Mechanisms of Resetting of Arterial Baroreceptors: An Overview

Mechanisms of Resetting of Arterial Baroreceptors: An Overview BY MARK W. CHAPLEAU, PHD, FRANCOIS M. ABBOUD, MD

GEORGE HAJDUCZOK, PHD,

ABSTRACT: Arterial baroreceptors are reset when their afferent nerve activity is reduced at an equivalent arterial pressure and vascular strain. Resetting occurs as a result of stretch of the baroreceptors, usually during an acute or chronic rise in arterial pressure. It may be seen during the diastolic phase of a cardiac cycle (instantaneous resetting), after brief exposure to a sustained elevation of pressure (acute resetting), and after chronic elevation of pressure or in physiologic or pathologic states associated with structural changes in the vascular regions of baroreceptors (chronic resetting). The mechanisms reviewed here include mechanical, ionic and chemical factors. Viscoelastic properties of the carotid sinus and aortic arch may explain the instantaneous resettir.g that occurs with each cardiac cycle when activity begins in early systole and stops in early diastole. Viscoelastic properties and ionic mechanisms may playa role in acute resetting. Inhibition of Na+K+ ATPase reduces the magnitude of acute resetting. The release of chemicals from the endothelium may modulate baroreceptor activity. Exogenous prostacyclin suppresses and indomethacin augments acute resetting in the rabbit, suggesting that the release of endogenous prostacyclin during a rise in arterial pressure attenuates resetting. Changes in pulsatility and blood flow also may modulate baroreceptor activity. The addition of pulsatile pressure at an increased mean pressure attenuates resetting. Increases in flow From the Cardiovascular Center and the Departments of Internal Medicine and Physiology, University of Iowa College of Medicine, Iowa City, Iowa. While at University of Iowa, Drs. Cheryl M. Heesch and Hsing I. Chen performed the experiments investigating the ionic and mechanical mechanisms of resetting and the role of prostaglandins in resetting, respectively. The work was supported by National Institutes of Health Grant HL 14388 and Iowa Heart Grants 85-G-I and 87-G-9. The authors thank Laurie Fankhauser for expert technical assistance, Carolyn Wagner for preparing the figures, and Nancy Stamp for typing the manuscript. Reprint requests: Francois M. Abboud, MD, Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. THE AMERICAN JOURNAL OF MEDICAL SCIENCES

through the carotid sinus cause increases in baroreceptor activity at a constant sinus pressure and diameter, indicating that rheorecep:.. tors may be important regulators of the circulation. The relative roles of mechanical, ionic, and chemical mechanisms of resetting in normal and disease states provide a challenging area for future research. KEY INDEXING TERMS: Baroreceptor Resetting; Hypertension; Carotid Sinus; Aortic Arch; Na+K+ ATPase; Creep; Pulsatile Pressure; Endothelium; Rheoreceptors. [Am J Med Sci 1988; 295(4):327-334.]

A

rterial baroreceptors in the carotid sinus and aortic arch are stimulated by a rise in arterial pressure and trigger afferent nerve activity in the glossopharyngeal and aortic nerves that suppresses efferent sympathetic activity. The phenomenon of resetting of arterial baroreceptors involves a decrease in their sensitivity, which may result in neurocirculatory adjustments with significant physiologic and pathophysiologic implications. Baroreceptor resetting generally occurs as a result of stretch and activation of the baroreceptors by a rise in arterial pressure. There are two main difficulties in the study of baroreceptors. First, it is not possible to measure the strain or deformation of the nerve ending or the transducer. One can measure the stress or strain of the vascular wall in which the nerve endings are imbedded, but the mechanical characteristics of the coupling between the vascular wall structures and the neural elements responsible for transduction of the signal cannot be measured directly. Second, the relationship between the generator potential and activation of the spikeinitiating region leading to afferent nerve impulses may not be fixed or constant. The generator potential of baroreceptors is difficult to measure. Thus, the events that link the arterial pressure to the afferent nerve discharge are not characterized and represent a limitation in our attempt to understand the phenomenon of resetting. With this in mind, we present an overview of experimental work that provides some insight into various mechanisms involved in baroreceptor resetting.

327

Mechanisms of Baroreceptor Reselling

.--- .,,--,/Acute I Resetting Baroreceptor Discharge

I --+1 /

/

/

./

.".'

-'.

./ Chronic Resetting

1//

~. Plh

Plh

Arterial Pressure Figure 1. Brief exposure to elevated pressure caused an Increase In the threshold pressure needed for activation of baroreceptors and a rightward shift In the pressure-activity relationship. As a result, the steep pcirt of the curve was shifted to higher pressures, which would allow control of pressure at the higher level. With chronic resetting, maximal activity also may be decreased. Pth = pressure threshold.

Definition of Baroreceptor Reselling

Exposure to an increased level of arterial pressure causes an increase in the threshold pressure that is necessary for baroreceptor activation and a rightward shift in the pressure-activity relationship (Figure 1). There may also be a decrease in maximal baroreceptor activity. This response, termed resetting, enables the baroreceptors to regulate pressure at the new higher level; it also may contribute to the maintenance of the elevated pressure. The phenomenon may be viewed as one of decreased pressure-sensitivity of the baroreceptors. It also may be that the same pressure causes less strain or deformation of the vascular wall, and the reason for the decreased nerve activity may be the decreased strain. On the other hand, the same pressure may be associated with the same or greater strain or deformation of the wall and decreased nerve activity. This condition may be described as one of decreased strain sensitivity. How Rapidly Can Reselling Take Place?

Resetting is evident not only during chronic hypertensive states l - 7 but also after acute changes in pressure. The change in sensitivity of baroreceptors in diastole compared to systole during a single cardiac cycle may represent a form of resetting. Thus, three types of resetting may be considered. Instantaneous Reselling. During the cardiac cycle, the baroreceptors stop firing in diastole at levels of pressure and diameter greater than those that trigger activity in systole (Figure 2). Hysteresis is evident during diastole, when diameter and strain are greater than during systole at the same pressure, yet the nerve activity is suppressed or even absent in early diastole. 7-1o Acute Reselling. Acute resetting of baroreceptors has been demonstrated in studies from severallabora-

328

tories (Table 1). Resetting occurs within seconds to minutes after a change in pressure both in vivo and in isolated preparations for which neurohumoral factors are not present. The threshold pressure for discharge and the operating range of the receptors shift in the direction of the prevailing pressure during increases and decreases in pressure (Figures 1 and 3). Chronic Reselling. As the arteries (carotid sinus and aortic arch) mature and grow, increasing in diameter, the strain on the endings is presumed to increase, yet the afferent activity does not increase.7,ll Similarly, in chronic hypertension and arteriosclerotic vascular disease, activity decreases. This may be, in part, related to decreased compliance or increased stiffness of the vessels, resulting in lesser strain and decreased activity.1-7 Mechanisms of Reselling

Several mechanisms are proposed, including mechanical: changes in the mechanical properties of the vessel wall; ionic: mechanisms at the level of the receptor membrane, such as activation of Na+K+ ATPase; and chemical: substances released from the endothelium that modulate activity. Contribution of Altered Vessel Wall Mechanics.

Structural changes occur in the vessel wall with aging, chronic hypertension, arteriosclerosis and diabetes. In chronic hypertension, compliance of the wall decreases because of increases in collagen, leading to decreased strain and consequently decreased baroreceptor activity.1,7 In acute hypertension, the role of mechanical factors in resetting is more difficult to ascertain. When arterial pressure is increased acutely, arteries resist distension and may contract.12 When pressure is held constant, the diameter of the vessel increases despite a constant arterial pressure. 12 The slow increase in diameter at constant pressure is known as creep, which is similar to stress relaxation. This mechanical change in the vessel wall may be responsible for baroreceptor resetting. lO,13,14 It has been claimed that viscoelastic changes in the supporting tissues can essentially explain the adaptation or decreased activity of other slowly adapting mechanoreceptors during a sustained stimulus. 15 As the elements in the vessel wall that are in series with the baroreceptors lengthen, the tension on the receptors may decrease, ie, the receptors are unloaded, despite an increase in the overall diameter or strain of the vessel wall. It has been observed that resetting of aortic baroreceptors becomes complete, ie, the threshold pressure shifts by the same magnitude as the original shift in holding pressure, in about 48 hours. 16-20 This complete resetting coincides with the time it takes for the vessel to dilate maximally.18 The association suggests that mechanical changes may play an important role in the progressive resetting that occurs over several hours or April 1988 Volume 295 Number 4

Chapleau, HaJduczok, and Abboud

days. Similarly, during the diastolic phase of the pressure pulse, hysteresis may occur so that the vessel diameter is greater than during systole at equivalent pressure. IO The receptors may be unloaded during diastole, resulting in instantaneous resetting with each cardiac cycle. It is impossible to say with certainty that viscoelastic changes or creep cause the shift in the pressure-activity or strain-activity relationship, since we cannot determine the forces or strain acting directly on the receptors. Although viscoelastic changes in the vessel wall most likely contribute to baroreceptor resetting, other mechanisms also are involved. Two studies have reported that resetting can be dissociated from the mechanical changes of the vessel wall. 21 .22 Resetting was consistently observed in the isolated aortic arch of the rat in response to a sustained increase in arterial pressure, yet the diameter of the arch did not increase or creep consistently.21 In many experiments, the diameter at equivalent pressure obtained during a pressure ramp was actually less after the elevated pressure, presumably because of a stretch-induced myogenic response. In studies performed in our laboratory by Heesch et aF2 the threshold pressure of baroreceptors and the diameter of the isolated carotid sinus were increased after exposure to elevated pressure. Very importantly, after a brief exposure to a lower pressure, the threshold pressure decreased to control levels, whereas the diameter of the sinus remained increased. Thus, resetting was reversed at a time when creep of the carotid sinus was still evident (Figure 3). Studies of low pressure mechanoreceptors23 and other slowly adapting mechanoreceptors 24 have also dissociated acute resetting or adaptation

from mechanical changes. These results indicate that changes in vessel diameter or circumference are not directly or exclusively responsible for acute resetting of baroreceptors. Associated changes in viscoelastic behavior of the receptors or the coupling between receptor and vessel wall, which may not be detected by measurement of whole vessel wall mechanics, may contribute to resetting. The finding that resetting occurred during elevated pressure in the isolated aortic arch of the rat devoid of endothelium or smooth muscle 25 further suggests that a component of resetting may be a property of baroreceptors located in the adventitia. Contribution of Ionic Mechanisms. It has been suggested that the post-tetanic hyperpolarization of the slowly adapting stretch receptor of the crayfish that occurs after repetitive stimulation is caused by activation of the Na+K+ ATPase on the receptor membrane. Hyperpolarization was prevented when Na+K+ ATPase was inhibited by reducing K+ concentration, replacing Na+ with Li+, or by adding 2,4-dinitropheno1.26 Activation of Na+K+ ATPase also may contribute to baroreceptor resetting during exposure to elevated pressure. The movement of Na+ into the neuron during elevated pressure could activate the Na+K+ pump and lead to subsequent hyperpolarization immediately after the exposure to elevated pressure. In the hyperpolarized state, the receptor would require a greater pressure or strain to achieve threshold. Studies by Heesch et aF7 demonstrated that exposure of the isolated carotid sinus of the dog to ouabain prevented the increase in threshold pressure that occurred after a 15 minute exposure to elevated pressure in the absence of ouabain (Figure 4). In addition,

B

A (spikes/sec)

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125]

(mmHg)

75

\/

100

.

; I I

!, ENG

• Instantaneous 75

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50 25 0

DIASTOLE

,

i

,

i

i

50

70

90

110

130

Arterial Pressure Figure 2. Instantaneous resetting. Panel (A) Pulse synchronous discharge Is evident In the multiple unit activity (ENG) recorded from the carotid sinus nerve of the dog during stimulation with sinusoidal pressure waves. Impulses were Initiated at relatively low pressure during systole, but activity ceased during diastole at a much higher level of pressure. Thus, activity at an equivalent pressure was reduced dramatically during the diastolic phase of the pressure pulse. Panel (8) The Instantaneous firing frequency (1l1ntersplke Interval) of a single baroreceptor fiber Is plotted vs the arterial pressure measured during a single sinusoidal pressure pulse. The frequency of Impulses at equivalent pressure was much greater during systole than during diastole. Activity ceased during diastole at a pressure that caused maximum activity during systole. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

329

Mechanisms of Baroreceptor Resetting

TABLE 1 Published Studies of Acute Baroreceptor Resetting Authors/Year

Duration of Altered Pressure

Preparation

Species

Krieger. 1970 16 Salgado and Krieger. 197347 Saum et al. 197628 Salgado and Krieger. 197820 Coleridge et al. 1980 13 Brown. 1980 (revlew)7 Coleridge et al. 1981 14 Salgado and Krieger. 1981 19 Dorward et al. 198243 Munch et al. 198346 Coleridge et al. 1984 10

Rats Rats

In vivo aortic receptors. multiple fibers In vivo aortic receptors. multiple fibers

6 to 48 hours 1 to 6 hours

Rats Rats

Isolated aortic arch. single fibers In vivo aortic receptors. multiple fibers

1 to 20 seconds 1 to 48 hours

Dogs Rats Dogs Rats

In vivo aortic receptors. single fibers Isolated aortic arch. single fibers In vivo aortic receptors. single fibers In vivo aortic receptors. multiple fibers

20 min-utes 1 to 20 seconds 20 minutes 24 to 48 hours

Rabbits Rats Dogs

Undesser. et al. 198448 Andresen. 19846 Heesch et al. 198422 Heesch et al. 198427

Rabbits Rats Dogs Dogs Rats R,ats Rabbits Rats Rabbits

In vivo aortic receptors. single and multiple fibers Isolated aortic arch. single fibers In vivo aortic receptors. single fibers Isolated aortic arch. single fibers In vivo aortic receptors. multiple fibers Isolated aortic arch. single fibers Isolated carotid sinus. single and multiple fibers Isol<;lted carotid sinus. single fibers Isolated aortic arch. single fibers Isolated aortic arch. single fibers In vivo aortic receptors. single and multiple fibers In vivo aortic receptors. multiple fibers In vivo aortic receptors. single and multiple fibers

Rats

In vivo multiple fibers. aortic receptors

Dogs

Isolated carotid sinus. single fibers

30 to 135 minutes 5 to 60 minutes 15 seconds to 20 minutes 15 to 60 minutes 20 to 60 minutes 5 to 15 minutes 5 to 15 minutes 15 to 30 minutes 3 to 10 minutes 20 to 30 seconds 6 to 48 hours 20 seconds to 15 minutes 5 minutes to 48 hours 5 to 15 minutes

Munch and Brown. 19852 Kunze. 1985 (revlew)25 Burke. et al. 198645 Krieger. 1986 (revlew)17 Dorward and Korner. 1987 (revlew)44 Krieger •. 1987 (revlew)18 Chapleau et al. 1987 34

exposure of the sinus to a low K+ solution attenuated significantly the increase in threshold pressure observed after exposure to elevated pressure {Figure 5).27 These results support the hypothesis that activation of Na+K+ ATPase contributes to acute resetting of baroreceptors. Similar results were obtained in the isolated aortic arch of the rat during a brief exposure to elevated pressure. 7,28 Baroreceptor activity was suppressed markedly when the pressure was returned to a low value after exposure to elevated pressure (post-excitatory depression). After treatment with ouabain or a low K+ solution, the suppression of activity was less evident, ie, post-excitatory depression was attenuated. The observation that the adaptation or decreased activity early during the pressure step or in a single cardiac cycle was unaltered by treatment with ouabain or low K+ 7,28-30 suggests that the Na+ pump may not have contributed to the decreased activity at this

330

:

time. Perhaps the early or instantaneous resetting involves primarily a mechanical mechanism, whereas an ionic mechanism becomes more important after a somewhat longer, ie, seconds or minutes, exposure to elevated pressure. Contribution of Endothelial Factors. Increases in arterial pressure and vascular stretch, and in particular pulsatile stretch, not only activate baroreceptors but also stimulate the vessel wall, and in particular the endothelium, to release various stibstances.31 - 33 This led us to hypothesize that factors released from the endothelium during a sustained increase in arterial pressure may contribute to or modulate acute baroreceptor resetting. Puisatility. We have shown recently that in the isolated carotid sinus, pulsatile pressure can modulate the degree of resetting that occurs during exposure to elevated pressure. 34 We determined the threshold pressures of single fibers after exposure to three levels (76, 115, and 170 mm Hg) of elevated static or puis aApril 1988 Volume 295 Number 4

Chapleau, Hajduczok, and Abboud

Carotid Sinus Baroreceptor Discharge (ilsec)

Carotid Sinus Diameter (mm)

A

100

A Normal [K+l o

B

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3.1

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Figure 3. Increases In single unit baroreceptor discharge and carotid sinus diameter during Increases In carotid sinus pressure. The lines Indicate regression curves obtained from mean coefficients of third-order polynomials. (A) After exposure to a 90 mm Hg pressure step for 5 minutes, the pressure-activity curve was shifted to the right. The curve was shifted back after pressure was returned to 70 mm Hg for 10 minutes. The arrows Indicate statistically significant shifts In the curve. (8) The pressure-diameter curve, determined simultaneously with the baroreceptor activity curve, was shifted significantly to the left after exposure to the elevated pressure. The carotid sinus remained dilated 10 minutes after pressure was returned to 70 mm Hg. Thus, the baroreceptor resetting (A) was reversed when carotid sinus diameter remained elevated (creep) (8). (From Heesch et al 22 with permission of the authors and publisher.)

tile pressure. Exposure to elevated static pressure caused progressive increases in threshold pressure. Exposure to pulsatile pressure prevented resetting after exposure to a mean pressure of 76 mm Hg, attenuated resetting after exposure to 115 mm Hg and did not alter resetting after exposure to 170 mm Hg (Figures 6, 7). The suppression of resetting was not related to the intensity of baroreceptor activity during the period of pulsatile pressure (Figure 7), suggesting that decreased Na+K+ pump activity and postexcitaA

Before Ouabain (n=5)

B

After Ouabain (0.1·0.5Ilg /ml )

*

125 SEM

Threshold Pressure (mmHg)

180

Carotid Sinus Holding Prelluro (mmHg)

100

Figure 5. Effect of a low K+ solution on acute resetting. (A) The threshold pressure Increased significantly after a 5 minute exposure to a 90 mm Hg Increase In pressure (70 to 160 mm Hg). The resetting was reversed 10-15 minutes after pressure was returned to 70 mm Hg. (8) The Increase In threshold pressure after exposure to elevated pressure was significantly less when K+ was eliminated from the perfusate. (C) The degree of resetting returned to that seen In A when K+ was reintroduced. (From Heesch et al 27 with permission of the authors and publisher.)

tory ionic mechanisms probably were not responsible. Figure 8 shows how pulsatile pressure can influence the acute resetting that occurs during increases in mean arterial pressure. The resetting seen after elevated static pressure was not seen after elevated pulsatile pressure when the holding pressure was low. When the holding pressure was moderate, the resetting was less after pulsatile than after static pressure, and at high holding pressure, the magnitude of resetting was similar after static and pulsatile pressure.

STATIC PRESSURE

A Carotid

1~~~:fL

Nerve Actlvl1y (spikes)

PI~

12:[

50 L-.I_-'-_ 100 130

100

130

Carotid Sinus Holding Pressure (mmHgl

Figure 4. Effect of ouabain on acute resetting of single units. (A) After holding pressure was Increased by 30 mm Hg for 15 minutes, the threshold pressure Increased significantly. (8) In contrast, during ouabain the threshold pressure was unaltered after elevated pressure. (From Heesch et al 27 with permission of the authors and publisher.) THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

PI~

0" =3.08 mm

=97 mmHg

0 - 3.38 mm

~~!/l~?n-J \~!"""""""II!~ __

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P" =81 mmHg

Carotid

P"

=71 mmHg

,!~~i~~ :~l---==:C-" =....l'iiir ill/j -~~0~/ o.

75

=83 mmHg

10 sec

Figure 6. Nerve activity during a pressure ramp In a single carotid baroreceptor unit before and after two periods of elevated pressure, (A) one static and (8) one pulsatile. Acute elevation of static pressure to a level Insufficient to cause sustained activation of the unit caused an Increase In pressure threshold (Pth) from 83 to 97 mm Hg. The diameter at threshold (Dth) also was Increased by 10%. Conversely, acute elevation of pulsalile pressure to an equivalent level activated the unit, but the Pth dropped to 71 mm Hg and Dth was essentially back to the control level. Thus, pulsalile elevation In pressure not only prevented resetting but sharply decreased the Pth and wall tension at threshold In this experiment. (From Chapleau et al 34 with permission of the authors and publisher.)

331

Mechanisms of Baroreceptor Resetting

Pressu,e

AII.r Elent.d

-Slelle Pr ... ur. -Pullltlle P, ... ur.

0 D

200 (mmHgl

Inc' .... In Plh All., Holding Pr... u,.

Activity Ou,lng Holding Pr... u,.

ImmHgl 75

25

60

20

A

I.plk.,' •• cl

3D

15

45

B

B

3D

10

5

o

15

o

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Holding Pr ••• ure (mmHgl

Figure 7. The Influence of elevated static pressure and elevated pulsatile pressure on baroreceptor pressure threshold (Pth). (A) Increases In Pth. (8) Levels of activity during elevated pressure. The Increase In Pth measured after elevated static pressures was prevented by pulsatlllty at a mean pressure of 76 ± 4 mm Hg, attenuated by pulsatlllty at 115 ± 6 mm Hg, and not changed by pulsatlllty at 170 ± 6 mm Hg (A). Upward resetting occurred after elevated static pressure at 76 ± 4 mm Hg despite absence of nerve activity, but resetting did not occur after pulsatile pressure, despite the ~resence of activity. Asterisks denote a significant difference (p < 0.05) between the Increases In Pth and between the levels of activity during static vs pulsatile pressures. Error bars represent ± 5EM. (From Chapleau et al 30 with permission of the authors and publisher.)

We believe that the influence of pulsatility on the degree of resetting is a function of pulsatile strain. Since pulsatile strain is minimal at high holding pressure, pulsatility did not prevent resetting. 34 ,35 Role of Prostaglandins. In preliminary experiments the role of prostaglandins in acute resetting of carotid baroreceptors was examined in the rabbit. Chen et aP6 have observed that exposure of the sinus to exogenous prostacyclin, which is the major cyclo-oxygenase metabolite formed by the endothelium, sensitized baroreceptors, particularly after the receptors were exposed to an elevated pressure. As a result, the acute resetting that was evident after elevated pressure was prevented by the addition of prostacyclin. More importantly, treatment with indomethacin suppressed baroreceptor activity and enhanced acute resetting,37 suggesting that the endogenous production of a cyclo-oxygenase metabolite may attenuate the acute resetting during elevated pressure. Role of Other Endothelial Factors. In recent experiments in dogs, we found that the introduction of microcarrier beads coated with a culture of bovine aortic endothelium into a carotid sinus denuded of endothelium could suppress baroreceptor activity when the endothelial culture was activated with calcium ionophore. 38 Thus, both excitatory and inhibitory factors

332

Figure 8. Effect of pulsatile pressure on acute resetting. (A) Sustained Increases In arterial pressure from a low level of static pressure (C) to three levels of static (510 52, 53) or pulsatile (P Io P2, P3 ) pressure. (8) The respective arterial pressurebaroreceptor activity curves. Progressive ,Increases In static pressure caused progressive shifts to the right In the pressure-activity curve (resetting). The presence of pulsatile pressure at the elevated pressure prevented resetting after a slight Increase In mean pressure (left), attenuated resetting after a moderate Increase In mean pressure (middle), and did not change resetting after a large Increase In mean pressure (right).

may be released by the endothelium to modulate baroreceptor activity. Flow and Rheoreceptors. Another factor that may exert an important influence on arterial baroreceptors and act through an endothelium-dependent mechanism is a change in blood flow. We recently have observed that increases in the flow of a physiologic saline solution through the isolated carotid sinus of the dog increases baroreceptor activity recorded from multiple units (Figure 9) and decreases the

Carotid Sinus Pressure (mmHg) Mean Nerve Actlvlly ImpUlSeS) ( sec

]---v---------

f

'---------

3200~ ~---"

";::,:t~"']/JII////I /I~_ Flow (18 mllmln)

1~

Figure 9. Influence of flow of perfusate through the Isolated carotid sinus on baroreceptor activity. The Introduction of flow at constant pressure Increased the activity recorded from multiple units of the carotid sinus nerve. The shift to the flow condition caused transient changes In pressure, but the Increase In nerve activity perSisted once pressure was corrected. The Increased activity was similar In magnitude to that observed during a 50 mm Hg Increase In carotid sinus pressure. Carotid sinus diameter (sonomlcrometers) was unaltered by the Introduction of flow. April 1988 Volume 295 Number 4

Chapleau, HaJduczok, and Abboud

threshold pressure of single baroreceptor units. 39 The increased baroreceptor activity during flow occurred at distending pressures and diameters equivalent to those obtained in the absence of flow. We believe this finding indicates that changes in flow, independently of changes in pressure and diameter, activate rheoreceptors that may cause significant circulatory adjustments. Physiologic Significance. Resetting of arterial baroreceptors has important implications for the control of the circulation in both physiologic and pathologic states. Instantaneous resetting, ie, decreased activity in diastole compared to systole, may promote sustained inhibition of sympathetic nerve activity by enhancing the phasic pattern of baroreceptor activation. The excitability of central neurons is suppressed for about 150 milliseconds after an excitatory input. 4o Thus, the momentary lack of baroreceptor activity in diastole may allow time for central neurons to regain a maximum level of excitability. Indeed, the phasic pattern of afferent activity impinging on central neurons has been shown to cause a greater and more prolonged inhibition of sympathetic neurons than a steady level of afferent activity at equivalent spike frequency per unit time. 41 •42 The acute baroreceptor resetting that occurs after brief (seconds to minutes) exposure to elevated arterial pressure might at first appear to be disadvantageous. The parallel, rightward shift in the pressurebaroreceptor activity curve severely limits any sustained increase in baroreceptor activity in response to the increase in pressure. As a result, the rise in pressure is not buffered as well as if the receptors had not reset. The advantage of acute resetting is that the setpoint or the prevailing pressure level tends to remain on the steep part of the pressure-activity curve. This enables the baroreceptors to respond with a high degree of sensitivity to acute changes in arterial pressure around the new setpoint. 7,43,44 The resetting of baroreceptors that occurs during growth and development illustrates the significance of chronic resetting. Despite an increase in vessel strain and compliance during development, baroreceptor activity remains stable. 7 ,1l Thus, strain-sensitivity decreases during maturation. If this change in sensitivity did not occur, sympathetic activity and arterial pressure would be progressively inhibited during growth. References 1. McCubbin JW, Green JH, Page IH: Baroreceptor function in chronic renal hypertension. Cire Res 4:205-210, 1956. 2. Nosaka S, Wang SC: Carotid sinus baroceptor functions in the spontaneously hypertensive rat. Am J Physiol 222:1079-1084, 1972. 3. Angell-James JE: Characteristics of single aortic and right subclavian bar.neceptor fiber activity in rabbits with chronic renal hypertension. Cire Res 32:149-161, 1973. 4. Sapru HN, Wang SC: Modification of aortic baroceptor resetTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

ting in the spontaneously hypertensive rat. Am J Physiol 230:664-674, 1976. 5. Sleight P: Neurophysiology of the carotid sinus receptors in normal and hypertensive animals and man. Cardiology 61(Suppl 1):31-45, 1976. 6. Andresen MC: Short- and long-term determinants of baroreceptor function in aged normotensive and spontaneously hypertensive rats. Circ Res 54:750-759, 1984. 7. Brown AM: Receptors under pressure: an update on baroreceptors. Cire Res 46:1-10, 1980. 8. Bronk DW, Stella G: The response to steady pressures of single end organs in the isolated carotid sinus. Am J Physiolll0:708714,1935. 9. Chapleau MW, Abboud FM: Contrasting effects of static and pulsatile pressure on carotid baroreceptor activity in dogs. Circ Res 61:648-658, 1987. 10. Coleridge HM, Coleridge JCG, Poore ER, Roberts AM, Schultz HD: Aortic wall properties and baroreceptor behaviour at normal arterial pressure and in acute hypertensive resetting in dogs. J Physiol (Lond) 350:309-326, 1984. 11. Andresen MC, Krauhs JM, Brown AM: Relationship of aortic wall and baroreceptor properties during development in normotensive and spontaneously hypertensive rats. Cire Res 43:728-738, 1978. 12. Murphy RA: Mechanics of vascular smooth muscle, in Bohr DF, Somlyo AP, Sparks HV Jr (eds): Handbook of Physiology, Section 2, The Cardiovascular System, Vol II, Vascular Smooth Muscle. Bethesda, Maryland, American Physiological Society, 1980, pp 325-351. 13. Coleridge HM, Coleridge JCG, Kaufman MP, Dangel A, Baker DG: Aortic baroreceptors in the dog: in vivo sensitivity and short-term resetting, in Sleight P (ed): Arterial Baroreceptors and Hypertension. Oxford, Oxford University Press, 1980, pp 53-58. 14. Coleridge HM, Coleridge JCG, Kaufman MP, Dangel A: Operational sensitivity and acute resetting of aortic baroreceptors in dogs. Circ Res 48:676-684, 1981. 15. Matthews PBC: Muscle spindles and their motor control. Physiol Rev 44:219-288, 1964. 16. Krieger EM: Time course of baroreceptor resetting in acute hypertension. Am J Physiol 218:486-490, 1970. 17. Krieger EM: Neurogenic mechanisms in hypertension: resetting of the baroreceptors. State of the Art Lecture. Hypertension 8(Suppll):I7-114, 1986. 18. Krieger EM: Aortic diastolic caliber changes as a determinant for complete aortic baroreceptor resetting. Fed Proe 46:41-46, 1987. 19. Salgado HC, Krieger EM: Baroreceptor resetting during pressure recovery from hypotension. Hypertension 3(Suppl 11):11147-11150, 1981. 20. Salgado HC, Krieger EM: Time course of baroreceptor resetting in short-term hypotension in the rat. Am J Physiol 234:H552-H556, 1978. 21. Munch PA, Brown AM: Role of vessel wall in acute resetting of aortic baroreceptors. Am J Physiol 248:H843-H852, 1985. 22. Heesch CM, Thames MD, Abboud FM: Acute resetting of carotid sinus baroreceptors. I. Dissociation between discharge and wall changes. Am J PhysioI247:H824-H832, 1984. 23. Mifflin SW, Kunze KL: Rapid resetting of low pressure vagal receptors in the superior vena cava of the rat. Cire Res 51:241249,1982. 24. Husmark I, Ottoson D: The contribution of mechanical factors to the early adaptation of the spindle response. J Physiol (Lond) 212:577-592, 1971. 25. Kunze DL: Role of baroreceptor resetting in cardiovascular regulation: acute resetting. Fed Proe 44:2408-2411, 1985. 26. Nakajima S, Takahashi K: Post-tetanic hyperpolarization and electrogenic Na pump in stretch receptor neurone of crayfish. J Physiol (Lond) 187:105-127, 1966. 27. Heesch CM, Abboud FM, Thames MD: Acute resetting of ca-

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Mechanisms of Baroreceptor Resetting

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April' 1988 Volume 295 Number 4