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(Hypertension. 1995;26:420-424.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Infusion of Angiotensin II Resets Baroreflex Control of Heart Rate by an Arterial Pressure–Independent Mechanism
From the Department of Physiology, Oregon Health Sciences University, Portland.
Correspondence to Virginia L. Brooks, PhD, Department of Physiology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098.
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Abstract |
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Abstract The purpose of this study was to test the hypothesis that chronic infusion of angiotensin II (Ang II) in rabbits resets the cardiac baroreflex to a higher arterial pressure level by a pressure-independent mechanism. This hypothesis was tested by determining whether the resetting would be reversed soon after the Ang II infusion was stopped even if the hypertension was maintained by infusion of another vasoconstrictor. Relationships between arterial pressure and heart rate were determined by infusion of increasing doses of nitroprusside to decrease pressure and increase heart rate, followed by increasing doses of phenylephrine to increase pressure and decrease heart rate. After 9 to 10 days of Ang II infusion (20 ng · kg-1 · min-1) arterial pressure was increased from 62±2 to 94±3 mm Hg (P<.001), and heart rate was unchanged from control values of 126±7 beats per minute. The baroreflex relationship between arterial pressure and heart rate was shifted to a higher pressure level after 3 to 4 and 9 to 10 days of Ang II infusion. On these same days the Ang II infusion was replaced with phenylephrine (5.0±0.4 µg · kg-1 · min-1), and 30 minutes later arterial pressure decreased slightly (P<.05); however, despite the relative hypotension, heart rate was decreased (P<.005) from 126±5 to 98±7 beats per minute (days 3 to 4) and from 132±4 to 103±7 beats per minute (days 9 to 10). Moreover, the cardiac baroreflex relationships were shifted back to a lower pressure level (P<.05). Similar results were found when Ang II was replaced with methoxamine (1.7 µg · kg-1 · min-1). These data indicate that angiotensin-induced chronic baroreflex resetting is partially reversed soon after Ang II infusion is stopped, despite maintenance of the hypertensive state, and suggest that long-term increases in angiotensin reset the cardiac baroreflex in part by an arterial pressure–independent mechanism.
Key Words: hypertension, essential • rabbits • heart rate • blood pressure • sympathetic nervous system • nitroprusside • phenylephrine • methoxamine
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Introduction |
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It is well known that the baroreceptor reflex shifts or adapts to the elevated arterial pressure level in experimental or human essential hypertension (for reviews, see References 1 through 31 2 3 ). As a result of this so-called baroreflex resetting, the reflex actively maintains the abnormal hypertensive blood pressure level. It is generally accepted that the resetting is largely a direct result of the increased arterial pressure on baroreceptors. However, we have recently concluded that the baroreflex resetting that occurs with the hypertension caused by chronic angiotensin II (Ang II) infusion is in part pressure independent. The evidence for this conclusion was that the hypertensive resetting was sustained despite elimination of the hypertension by simultaneous infusion of the vasodilator nitroprusside along with Ang II.4 Thus, it appears that Ang II may have an action within the baroreflex loop to reset the reflex independently of the higher blood pressure level.
It has been shown that the baroreceptor resetting that occurs with chronic hypertension takes hours to be totally reversed.3 Therefore, it might be argued that the resetting remaining after elimination of the Ang II–induced hypertensive blood pressure level was due to the slow time course of the reversal of chronic resetting. This argument is unlikely because we also demonstrated that the chronic Ang II–induced resetting is completely normalized within 30 minutes after termination of the Ang II infusion. Nevertheless, to more directly examine this argument, we used another approach in the present experiments. The purpose of these experiments was to determine whether the cardiac baroreflex resetting would be reversed soon after Ang II infusion was stopped even if the hypertension was maintained by infusion of another vasoconstrictor.
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Methods |
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Experiments were performed with seven male New Zealand White rabbits weighing 2.9±0.1 kg (range, 2.6 to 3.0 kg). The rabbits were fed a fixed quantity (100 g/d) of a high-fiber rabbit chow (Ralston Purina) and were allowed free access to water.
Surgery
Anesthesia was induced with an intramuscular
injection of a mixture containing ketamine (5.9 mg/kg),
xylazine (5.8 mg/kg), and acepromazine (1.2 mg/kg) and was maintained
with intravenous injections of ketamine. Abdominal
aortic and vena caval catheters were implanted with the use of sterile
techniques and previously described procedures.5 Briefly,
after a midline incision two nonocclusive silicone elastomer–tipped
catheters were inserted into the vena cava and one into the aorta. One
vena caval catheter and the aortic catheter were tunneled
subcutaneously to the top of the head where they emerged through a
polytetrafluoroethylene headpiece that was fixed to the skull with
stainless steel screws and dental cement. The second venous catheter
emerged via a small incision at the back of the neck. The rabbits were
given an intramuscular injection of penicillin (60 000 U) the day
before and the day after surgery. Catheters were filled with heparin
(1000 U/mL) when not in use and were flushed with sterile isotonic
saline about three times per week. The rabbits were given a minimum
2-week recovery period before the first experiment during which they
were trained to remain quietly in an opaque Plexiglas box.
Chronic Ang II Infusions
After rabbits had recovered from surgery, control experiments
were performed. The rabbits were connected to a swivel-tether system
that allowed continuous infusions with an infusion pump
(Razel).4 For the first 3 to 4 days vehicle (5% dextrose
in water) was infused at about 30 mL/d IV. The Ang II infusion (20
ng · kg-1 · min-1) was then begun and
continued for 2 weeks. Ang II (Peninsula Laboratories) was prepared
fresh daily by dissolving a 100 µg/mL frozen stock in the vehicle.
Solutions were infused through a micropore filter (Gelman Sciences) to
maintain sterility.
Protocols
For experiments, rabbits were placed in a box and allowed to
rest for 30 to 45 minutes. Arterial pressure and heart rate
were measured via the aortic catheter with a Statham strain gauge, a
Grass tachometer, and a Grass polygraph. After control measurements
were made, the baroreflex relationship between arterial
pressure and heart rate was determined under the following
conditions.
Control
Before the Ang II infusion was begun, baroreflex curves were
generated with the use of the following procedure. First,
arterial pressure was lowered by infusion of increasing
doses of nitroprusside (3, 6, 12, 24, and 48
µg · kg-1 · min-1). After recovery
(15 to 30 minutes) arterial pressure was then raised by
infusion of increasing doses of phenylephrine (0.5, 1, 2,
4, and 8 µg · kg-1 · min-1). Each
drug dose was infused until pressure and heart rate stabilized,
approximately 2 to 5 minutes.
Ang II Infusion
We studied the baroreflex after 3 to 4 and 9 to 10 days
of Ang II infusion to document the change in the baroreflex with
chronic Ang II–induced hypertension using the procedure described
above for controls. For these experiments the Ang II infusion was
continued via the swivel-tether, and nitroprusside and
phenylephrine were infused via the second venous
catheter.
Ang II Replaced With Phenylephrine or
Methoxamine Infusion
The purpose of this experiment was to determine whether the
baroreflex resetting produced by chronic Ang II infusion is reversed
soon after termination of the infusion even if the hypertension is
maintained by infusion of another vasoconstrictor. In five rabbits,
after generation of baroreflex curves on days 3 to 4 and 9 to 10 of Ang
II infusion, Ang II was replaced with 5.0±0.4
µg · kg-1 · min-1 (range, 3.0 to
7.2 µg · kg-1 · min-1)
phenylephrine. Because of evidence that prolonged
phenylephrine infusion may produce exaggerated
sympathoinhibition, in three rabbits Ang II was replaced instead with
1.7±0.2 µg · kg-1 · min-1
methoxamine on day 10 of Ang II infusion. Thirty minutes after
infusion of either phenylephrine or methoxamine,
baroreflex curves were again generated. A different protocol was used
because the rabbits were less able to maintain arterial
pressure during nitroprusside infusion after the Ang II infusion was
stopped. In two rabbits receiving phenylephrine, pressure
was first lowered by decreasing the dose of
phenylephrine by one or two steps, followed by infusion of
lower doses of nitroprusside (range, 0.8 to 25.3
µg · kg-1 · min-1). In the
remaining rabbits given phenylephrine and all rabbits given
methoxamine, pressure was lowered by infusion of a lower range
of nitroprusside doses (1.6 to 39.6
µg · kg-1 · min-1). Pressure was
then increased by infusion of phenylephrine (dose range,
7.2 to 14.4 µg · kg-1 · min-1).
Data Analysis
Results are expressed as mean±SEM. The effect of chronic Ang II
infusion or termination of the infusion on control values of
arterial pressure and heart rate was determined with
one-way ANOVA for repeated measures or the paired t
test.6
Baroreflex relationships between arterial pressure and
heart rate were compared between groups by first fitting a sigmoid
curve to all collected data points in each experiment with the logistic
equation
HR=P4+P1/{1+exp[P2(MAP-P3)]},7
where HR is heart rate and MAP is mean arterial pressure.
The four logistic parameters determined for each curve were
P1, the heart rate range; P2, the
parameter used for calculation of maximal gain;
P3, the arterial pressure associated
with the heart rate value midway between the highest and lowest heart
rate, an index of set point; and P4, the lowest
heart rate. From these parameters, other indexes were
calculated, including maximal heart rate
(P1+P4) and maximal gain
(-P1xP2x
).7
Within-animal treatment effects (eg, effects of chronic Ang II or Ang
II replaced with phenylephrine) on these
parameters were determined with one-way ANOVA for repeated
measures and Duncan's multiple range test.6 The positive
values for maximal gain were first subjected to logarithmic
transformation to reduce variability. Differences with probability
values less than .05 were considered statistically significant.
The curves were represented graphically in most cases by plotting mean±SEM of pressure and heart rate for each dose of nitroprusside and phenylephrine and by drawing the best-fit logistic curve through these mean values. Because each rabbit received different doses of nitroprusside and phenylephrine for the determination of curves after Ang II was replaced with phenylephrine or methoxamine, mean pressure and heart rate values were calculated for graphic purposes from selected values approximately every 5 mm Hg, and the best-fit logistic curve was drawn through these mean values.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Chronic infusion of Ang II produced sustained increases in arterial pressure of approximately 30 mm Hg from control values of 62±2 mm Hg (Table 1). Heart rate averaged 126±7 beats per minute in vehicle-infused rabbits and was unchanged after approximately 3 and 9 days of Ang II infusion (Table 1).
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The Ang II–induced hypertension was associated with resetting of the heart rate–arterial pressure baroreflex curves to a higher arterial pressure level (Figs 1 through 3, Table 2). To determine whether the chronic resetting was due to an effect of Ang II independent of the hypertension, the Ang II infusion was replaced with phenylephrine. On days 3 to 4 of Ang II infusion, 30 minutes after the phenylephrine infusion was begun, arterial pressure dropped slightly from 97±3 to 90±4 mm Hg (P<.01); but despite the relative hypotension, heart rate also decreased from 126±5 to 98±7 beats per minute (P<.001). On days 9 to 10, pressure (95±2 to 86±1 mm Hg) and heart rate (132±4 to 103±7 beats per minute) again decreased (P<.005, Fig 4).
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These data suggest that termination of the Ang II infusion caused heart rate to fall relative to arterial pressure. This point was reemphasized in baroreflex curves generated after Ang II was replaced with phenylephrine (Figs 1 and 2, Table 2). After both 3 to 4 and 9 to 10 days of Ang II, stopping Ang II caused the baroreflex curves to shift to a lower pressure level, despite near maintenance of the hypertension. However, the curves remained displaced to the right of control curves (Figs 1 and 2, Table 2).
Similar results were produced when Ang II was replaced with methoxamine (Fig 3, Table 2). Thirty minutes after methoxamine was begun, arterial pressure was maintained at the Ang II–induced hypertensive level (89±1 to 90±1 mm Hg), but heart rate decreased (P<.05) from 132±6 to 114±6 beats per minute. Baroreflex curves again achieved a position in all rabbits intermediate between control and Ang II–infused curves.
As shown in Table 2, chronic infusion of Ang II reduced baroreflex gain. This effect was generally not reversed on termination of the Ang II infusion.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The important new finding of this study is that the resetting of the cardiac baroreflex observed in chronically Ang II–infused rabbits is partially reversed soon after termination of the Ang II infusion, despite maintenance of the hypertension by infusion of other vasoconstrictors. In agreement with a previous study,4 these results indicate that Ang II is capable of producing sustained baroreflex resetting by a mechanism other than by causing hypertension. The fact that the resetting was not completely normalized after Ang II was stopped suggests that another mechanism, possibly pressure-dependent resetting, is also involved in the shift of the curves to a higher pressure level.
Imaizumi et al8 reported that 1- to 3-minute infusions of phenylephrine produced slowly reversible sympathoinhibition caused by an action of phenylephrine in the central nervous system to enhance baroreflex gain. Thus, one potential explanation for the leftward shift in the cardiac baroreflex curve when Ang II was replaced with phenylephrine is that the shift was not due to the loss of Ang II but instead to a central action of phenylephrine to decrease sympathetic activity. There are several reasons why this explanation is unlikely. First, although other investigators have reported prolonged sympathoinhibition after infusion of vasoconstrictors, the inhibitory effect was due to the increased pressure causing activation of baroreceptor afferents, not to a central action of the drugs.1 9 10 Importantly, in the present study phenylephrine was used to maintain pressure, not increase it. Second, infusion of phenylephrine does not produce prolonged or exaggerated inhibition of heart rate.9 Indeed, infusion of a dose similar to that used in the present study tends to shift the cardiac baroreflex curve to a higher pressure level.4 Third, we found a similar leftward shift when Ang II was replaced with methoxamine, which does not appear to alter the set point of the renal sympathetic baroreflex.10
Another potential explanation for the leftward curve shifts after the chronic Ang II infusion was replaced with phenylephrine is that central venous pressure and stimulation of cardiac afferents was greater during phenylephrine infusion compared with Ang II infusion. However, this explanation is unlikely because in another study we found that central venous pressure decreases similarly when the Ang II infusion is replaced with phenylephrine or when the Ang II infusion is stopped and arterial pressure is allowed to fall (V.L.B. and D.C. Hatton, unpublished observations, 1993). Thus, we conclude that the reversal of resetting after replacement of Ang II with phenylephrine is not due to nonspecific effects of phenylephrine but is instead due to the loss of an effect of Ang II, which is independent of the increase in arterial pressure.
In the present experiments chronic infusion of Ang II was associated with a decrease in maximal baroreflex gain. This effect may be due to a continuation of the acute gain-reducing action of Ang II reported by some investigators4 11 12 or to the chronic increase in arterial pressure.1 2 3
Whether the ability of Ang II to increase heart rate relative to arterial pressure is due to withdrawal of parasympathetic activity to the heart or to increased cardiac sympathetic activity has been investigated in acute experiments. Evidence that favors a role for the parasympathetic nervous system includes reports that Ang II decreases cardiac vagal tone13 14 and that atropine markedly reduces the Ang II–induced baroreflex resetting and increase in heart rate.11 15 Interestingly, some residual Ang II–induced tachycardia has been observed after vagotomy13 16 or atropine treatment,11 suggesting possible involvement of another mechanism, perhaps sympathetic activation. Blockade of cardiac sympathetic nerves with the ß-adrenergic antagonist propranolol does not alter either the increase in heart rate or the baroreflex resetting, suggesting that an increase in sympathetic activity is not required.11 15 However, although the effect of intravenous Ang II administration has not been studied, it has been shown that intravertebral Ang II infusion either increases or has no effect on cardiac sympathetic activity, despite the pressor effect.17 Thus, the results of these acute studies suggest that the cardiac effect of Ang II may be mediated by both a decrease in vagal and an increase in sympathetic tone to the heart, but further experiments are required to determine whether this is also true with chronic Ang II infusions.
The present results suggest that Ang II produces sustained arterial pressure–independent baroreflex resetting of heart rate. Is reflex regulation of other effectors, such as sympathetic activity or plasma hormonal concentrations, also altered chronically by Ang II? The fact that sympathetic activity and plasma hormone levels are normal or elevated, despite the hypertension, in Ang II–infused animals is consistent with chronic baroreflex resetting (see Reference 44 for review). However, whether the resetting is mediated by the increased pressure or a pressure-independent action of Ang II has not been investigated. On the other hand, there have been studies of the role of Ang II in baroreflex resetting of sympathetic activity in renal hypertensive subjects. Kumagai and colleagues18 reported that acute administration of the Ang II antagonist saralasin shifts renal sympathetic nerve and heart rate baroreflex curves to a lower pressure level in conscious rabbits early in the development of hypertension when plasma Ang II concentration is elevated. No role for Ang II in the maintenance of renal sympathetic activity was found later in hypertension.19 Moreover, patients with renovascular hypertension exhibit increased levels of Ang II and muscle sympathetic activity, increases that are reversed 4 to 10 days after renal angioplasty.20 Importantly, Heesch21 has shown that the leftward shifts in baroreflex control of lumbar sympathetic activity after converting enzyme inhibition in anesthetized renal hypertensive rats are independent of effects of Ang II blockade to decrease arterial pressure. In spontaneously hypertensive rats Ang II blockade has also been found to shift baroreflex curves of renal sympathetic activity to the left.22
These reports suggest that Ang II can produce sustained pressure-independent resetting of sympathetic activity in models of hypertension. However, it is also possible that this resetting is important in other pathophysiological states (for review, see Reference 2323 ). There is evidence that sympathetic activity is increased in states of effective arterial volume depletion, such as sodium depletion or congestive heart failure.24 25 26 27 Although the baroreceptor reflex is often proposed to be the mediator for these changes,27 28 this proposal is untenable because of the adaptation of the baroreflex to chronic changes in pressure or volume. On the other hand, the release of renin and subsequent Ang II production do not show adaptation: sustained increases in Ang II are produced with chronic extracellular volume decreases.29 Moreover, the evidence that Ang II can produce persistent increases in heart rate relative to arterial pressure, that is, pressure-independent baroreflex resetting, is consistent with the hypothesis that changes in plasma Ang II may mediate these chronic changes in the sympathetic nervous system. Thus, we speculate that Ang II may play a critical role in the long-term regulation of arterial pressure via long-term alteration of the sympathetic nervous system.
In summary, chronic infusion of Ang II produces a shift in the cardiac baroreflex curve to a higher pressure level. Termination of the Ang II infusion causes heart rate to decrease within 5 minutes if arterial pressure is maintained near the hypertensive level by infusion of phenylephrine or methoxamine. Moreover, the reflex resetting is incompletely reversed, despite maintenance of the hypertension. These results indicate that chronic Ang II infusion produces cardiac baroreflex resetting that is, in part, independent of increases in arterial pressure. We speculate that this direct resetting action may be important in long-term arterial pressure homeostasis during conditions of chronic extracellular fluid excess or deficits.
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-35872 and a Grant-in-Aid from the American Heart Association. The author is grateful for the technical assistance of Rebecca Quesnell and Linda Horton.
Received January 13, 1995; first decision February 16, 1995; accepted May 16, 1995.
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References |
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