed in the holding box. The arterial and venous catheters were connected to pressure transducers (Hewlett-Packard) for measurement of MAP and CVP. HR was measured by a cardiotachometer triggered by the arterial pressure pulse. RSNA was recorded by preamplification of the signal with a preamplifier (P18, Grass Instrument Co), with the band-pass filters set between 100 Hz and 1 KHz. The amplified signal was displayed on a storage oscilloscope and passed through an audio amplifier and loudspeaker. The raw nerve activity was full-wave–rectified and integrated with a voltage integrator (model 1801, Buxco Electronic, Inc). The signals were led to a MacLab data-acquisition system (model 8s, Apple Computer, Inc) and sampled at 100 Hz per channel. All sympathetic nerve recordings had a signal-to-noise ratio of at least 3.
Experimental Protocol
Normal Group (n=6)
To investigate the role of endogenous Ang II on baroreflex control of RSNA, we compared baroreflex curves before and after intravenous injection of L-158,809, a selective nonpeptide AT1 receptor antagonist (0.3 mg/kg, provided by Merck and Co).12 Ang II blockade was demonstrated by the complete inhibition of the pressor response to 0.1 µg Ang II (Sigma Chemical Co) administered intravenously. Ten to 15 minutes was allowed to elapse before the postblockade curve was constructed. Baroreflex curves were generated by measurement of the RSNA response to increases and decreases in arterial pressure by intravenous administration of either phenylephrine (American Reagent Laboratories Inc, 30 µg/kg) or sodium nitroprusside (Hoffmann–La Roche Inc, 100 µg/kg), which was carried out in random order. MAP was altered at a rate of 1 to 2 mm Hg/s.
HF Group (n=6)
After recovery from the surgeries and at least 2 to 3 days after implantation of the renal nerve electrode, the HF rabbits were placed into the experimental box and the pacemaker was turned off. Baroreflex curves (RSNA versus MAP) were generated as described for the normal rabbits; that is, a control curve was followed by a curve after L-158,809 administration.
Ang II Infusion (n=5)
To determine whether acute Ang II infusion exhibited the opposite effect to that of AT1 blockade, we recorded arterial pressure and RSNA in normal rabbits. Baroreflex function curves relating MAP to RSNA were constructed before and 30 minutes after Ang II infusion at a dose of 20 to 30 ng/kg per minute. This experiment was carried out in normal rabbits because HF rabbits had blunted baroreflex responses to begin with.
Data Analysis
RSNA and MAP data were recorded every 2 seconds from the threshold to the saturation point. The maximum RSNA was determined for each experiment as the maximum response after MAP reduction to at least 40 mm Hg. The noise level was determined for each experiment as the voltage after an increase in MAP to approximately 120 mm Hg with the use of phenylephrine. This value was subtracted from the RSNA value. RSNA is expressed as the percentage of maximum activity for each experiment.
A sigmoid logistic function was fit to the data with a nonlinear regression analysis (SigmaPlot version 4.16, Jandel Co) run on a Macintosh computer. Four parameters were derived from the equation % RSNA=A/{1+exp[B(MAP-C)]}+D, where A is percent RSNA range, B is the slope coefficient, C is the pressure at the midpoint of the RSNA range (BP50), and D is the minimum RSNA. Peak slope was determined by taking the first derivative of the baroreflex curve described by the equation. All values are expressed as mean±SE.
We constructed composite baroreflex curves by averaging the four parameters of the logistic equation for all curves before and after L-158,809 and using the mean parameters to construct a single curve.
Data were analyzed with a paired t test when comparing effects of L-158,809 in each group. Student's t test was used when comparing the mean parameters between normal and HF groups. A value of P<.05 was considered statistically significant.
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Results |
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Effects of L-158,809 on Baroreflex Control of RSNA in Normal Rabbits
The Table
shows the effects of L-158,809 on MAP, HR, CVP, and some of the curve parameters in the normal state. L-158,809 had no significant effect on baseline hemodynamics and curve parameters. Mean baroreflex curves generated during control and after L-158,809 are shown in Fig 1. These curves are nearly superimposable. The individual and mean values of the maximum gain before and after L-158,809 administration are shown in Fig 2 (top). The average maximum gain was 4.2±0.4%/mm Hg before L-158,809 and 4.6±0.3 after L-158,809.
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Effects of L-158,809 on Baroreflex Control of RSNA in Rabbits With Pacing-Induced HF
The Table
shows the effects of L-158,809 on MAP, HR, CVP, and some of the curve parameters of paced rabbits. Resting HR and CVP did not differ significantly before versus after L-158,809 administration. L-158,809 significantly reduced MAP in the HF group. Composite baroreflex curves generated during control and after L-158,809 are shown in Fig 3. In contrast to the normal rabbits, L-158,809 administration significantly increased maximum gain. The individual and mean values of the maximum gain before and after L-158,809 administration are shown in Fig 2 (bottom). The maximum gain increased in every rabbit after L-158,809, increasing from 2.6±0.3 to 5.0±0.7% RSNA/mm Hg (P<.05).
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Adjusted Baseline RSNA
Even though there were no significant differences in MAP before and after L-158,809 administration in the normal group and a small but significant difference in the HF group, there were individual differences in MAP before and after L-158,809 administration. These differences make it difficult for one to assess baseline RSNA before and after L-158,809 administration. In fact, as shown by the baseline values in Fig 3, L-158,809 slightly increased RSNA in HF rabbits. To assess baseline RSNA more precisely, we calculated an adjusted value for baseline RSNA by using the individual RSNA-MAP curves. To calculate the adjusted RSNA, we took the RSNA from the curve after L-158,809 at the baseline pressure that existed before L-158,809.
The adjusted baseline RSNA in normal rabbits is shown in the top panel of Fig 4. Adjusted baseline RSNA did not differ significantly in normal rabbits before and after L-158,809 administration. The adjusted baseline RSNA in rabbits with pacing-induced HF is shown in the bottom panel of Fig 4. In contrast to values in normal rabbits, the adjusted baseline RSNA in HF rabbits was significantly decreased from 33±5% to 17±4% of maximum after L-158,809 administration (P<.05).
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Effects of Ang II Infusion
As can be seen in Fig 5, acute infusion of Ang II for 30 minutes profoundly impaired baroreflex control of RSNA. Ang II infusion increased MAP from 83.5±3.3 to 102.2±5.2 mm Hg (P<.05), resulting in a reduction in RSNA from 26.8±2.1% to 7.9±2.2% (P<.05). However, the slope of the baroreflex curve after Ang II infusion was decreased from 3.1 to 2.1%/mm Hg (P<.05). The most dramatic decrease in baroreflex sensitivity after Ang II was seen over the hypotensive range. There was no change in BP50 (74.3±3.6 mm Hg control versus 75.7±1.9 after Ang II) or the minimum RSNA (1.0±0.5% control versus 1.9±1.1% after Ang II).
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Discussion |
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The major findings of the present study are as follows: (1) The impaired baroreflex control of RSNA in conscious rabbits with pacing-induced HF is restored by blockade of endogenous Ang II with the selective AT1 receptor antagonist L-158,809; (2) the major effect on the baroreflex control of RSNA after AT1 receptor blockade in HF rabbits appears to be due to blockade of enhanced sympathetic outflow; and (3) blockade of endogenous Ang II in conscious normal rabbits had no effect on the baroreflex control of RSNA.
In these studies, we used rapid ventricular pacing to produce HF. This model has been used extensively in a variety of species, including dogs,13 sheep,14 and rabbits.15 In a previous study from this laboratory, paced rabbits exhibited characteristics of HF after 14.5±1.4 days of pacing.1 In the present study, we implanted the renal nerve electrode after 14.0±0.7 days of pacing. Because HF rabbits are fragile, we deemed it necessary to stop the pacing the day before surgery. The day after surgery, the pacemaker was programmed back to 360 to 380 beats per minute. At least 2 days after ventricular pacing was resumed, while CVP was still above 6 mm Hg (see the Table), the experimental protocol was carried out. The hemodynamic state of the rabbits in the present study was similar to that reported by Masaki et al15 using the same experimental model.
A previous study from our laboratory indicated that the baroreflex control of RSNA was depressed in canine experimental HF.16 In the present study, rabbits with HF exhibited a decrease in the maximum gain of the baroreflex control of RSNA. The impaired maximum gain was restored by AT1 receptor blockade. AT1 receptor blockade had no effect in normal rabbits, in agreement with a recent study by Kumagai and Reid.17 In contrast to the effects of AT1 blockade on baroreflex gain in HF rabbits, infusion of Ang II into normal rabbits reduced baroreflex gain (Fig 5).
Because we recorded multifiber nerve activity, it is inherently difficult to compare the raw nerve activity among different preparations.18 19 20 21 Therefore, RSNA was normalized to the maximal response to sodium nitroprusside–induced hypotension for each experiment. The maximal activity was set at 100%. Because of the necessity of this analysis, it is difficult to assess resting or baseline nerve activity in each rabbit. L-158,809 slightly lowered MAP and raised baseline nerve activity because of an arterial baroreflex effect. Therefore, its effect on RSNA in HF was obscured by its concomitant blood pressure effect. To obtain some index of resting nerve activity in the normal and HF states after adjusting for baroreflex effects, we adjusted the baseline RSNA to the MAP from the baroreflex curves before administering L-158,809. With this analysis, the resting RSNA in the HF group was significantly reduced after blockade of AT1 receptors, whereas it did not change in the normal group (Fig 4). On the basis of these data, it seems reasonable to conclude that Ang II plays a role in mediating the sympathoexcitation of HF. It is notable that AT1 blockade caused a small (5 mm Hg) but significant fall in MAP in HF rabbits (Table and Fig 3). Despite this small effect on resting MAP, AT1 blockade increased maximum baroreflex sensitivity by 92%.
Although the specific mechanisms by which Ang II restores baroreflex sensitivity in HF are unclear, it is well accepted that Ang II modulates sympathetic function by several mechanisms in normal animals. First, Ang II augments norepinephrine release from presynaptic nerve endings,22 23 24 facilitates ganglionic transmission,25 enhances postjunctional 
-adrenergic vasoconstriction,26 and augments central sympathetic outflow.27 Apropos of the latter mechanism, Ang II has major effects in the nucleus tractus solitarius and plays a prominent role in a central hypertensive process.28 All of these actions may contribute to the sympathoexcitation of HF and to impairment of baroreflex control of RSNA.
Since after L-158,809 administration there were small changes in resting arterial pressure and HR, it is likely that L-158,809 acted by a specific neuronal mechanism to restore baroreflex gain. It is unlikely that this mechanism operates at the afferent level because Ang II does not have direct effects on baroreceptor afferents.28 Therefore, the most likely effect of L-158,809 is blockade of AT1 receptors somewhere in the central baroreflex pathway. This conclusion is supported by the recent study of DiBona et al,29 who showed a restoration of baroreflex sensitivity in rats with HF after intracerebroventricular administration of losartan. The results of the present study can be applied only to the control of RSNA. It is possible that the effects of Ang II blockade on sympathetic outflow to other beds is different than that observed for the renal bed. However, the data obtained in humans with HF who are taking angiotensin-converting enzyme inhibitors11 30 would suggest that the effect of Ang II on muscle sympathetic outflow is a global phenomenon. On the other hand, Goldsmith et al31 failed to find positive evidence for the effect of Ang II or angiotensin-converting enzyme inhibition on forearm venous norepinephrine spillover in HF patients. Although these investigators concluded that these data weaken the hypothesis that Ang II is a regulator of sympathetic nerve activity in HF, it is still possible that the effect of Ang II is primarily manifested on the central control of renal sympathetic outflow in conscious rabbits with pacing-induced HF.
In summary, these data strongly suggest that Ang II plays an important role via AT1 receptors in altering the baroreflex control of RSNA in rabbits with pacing-induced HF. It appears that the primary effect of Ang II is to increase sympathetic outflow. Further study will be necessary for determination of the exact location of the effect of Ang II on sympathetic regulation in HF.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-38690 and a postdoctoral Fellowship from the American Heart Association, Nebraska Affiliate (No. 95-04613). We thank Merck and Co for the generous supply of L-158,809. The authors would like to thank Johnnie F. Hackley and Pamela Curry for their expert technical assistance.
Received March 15, 1996;
first decision April 10, 1996;
first decision September 4, 1996;
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References |
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 Q.-G. Xia, O. Chung, H. Spitznagel, S. Illner, G. Janichen, B. Rossius, P. Gohlke, and T. Unger Significance of timing of angiotensin AT1 receptor blockade in rats with myocardial infarction-induced heart failure Cardiovasc Res, January 1, 2001; 49(1): 110 - 117. [Abstract] [Full Text] [PDF]
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H. Kawai, S. Y. Stevens, and C.-S. Liang Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3012 - H3019. [Abstract] [Full Text] [PDF]
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 G. F. DiBona Nervous Kidney : Interaction Between Renal Sympathetic Nerves and the Renin-Angiotensin System in the Control of Renal Function Hypertension, December 1, 2000; 36(6): 1083 - 1088. [Abstract] [Full Text] [PDF]
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J.-L. Liu, S. Irvine, I. A. Reid, K. P. Patel, and I. H. Zucker Chronic Exercise Reduces Sympathetic Nerve Activity in Rabbits With Pacing-Induced Heart Failure : A Role for Angiotensin II Circulation, October 10, 2000; 102(15): 1854 - 1862. [Abstract] [Full Text] [PDF]
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J. Zanzinger Role of nitric oxide in the neural control of cardiovascular function Cardiovasc Res, August 15, 1999; 43(3): 639 - 649. [Abstract] [Full Text] [PDF]
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J.-L. Liu, H. Murakami, M. Sanderford, V. S. Bishop, and I. H. Zucker ANG II and baroreflex function in rabbits with CHF and lesions of the area postrema Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H342 - H350. [Abstract] [Full Text] [PDF]
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T. Sato, T. Kawada, M. Inagaki, T. Shishido, H. Takaki, M. Sugimachi, and K. Sunagawa New analytic framework for understanding sympathetic baroreflex control of arterial pressure Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H2251 - H2261. [Abstract] [Full Text] [PDF]
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W. Zhang, B. S. Huang, and F. H. H. Leenen Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction Am J Physiol Heart Circ Physiol, May 1, 1999; 276(5): H1608 - H1615. [Abstract] [Full Text] [PDF]
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 H. P. Brunner-La Rocca, G. Vaddadi, and M. D. Esler Recent insight into therapy of congestive heart failure: focus on ACE inhibition and angiotensin-II antagonism J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1163 - 1173. [Abstract] [Full Text] [PDF]
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