(Hypertension. 1997;29:1284-1290.)
© 1997 American Heart Association, Inc.
Articles |
Baroreflex Control of Heart Rate and Cardiac Hypertrophy in Angiotensin II–Induced Hypertension in Rabbits
From the Baker Medical Research Institute, Prahran, Victoria, Australia.
Correspondence to Dr Simon C. Malpas, Department of Physiology, University of Auckland Medical School, Private Bag 92019, Auckland, New Zealand. E-mail s.malpas{at}auckland.ac.nz
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Abstract |
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Abstract The cardiac hypertrophy observed in hypertension is thought to be responsible for the accompanying deficiency in the baroreflex control of heart rate. In this study, we assessed the baroreflex relationship between heart rate and arterial pressure in a group of seven rabbits during a normotensive period, during the early phase of angiotensin II (Ang II)–induced hypertension (1 week) (50 ng/kg per minute IV via osmotic minipumps), after 7 weeks of continuous hypertension, then 2 days after Ang II was stopped, and finally 7 days after Ang II. Left ventricles were weighed for measurement of left ventricular weight–body weight ratio. One week of intravenous Ang II infusion produced hypertension (mean arterial pressure from 80±2 up to 115±8 mm Hg), with significantly increased heart rate and hematocrit. The heart rate–arterial pressure baroreflex curve was shifted to the right, with a significant 45% reduction in the gain of the reflex (-6.4±1.5 to -3.5±0.2 beats per minute/mm Hg). After 7 weeks of Ang II, arterial pressure was still elevated (112±4 mm Hg) and the gain of the baroreflex curve still somewhat attenuated, although it was no longer markedly different from normotensive levels (gain, -5.09±0.95, 20% reduction from normotensive level). Two days after the Ang II infusion was stopped, arterial pressure had returned to normotensive levels, although hematocrit and heart rate remained elevated. At this time, the baroreflex curve was similar to prehypertensive control levels, with no further changes when measured again 7 days after Ang II. Cardiac hypertrophy was present when measured at 7 days after angiotensin (left ventricular weight–body weight ratio: 1.78±0.05 versus 1.35±0.04 g/kg, hypertensive versus normotensive, P<.05). Thus, although Ang II infusion produced an initial deficit in the baroreflex control of heart rate, this effect became less as the hypertension continued. Furthermore, although cardiac hypertrophy developed, its presence did not appear to be sufficient to produce a decrease in barosensitivity independent of raised arterial pressure.
Key Words: hematocrit • heart rate • blood pressure • hypertrophy, left ventricular
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Introduction |
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Although most diagnosis and treatment of hypertension is focused on blood pressure level, the variability per se and ability to buffer changes in blood pressure may also be of considerable importance. This is demonstrated by the observation that diminished baroreflex sensitivity is an independent risk factor for sudden death following myocardial infarction.1 Thus, consideration of the mechanisms underlying the hypertension-induced changes in baroreflexes is of considerable clinical relevance. It is well established that reflex control of heart rate (HR) is diminished in most forms of hypertension.2 3 This deficit may be due to dysfunction in the afferent sensing of arterial pressure, altered central processing, and/or changes in efferent effector mechanisms.4 5 6 However, the difficulties associated with isolating one component of the integrated reflex has meant that the relative contribution of these factors is not well understood. Cardiac hypertrophy is proposed to be one of the major determinants of the reduced baroreflex sensitivity seen in hypertension,6 7 where thickening and loss of compliance of the cardiac wall, typical of this condition, make it less sensitive to physiological stimuli.8 This loss of sensitivity may have widespread consequences for the reflex control of many end-organ functions, in particular, fluid balance. In spontaneously hypertensive rats, cardiac hypertrophy develops between 6 and 20 weeks of age, which corresponds to the time when a deficit in the sensitivity of the cardiac baroreflex occurs.9 Further evidence suggests that decreased sensitivity does not depend on elevated arterial pressure per se since treatment of spontaneously hypertensive rats with angiotensin-converting enzyme inhibitors decreased arterial pressure to normotensive levels, but the impaired baroreflex sensitivity remained.10 Similarly, after removal of the hypertensive stimulus by unclipping of the renal artery in rats, there was evidence of a strong inverse correlation between the level of baroreflex sensitivity and degree of cardiac hypertrophy.11 These previous studies have based their conclusions on a correlation between diminished sensitivity and cardiac hypertrophy, which in itself does not prove a cause-and-effect relationship. Rather, it remains to be established whether the presence of cardiac hypertrophy alone is sufficient to cause decreased baroreflex sensitivity or whether it is a concurrent but unrelated response. Such a hypothesis has been difficult to assess previously because of the use of genetically hypertensive rats in which numerous other concurrent factors between different rat strains could account for the deficit observed. Furthermore, surgical or drug treatment of hypertension to lower blood pressure does not necessarily restore all other factors that may also influence cardiac baroreflexes, such as blood volume, hematocrit, or body weight.4 6
Chronic angiotensin II (Ang II) infusion produces a stable form of hypertension with the advantage that it allows sequential assessment of baroreflexes before and during the onset of hypertension with animals acting as their own controls. Furthermore, the Ang II infusion can be stopped without surgical intervention, leading to a return to normal arterial pressure but the maintenance of structural changes that occur as a result of the hypertensive period. Previous studies have established that angiotensin-based hypertension is associated with decreased barosensitivity.12 13 In part, this reduction is by a mechanism independent of the raised blood pressure, and a possible, although untested, mechanism is cardiac hypertrophy. In this study, we used a continuous infusion of Ang II in rabbits for 7 weeks to test the hypothesis that cardiac hypertrophy without concomitant hypertension causes reduced baroreflex sensitivity.
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Methods |
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Animal Preparation
Experiments were conducted in 13 rabbits weighing 2.55 to 2.95 kg and performed in accordance with the Statement on Animal Experimentation by the National Health and Medical Research Council of Australia and approved in advance by the Baker Medical Research Institute Animal Ethics Committee. Arterial pressure was recorded throughout the study via a telemetry implant (PA-C40, Data Sciences International). With rabbits under halothane anesthesia, the bifurcation of the iliac arteries was identified and a catheter inserted into the deep circumflex iliac artery, a small sub-branch of the iliac artery, so that the catheter tip lay in the aorta but well below the level of the left renal artery. The implant was sutured to the abdominal muscle layer to prevent movement. A minimum of 3 weeks of recovery was allowed before animals began the experimental study. Rabbits were divided into two groups. One group (n=6) served as time controls, undergoing identical procedures but receiving no Ang II. The other group (n=7) was made hypertensive via continuous infusion of Ang II (human, Auspep) into the external jugular vein. Ang II was infused at a concentration of 50 ng/kg per minute with osmotic minipumps (model 2ML4, Alza Corp) implanted with rabbits under halothane anesthesia. The pump was tunneled under the skin to lie on the back of the rabbit. Because this model of minipump has an infusion duration of 4 weeks, new pumps were inserted with rabbits under brief propofol anesthesia (10 mg/kg). Control animals received a sham pump, which was also changed after 4 weeks.
Experimental Protocol
Each animal was studied six times over the course of 9 weeks:
two control experiments, two experiments in the presence of Ang II (1
and 7 weeks), and two post–Ang II experiments (2 and 7 days after Ang
II, the osmotic minipumps were removed with rabbits under local
anesthetic after the experiment on week 7 of Ang II). On the day of the
last experiment, the animals were killed by overdose of anesthetic, and
the hearts and kidneys were excised. The left ventricle was trimmed of
excess tissue and fat and weighed for determination of left
ventricular weight–body weight ratio.
On each of the experimental days, two marginal ear veins were catheterized for drug administration. Telemetered arterial pressure was converted to an analog voltage signal with an analog pressure adapter (model R11CPA, Data Sciences International) and an atmospheric pressure compensation unit (Data Sciences model C11PR) to produce a calibrated continuous pulsatile arterial pressure signal. The arterial pressure waveform was sampled at 1000 Hz by a data-acquisition card (Lab PC+, National Instruments) using a purpose-written program in the LabVIEW graphical programming language (National Instruments). The pulsatile arterial pressure was converted to mean arterial pressure (MAP), and HR was calculated by triggering from the peak of the systolic pressure waveform. MAP and HR were saved to disk as 2-second averages for later off-line analysis.
The cardiac baroreflex was assessed on each of the six experimental sessions over the full range of physiologically relevant pressures using the ramp method.14 This was derived from slow ramp rises and falls in MAP by intravenous infusions of phenylephrine (0.5 mg/mL) and sodium nitroprusside (1.0 mg/mL), respectively. Injections lasted 1 to 2 minutes, and the rate of change in MAP was controlled between 1 and 2 mm Hg/s. These were administered in sufficient dose to cause a change in pressure of 30 to 40 mm Hg from resting, resulting in maximal bradycardia or tachycardia.
Data Analysis
Calculation of HR-MAP Baroreflex Curves
From 2-second average values of MAP and HR, the differences
between values during the ramp and control were calculated. These
points were then added to the average resting values, and a general
nonlinear regression program was used to fit the collected HR and
arterial pressure data to a sigmoidal logistic function to
produce baroreflex curves.
The transformed variables are fitted by the Marquardt-Levenberg
method15 to the following curve:
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Statistical Analysis
Values are expressed as mean±SEM. Statistical analysis
of both baroreflex curve changes and changes in resting MAP and HR were
performed with a two-factor repeated measure ANOVA with orthogonal
partitioning. The between-animal sums of squares (SS) as well as the
main treatment effects (before, during, and after the Ang II period)
were removed from the total SS so that the residual SS reflected the
variability or within-animal error. From the latter, the estimate of
the average within-animal SEM was calculated.16 The
significance of the main treatment effects was determined with a set of
orthogonal partitionings, with the two comparisons between the pre–
and post–Ang II periods combined versus the Ang II infusion period, as
well as the between the pre– and post– Ang II periods, being the
most relevant to the analysis. The main reason for including
the control replications in the analysis was to improve the
power of the analysis by providing a better estimate of the
residual "error" term. Contrasts were considered significant and
the null hypothesis was rejected at a value of P<.05.
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Results |
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Intravenous Ang II for 7 weeks produced a sustained significant increase in resting MAP, HR, hematocrit and fall in body weight (Table 1
). These changes were evident when
measured after only 1 week of Ang II and were not subsequently altered
when measured again after 7 weeks of Ang II. The osmotic minipump was
removed at this time. Arterial pressure was found to have
returned to levels not significantly different from that of the
pre–Ang II control periods when measured 48 hours and 1 week later.
Hematocrit and HR, however, remained significantly elevated after Ang
II was stopped at both 48 hours and 1 week later (Table 1). At
postmortem (1 week after the Ang II infusion was stopped), the hearts
and kidneys were removed and weighed. Left ventricular
weight–body weight ratios were significantly higher in the Ang II
infusion group (1.78±0.05 versus 1.35±0.04 g/kg, hypertensive versus
normotensive), indicating a significant level of cardiac
hypertrophy. The kidney weights, expressed as kidney
weight–body weight ratio, were also significantly higher in the
hypertensive group (4.16±0.39 versus 2.66±0.06 g/kg, hypertensive
versus normotensive).
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Effect of Ang II Infusion on Cardiac Baroreflex Curve
After 1 week of Ang II, the cardiac baroreflex curve was
shifted to the right along the MAP axis (Fig 1, top),
indicating the baroreflex had reset to operate about the new elevated
MAP. Ang II infusion resulted in a significant reduction in the upper
plateau at 1 week, from 325±7 to 309±5 beats per minute (bpm) and in
the sensitivity of the reflex (mean control, -6.4±1.5 to -3.5±0.2
bpm/mm Hg) (Table 2). Additional evidence for
diminished HR control was found from the increased arterial
pressure activation range (48±6 to 72±8 mm Hg), meaning that a
larger pressure change was now required to elicit the same reflex
change in HR. After 7 weeks of Ang II (Fig 1, bottom), the position of
the curve along the arterial pressure axis was unchanged
from week 1; however, there were clear improvements in the sensitivity
of the curve. This was predominantly due to an increase in the
curvature as compared with week 1 of Ang II treatment, leading to a
significant reduction in the arterial pressure activation
range (Fig 2). The HR range elicited by alterations in
arterial pressure was not affected by the hypertension,
although there was a statistically significant decrease in the upper
plateau at week 1 of the hypertension (Fig 3). Two days
after the Ang II infusion was stopped, the curve had completely
returned to the pre–Ang II control position along the pressure axis
(Fig 1, bottom), and all parameters, except for the upper
plateau, had returned to control levels (Fig 2). There was a small but
significant increase in the upper plateau of the baroreflex curve when
measured at both 2 and 7 days after Ang II (Fig 3). In rabbits that
acted as time controls, undergoing all experimental procedures except
for the Ang II infusion, all baroreflex curve parameters
were not significantly different across the six experimental periods
(Table 3), and the fitted curves, lying on top of one
another (Fig 4), indicated a high degree of
reproducibility.
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P<.05).
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Discussion |
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We have assessed cardiac baroreflexes in rabbits before, during, and immediately after a 7-week period of continuous Ang II–induced hypertension. Baroreflex sensitivity was initially diminished after 1 week of Ang II; however, after 7 weeks, although arterial pressure remained elevated, baroreflex parameters had begun to return to normal. When baroreflexes were measured at 48 hours and again at 7 days after the Ang II infusion was stopped, baroreflex parameters and arterial pressure had returned to pre–Ang II levels despite evidence of cardiac and renal hypertrophy, raised hematocrit, and increased HR.
Our study raises the important possibility that in the human, cardiac hypertrophy may not be a modulator of the baroreflex control of HR. Indeed, the definitive study involving serial measurements during the onset of hypertrophy of baroreflex control and left ventricular size has yet to be performed in humans. Although our group has seen such a relationship in rats,9 10 the hypothesis that hypertrophy is a factor responsible for decreased barosensitivity has not been tested in other species, including rabbits. Previous studies have generally relied on an association between the incidence of hypertrophy and altered HR control; for example, subjects who, through athletic training, have cardiac hypertrophy also have impaired baroreflexes.17 Similarly, Grassi et al18 found that treatment of hypertension to reduce ventricular hypertrophy led to improved baroreflex function in humans. However, such studies are still based on an association between two measured variables; in the study of Grassi et al, it would also be possible to make such an association to plasma norepinephrine, plasma renin activity, or central venous pressure, which were also significantly altered.
It has been considered that the impairment of baroreflex function develops during the onset of hypertension and remains attenuated as other secondary factors, such as structural changes, develop.4 6 However, we found that although the baroreflex sensitivity was initially impaired after 1 week of Ang II, after 7 weeks of Ang II, baroreflex sensitivity clearly improved. Since cardiac hypertrophy and renal hypertrophy were present when measured 2 weeks later, this suggests that baroreflexes were improving in this model of hypertension despite the development of structural changes. Several questions arise from these new observations: What is the reason for the improvement in baroreflex sensitivity after 7 weeks of Ang II? And why was the presence of cardiac hypertrophy not associated with decreased baroreflex sensitivity when the Ang II infusion was stopped and arterial pressure returned to normal?
Chronic Ang II infusion has previously been used to produce hypertension and causes a deficit in baroreflex sensitivity, which is in part due to a pressure-independent mechanism.12 13 Even though Ang II was administered for only 14 days, these studies suggested to us that cardiac hypertrophy or other vascular changes may influence the baroreflex sensitivity. Since increased angiotensin levels are an established part of many forms of experimental hypertension19 and are an important target of the current therapeutic treatment of human hypertension, we assessed the effect of a much longer period of angiotensin infusion on baroreflex sensitivity. The method we used to assess baroreflexes has been previously shown to involve inputs from both arterial and cardiopulmonary receptors,20 and it is changes in the ability to sense physiological stimuli in the latter receptor population that have been hypothesized to result from cardiac hypertrophy.18
The deficit seen in HR baroreflexes during many forms of hypertension is likely to be the product of a number of contributing factors, including altered central processing of afferent information,21 blood volume, and hematocrit3 6 as well as structural changes in both afferent and efferent aspects of the reflex arc.22 It is likely that in the early and later phases of hypertension, different factors dominate in the reduction in baroreflex sensitivity. However, an important difference between other studies and the present study is that although different forms of hypertensive stimuli such as renal clip and renal wrap are associated with diminished baroreflexes during the onset of hypertension, they generally continued to remain attenuated.23 24 25 However, we found that baroreflexes improved despite the maintenance of hypertension. It is possible that other factors occurred in those previous studies to maintain a deficit in baroreflexes and that these do not occur in an Ang II–induced model of hypertension. Alternatively, there may be factors that increase baroreceptor sensitivity during later phases of Ang II–dependent hypertension and counter other concurrent factors causing a decrease in sensitivity. Such factors may be a decrease in blood volume, which would lead to decreased cardiac output and has been previously shown to affect baroreflex gain.6 26 Although hematocrit was increased in our study, this does not necessarily mean that blood volume was altered, as the increased hematocrit is most likely due to Ang II stimulation of erythropoietin production.27 A further possibility is that angiotensin is interacting with other hormonal systems that have positive effects on baroreflex sensitivity. Ang II has been shown to increase atrial natriuretic factor in sheep,28 and our group has shown that this can lead to improvements in baroreflex sensitivity.29 However, although some of these factors may have been present at 48 hours after the Ang II was stopped, when pressure had only just returned to normal, it could be expected that these would return to normal within 7 days of normal arterial pressure, when the structural changes might be reasonably expected to be the remaining dominating factors. However, at this time there was no evidence of an attenuation of any baroreflex parameter.
In the present study, we have characterized the sigmoidal relationship between HR and blood pressure and found a significant reduction in the sensitivity of the baroreflex relationship during the initial phase of the hypertension. This was predominantly due to a reduction in the curvature and suggests an interaction with arterial baroreceptors and/or central processing of information.7 The effect on the vagus appears to be small, as only the upper plateau was significantly altered, with no overall change in the HR range.30 However, after 7 weeks of Ang II, all of these effects were considerably less despite the presumed ongoing development of cardiac hypertrophy; furthermore, there was actually a significant increase in the upper plateau after the Ang II infusion was stopped, suggesting an improvement in vagal tone at this time. It should be noted that our study focused on the sensitivity of the baroreflex curve during hypertension. It is also clear and well established that there is a resetting of the curve to the right along the pressure axis.31 However, it is not expected that cardiac hypertrophy would affect this resetting, as it is a well-described property of the baroreceptors themselves. Interestingly, we found that HR remained elevated even after cessation of Ang II. The reason for this is unclear; possible explanations include a persistent change in pacemaker circuits setting resting HR or an incomplete resetting of the resting HR on the baroreflex curve at this time point, despite resetting of all other baroreflex parameters. We were careful in the present study to control for many of the factors, such as genetic or between-animal variances, that may have affected baroreflexes that were unrelated to the effects of hypertension. Therefore, we designed our protocol so that each animal served as its own control, thus greatly increasing the power to detect a change in each variable. To this end, each rabbit was studied on six occasions before, during, and after the Ang II infusion; in particular, we waited 7 days before studying animals for the last time, when we proposed that many other nonstructural factors would have returned to normal.
We conclude that Ang II–based hypertension for 7 weeks in rabbits results in an initial impairment of baroreflex sensitivity but that this is not sustained. Furthermore, although cardiac hypertrophy develops in this species, its presence does not appear to be sufficient to result in a decrease in the baroreflex control of HR.
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Acknowledgments |
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This study was supported by a National Heart Foundation Project Grant and a grant from the Alfred Group of Hospitals. The advice of Dr Rod Dilley was most valued. Copies of the data-acquisition programs used in this study are available from S.C. Malpas.
Received September 17, 1996; first decision October 10, 1996; accepted November 26, 1996.
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References |
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