Mechanisms for activation of aortic baroreceptor C-®bres

in rabbits and rats

P . T H O R E N , 1 P . A . M U N C H 2 and A . M . B R O W N 3

1 Karolinska Institutet, Stockholm, Sweden

2 Cardiovascular Medicine, University of California, Davis, USA

3 Metro Health Medical Center, Cleveland, Ohio, USA

ABSTRACT

In an earlier study, we examined the pressure±response characteristics of rat aortic baroreceptors

with C-fibre (non-medullated) afferents. Compared with aortic baroreceptor fibres with A-fibre

(medullated) afferents, the C-fibres were activated at higher pressures and discharged more

irregularly when stimulated with a steady level of pressure. Here we examine the relationship

between discharge and the aortic diameter in these two types of afferents in rats and rabbits. An

in vitro aortic arch/aortic nerve preparation was used to record single-®bre activity simultaneously

with aortic arch pressure and diameter. Diameter was measured using a highly sensitive non-contact

photoelectric device. Baroreceptor discharge was characterized by stimulating the nerve endings

with either slow pressure ramps from subthreshold to 200±250 mmHg, at a rate of rise of

2 mmHg s)1, or pressure steps from subthreshold to suprathreshold levels, at amplitudes of

110±180 mmHg. In response to these inputs, C-®bres in rabbits (conduction velocities�0.8±2.2 m s)1) behaved much like those in rats. The C-®bres had signi®cantly higher pressure

thresholds (95 � 3 mmHg vs. 53 � 2 mmHg; mean � SEM), lower threshold frequencies (2.4 � 0.5

vs. 27.7 � 1.8 spikes s)1), lower maximum discharge frequencies (22.7 � 2.3 vs. 65 � 5.8

spikes s)1) and more irregular discharge in response to a pressure step when compared with A-®bres

(conduction velocities of 8±16 m s)1). When plotted against diameter, C-®bre ramp-evoked discharge

increased gradually at ®rst, and then rose steeply at increasingly higher ramp pressures where aortic

diameter became relatively constant. In contrast, A-®bre discharge was linearly related to diameter

over a wide range of pressure. These results suggest two interpretations: (1) The relation between

stretch and C-®bre discharge is highly non-linear, with a marked increase in sensitivity at large

diameters. (2) C-®bres are stimulated by changes in intramural stress rather than stretch.

Keywords A-®bres, arterial baroreceptors, C-®bres.

Received 24 April 1997, accepted 16 March 1999

In rats and rabbits there exist two populations of aortic

baroreceptors, those with C-®bre (non-medullated)

afferents and those with A-®bre (medullated) afferents.

These ®bres differ in several ways. Compared with

A-®bre afferents, the C-®bre affferents have higher

pressure thresholds, lower ®ring frequencies, and more

irregular discharge in response to step changes, in

pressure (Thoren et al. 1977, Thoren & Jones 1977,

Aars et al. 1978, Thoren 1981, Yao & Thoren 1983a,

Coleridge et al. 1987, Seagard et al. 1990, Seagard et al.

1992, van Brederode et al. 1990). In addition, data from

Seagard et al. (1993) also indicate that arterial

baroreceptor C-®bres are involved in tonic control of

arterial pressure.

These characteristic differences support the notion

that A-®bres are primarily important for barore¯ex

responses at normal and hypotensive pressures,

whereas C-®bres are important mainly at hypertensive

levels. The mechanism for C-®bre activation is of

interest because their response characteristics may in¯u-

ence barore¯ex control of pressure in various disease

states. For instance, in chronic hypertension, C-®bres in

both rats and rabbits are reset less than A-®bres (Jones

& Thoren 1977, Thoren et al. 1983). This suggests that

Correspondence: Prof. Peter Thoren, Department of Physiology and Pharmacology, Karolinska Institutet, S-17177 Stockholm, Sweden.

Acta Physiol Scand 1999, 166, 167±174

Ó 1999 Scandinavian Physiological Society 167

C-®bres may play an important role in cardiovascular

control when mean pressure is chronically elevated.

Relatively little is known about how C-®bre endings

are activated. Baroreceptors are generally thought to be

stretch receptors, but C-®bres tend to operate at high

pressures where the vessel wall is almost fully dis-

tended. Consequently, the relationship between C-®bre

activity and vascular dimension is unclear. This rela-

tionship is not readily apparent from aortic pressure±

diameter and baroreceptor pressure±frequency curves

because both these curves are non-linear. Furthermore,

studies showing continuous diameter±frequency plots

for single-unit C-®bres over their full range of opera-

tion are lacking. One technical limitation has been the

ability to accurately measure vascular dimension using

measuring devices that do not mechanically load the

vessel wall. In this study, the aim was to examine the

stimulus±response curves of baroreceptor C-®bres in

the aortic arch by recording single-®bre activity simul-

taneously with aortic pressure and diameter. This was

accomplished using an in vitro preparation in which

pressure was precisely controlled and diameter was

measured with a non-contact photoelectric device with

high resolution. Our data suggest that aortic C-®bres

may not primarily sense vascular stretch because their

pressure±response curves span pressures where there is

minimal change in aortic diameter. In fact, in some

cases, discharge increased without measurable changes

in diameter. Thus, the diameter±frequency relationship

for these ®bres was highly non-linear.

METHODS

In vitro nerve recordings

Successful recordings were obtained from eight Wistar±

Kyoto rats (WKY, 300±350 gm) and 14 New Zealand

white rabbits (2.2±3.5 kg). The rats were anaesthetized

with nembutal (60 mg kg)1 i.p.) and the rabbits with a

mixture of urethane (500 mg kg)1) and nembutal

(25 mg kg)1 i.v.). Following induction of anaesthesia,

the thorax was opened wide and the animals placed on

positive-pressure ventilation.

The surgical procedures for recording aortic baro-

receptors in vitro have been described previously in

detail (Thoren et al. 1977, Brown et al. 1978). In

essence, the left aortic nerve was dissected free from the

midcervical level to the aortic arch. The descending

aorta and innominate arteries were cannulated and all

remaining arterial branches ligated. The arch and

nerve were then transferred to a Plexiglas dish where

the arch was mounted in its approximate in situ con-

®guration. The preparation was covered with mineral

oil for nerve recordings and the arch was perfused

continuously with warm Krebs±Henseleit solution,

which was pumped through the lumen at a constant

pulseless pressure. The perfusate was equilibrated with

a gas mixture of 95% O2 and 5% CO2, and both the

perfusate and oil bath were maintained at 37 °C. The

mean perfusion pressure was adjusted using a modi-

®ed Starling out¯ow resistor. In the control situation,

the mean pressure was normally set to 75 mmHg in

rabbits and 100 mmHg in rats. A bellows driven by a

shaker (an electromagnetic device; Ling Dynamic

Systems, Stockholm, Sweden) was connected to the

perfusion circuit to produce pressure steps and slow

pressure ramps for constructing the aortic and baro-

receptor pressure± response curves.

Single-®bre recordings were obtained by cleaning

and splitting the aortic nerve with ®ne forceps and

needles until only one or a few active ®bres remained.

In multi®bre recordings, individual units were sorted

electronically based on differences in their spike

amplitude and waveforms. This was accomplished

using a dual time- and voltage-dependent window

discriminator (BAK Electronics, Davis, USA).

Conduction velocity in the same afferent ®bre was

measured by applying an electrical stimulus at the

baroreceptor area in the aortic arch using a bipolar

silver electrode connected to a stimulator.

Diameter measurement

The external diameter of the arch was measured just

proximal to the left subclavian artery. There is con-

siderable variability in the number and location of

arterial branches arising from the rabbit arch, but the

left subclavian artery is a consistent anatomical refer-

ence (Angell-James 1974). Diameter was measured

simultaneously with nerve activity using a photo-

electric device described earlier (Munch et al. 1985).

The basic scheme of the device involved using a

projection lens and a set of mirrors to display the

optical image of the arch (a shadow) onto a pair of

linear photodiode arrays. The contrast in light inten-

sity at the shadow's edge was used to track electron-

ically the outer surfaces of the vessel, whose locations

were then used to calculate the diameter. With

appropriate image magni®cation and diode scanning

rate, the diameter could be measured with high dy-

namic ®delity. This non-contact method avoided placing

a mechanical load on the vessel wall that might

obscure or modify its behaviour. A small problem

encountered in some experiments was that small

amounts of Krebs buffer leaked from the arch and

collected on the exterior surface. This could distort

the optical image, so these arches were frequently

inspected for leakage and great care was taken to

remove any excess buffer before each measurement.

Activation of baroreceptor C-®bres � P Thoren et al. Acta Physiol Scand 1999, 166, 167±174

168 Ó 1999 Scandinavian Physiological Society

Experimental protocol

At the beginning of each experiment the arches were

perfused at the control pressure for at least 1 h. When a

baroreceptor recording with a suf®cient signal-to-noise

ratio was obtained, the pressure±response relationship

was tested by gradually increasing pressure from a

subthreshold level up to 200±250 mmHg at a rate of

rise of 2 mmHg s)1. In many experiments, pressure

steps were also performed using amplitudes of

110±180 mmHg.

Data analysis

Baroreceptor activity and aortic pressure and diameter

were monitored on a Gould strip chart recorder and

stored on FM analogue tape. Nerve discharge was

quanti®ed either as the number of impulses per second

(discharge recorded with a time constant of 2±3 s, e.g.

Figs 2 and 6) or as the instantaneous spike frequency

(calculated by taking the reciprocal of the interspike

interval, e.g. Figs 1, 3 and 5). The data were digitized

on- or off-line and analysed. To examine the

baroreceptor's stimulus±response relationship, discharge

or instantaneous frequency was plotted against pressure

or diameter. Statistical comparisons between groups

were performed with Student's t-test for unpaired

observations.

RESULTS

Studies on rats

Recordings were obtained from seven baroreceptors

with irregular discharge and two baroreceptors with

regular discharge in a total of eight WKY. Earlier studies

indicate that the irregular units are C-®bres (Thoren

et al. 1977). Figure 1 shows the computer-generated

plots of a single irregular ®bre in response to a slow

pressure ramp from 80 to 250 mmHg. The ending had a

threshold of 120 mmHg and showed an irregular spike

frequency upon activation, which was typical of these

units. As the arch in¯ated, the diameter rose sharply

until pressure was about 140 mmHg. The change in

diameter then became increasingly smaller as a maxi-

mum value was approached. When instantaneous fre-

quency was plotted against the diameter, the interesting

®nding was that the major part of the baroreceptor

activity occurred with very small changes in diameter.

Figure 2 shows the relationship between the diam-

eter and discharge for the seven irregular and two

regular units. All irregular ®bres displayed a similar

pattern, with the major part of their discharge occurring

with only minor changes in the diameter. In contrast,

the discharge in both regular units was linearly related

to the diameter over a wide range of pressures.

Studies on rabbits

Two types of ®bres were found in the aortic nerve of

rabbits. With pressure held constant at a suprathreshold

level, one type discharged irregularly whereas the other

type discharged regularly. Overall, a total of 32 irregular

and 18 regular units were recorded from 15 rabbits.

Receptor characteristics

As this is the ®rst time irregular aortic baroreceptors in

rabbits were studied under in vitro conditions, the basal

characteristics of these units were examined as done

Figure 1 Relationship in one rat baroreceptor C-®bre afferent

between instantaneous frequency and pressure (a), diameter and

pressure (b), and instantaneous frequency and diameter (c) during a

slow pressure ramp (2 mmHg s)1). Note irregular activity typical of

C-®bre afferents.

Ó 1999 Scandinavian Physiological Society 169

Acta Physiol Scand 1999, 166, 167±174 P Thoren et al. � Activation of baroreceptor C-®bres

previously in normotensive rats (Thoren et al. 1977).

Figure 3 shows the typical discharge pattern of one

regular and one irregular unit in response to a pressure

step. The regular unit displayed an initial adaptation

over the ®rst 3±5 s, after which discharge changed

relatively little up to 1 min. The variability in interspike

interval was clearly very low. In contrast, the irregular

unit never reached a steady level of activity. Moreover,

its standard deviation of instantaneous frequency was

quite high. For a group of 12 irregular ®bres, which

were tested with pressure steps from subthreshold to

120±170 mmHg, the mean frequency during the last

5 s of a 60-s step was 12.6 � 1.5 Hz (mean � SEM)

with a standard deviation of 4.2 Hz, or 33% of the

mean frequency.

Pressure threshold

The threshold for activation during a slow pressure

ramp was measured for both irregular and regular ®bres

(Fig. 4). As reported for aortic baroreceptors in rats

(Thoren et al. 1977), the irregular units in rabbits gen-

erally had signi®cantly higher pressure thresholds

(95 � 3 mmHg vs. 53 � 2 mmHg; mean � SEM;

P < 0.01), lower threshold frequencies (2.4 � 0.5 vs.

27.7 � 1.8 spikes s)1; P < 0.01), lower maximum dis-

charge frequencies (22.7 � 2.3 vs. 65 � 5.8 spikes s)1;

P < 0.01) when compared with A-®bres. The data in

Fig. 4 are similar to data obtained earlier from rabbits

under in vivo conditions (Thoren & Jones 1977), which

suggests that the in vitro conditions did not greatly alter

the baroreceptor properties.

Conduction velocities

Conduction velocities were successfully measured in

16 irregular and 4 regular units. The values obtained

in irregular units ranged from 0.8 to 2.2 m s)1

(mean � SEM� 1.4 � 0.2 m s)1), whereas the values

in regular units ranged from 8 to 16 m s)1 (mean �

SEM� 12.4 � 0.2 m s)1). Thus, all irregular units in

rabbits seem to be C-®bre endings, as reported earlier

in rats.

Figure 3 Discharge frequency of one rabbit

aortic baroreceptor with regular discharge

(A-®bre) and one with irregular discharge

(C-®bre) in response to a pressure step lasting

45 s.

Figure 2 Relationship between diameter and discharge in two

baroreceptors with regular activity (A-®bre afferents) and seven

baroreceptors with irregular activity (C-®bre afferents) from a total of

eight WKY rats. Lines are best visual ®t of computer-generated plots

like those shown in Fig. 1. Baroreceptor discharge is presented as the

number of impulses s)1 (averaged over 3 s) vs. diameter.

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Activation of baroreceptor C-®bres � P Thoren et al. Acta Physiol Scand 1999, 166, 167±174

Discharge and aortic diameter

Nerve activity was recorded together with diameter and

pressure in only seven C-®bres and three A-®bres from

seven rabbits. Figure 5 shows a computer print-out of

the relationship between pressure and diameter, pres-

sure and frequency, and diameter and frequency for one

C-®bre unit. As in Fig. 1, the relation between diameter

and frequency was almost vertical, indicating that the

C-®bres became progressively more active with little if

any change in diameter.

The relationship between diameter and discharge

for all seven C-®bres and three A-®bres is shown in

Fig. 6. As in rats, the aortic C-®bres in rabbits

increased their discharge at high pressures despite

relatively small changes in diameter, whereas A-®bre

activity was almost linearly related to diameter over

most of the pressure range.

DISCUSSION

This study focused speci®cally on how baroreceptor

discharge related to changes in vessel diameter. As this

is the ®rst in vitro examination of aortic C-®bres in

rabbits, we also examined basal discharge characteristics

of these endings. Under in vitro conditions, the

characteristics of rabbit aortic C-®bres were similar to

their counterparts in rats (Thoren et al. 1977). Compared

with the A-®bre afferents, the C-®bre afferents had

considerably higher pressure thresholds and lower dis-

charge frequencies, as reported earlier in rats. Further-

more, the pressure thresholds in vitro were similar to

those found in vivo in rabbits and dogs (Thoren & Jones

1977, Yao & Thoren 1983a, Coleridge et al. 1987),

which indicated that the baroreceptors examined in vitro

in the present experiments behave normally. The rabbit

C-®bres also showed a larger degree of interspike

interval variability during pressure ramps, as well as

during adaptation to a pressure step. A-®bres adapted

within 3±5 s and then showed a relatively steady level

of discharge with low interspike interval variability.

C-®bres, on the other hand, never reached a steady

level of discharge during pressure steps of 1 min, and

Figure 4 Histogram showing distribution of pressure thresholds of

rabbit aortic baroreceptors with regular discharge (A-®bres, n� 18)

and irregular discharge (C-®bres, n� 32) in 15 rabbits.

Figure 5 Relationship in one rabbit

baroreceptor C-®bre afferent between

instantaneous frequency and pressure

(a), diameter and pressure (b), and

instantaneous frequency and diameter

(c) in one irregular ®ring unit during

a slow pressure (2 mmHg s)1).

Ó 1999 Scandinavian Physiological Society 171

Acta Physiol Scand 1999, 166, 167±174 P Thoren et al. � Activation of baroreceptor C-®bres

they showed marked variability in interspike interval. In

all these respects, the aortic C-®bres in rabbits were

similar to C-®bres in rats. The only notable difference

was that the pressure thresholds of the irregular units

were generally lower in rabbits compared with rats

(Thoren et al. 1977). This may re¯ect the lower mean

pressures in rabbits, which may condition the afferents

to operate over a lower range of pressure.

Mechanism of activation

An interesting question is what mechanical stimulus

activates aortic C-®bres. In both rabbits and rats,

C-®bres began discharging at relatively high ramp

pressures where progressive changes in wall diameter

were small. In fact, some endings with high pressure

thresholds (> 120 mmHg) increased activity with

almost no further change in diameter. In contrast, A-

®bres with considerably lower pressure thresholds

increased activity more or less linearly with diameter, as

reported previously (Aars 1971, 1972, Andresen 1984,

Munch & Brown 1985). One interpretation is that

aortic C-®bres are not stretch-receptors registering

changes in aortic diameter at normotensive pressures.

What, then, is the mechanism that activates these units?

The present results suggest the following. One,

baroreceptor activity is determined not by the gross

dimension of the vessel, but by the elastic properties of

the tissue coupled to the sensory endings. A-®bres may

be coupled primarily in parallel with elastin ®laments,

which are stretched at relatively low pressures and are

highly extensible. This may account for the relatively

low pressure thresholds of A-®bres and their steep

diameter±frequency curves. The linear relationship holds

even at high pressures because the endings are stretched

progressively less as elastin becomes taut. C-®bres,

on the other hand, may be coupled primarily in series

with collagen ®laments in the adventitia, which are not

stretched until relatively high pressures (Dobrin 1978).

This would account for their typically high pressure

thresholds. Once the slack is removed and the endings

are loaded, further increases, in pressure would produce

increases in stress, even though the diameter remained

constant. The relatively low elasticity of collagen would

transfer stress more directly to the nerve endings,

resulting in the upward in¯ection of the C-®bre diame-

ter±frequency curves. In this regard, it is interesting to

note the similarity between the C-®bre diameter±

frequency curves and the stress±strain relationship of

collagen (Bader 1963, Dobrin 1978, Armentano et al.

1991).

Thus, how A- and C-®bres are coupled to the vessel

wall may explain some differences in their respective

pressure±response properties. The baroreceptor A- and

C-®bre afferents also differ in their discharge pattern. It

is dif®cult to relate this to any mechanical stimulus, so it

seems that inherent differences must exist in the

membrane processes leading to spike initiation.

A second possibility is that C-®bres respond to

changes in wall stress, whereas A-®bres respond to wall

strain. (Strain is equated with the change in diameter

when the unstressed diameter is constant Dr/r0 and

stress is given by the pressure times the radius divided

by the wall thickness.) A-®bre activity was linearly

related to diameter (strain) and typically saturated at

pressures where the diameter became asymptotic. Thus,

A-®bre activity was consistent with wall strain in rab-

bits, as found previously in rats (Munch et al. 1987). In

contrast, C-®bre activity increased at pressures where

there was little change in diameter. The increase in

activity, however, was consistent with a rise in wall

stress. A change in stress but not diameter, might

produce the abrupt rise in the C-®bre diameter±

frequency plots.

Figure 6 Relationship between diameter and discharge in three

baroreceptors with regular activity (a) and seven baroreceptors with

irregular activity (b) in seven rabbits. Lines are curves ®t by eye to

computer-generated plots, as shown in Fig. 2. Note similarity between

these curves and those found in rats (Fig. 2), the only difference being

that the curves here are plotted at higher diameters because the arch

in rabbits is larger.

172 Ó 1999 Scandinavian Physiological Society

Activation of baroreceptor C-®bres � P Thoren et al. Acta Physiol Scand 1999, 166, 167±174

A third possibility is that C-®bre endings are located

primarily in the media, where they are activated by

compression when collagen in the adventitia becomes

maximally stretched and taut. This would correspond to

the ¯at part of the pressure±diameter relationship. This

possibility is suggested by identi®cation of baroreceptor

endings in the aortic media of several species (Aumonier

1972, Bock & Gorgas 1976). However, morphological

studies are not helpful because they cannot be related to

speci®c afferent recordings. Krauhs (1979) found that C-

®bre afferents in the rat aortic arch were intimately

associated with A-®bre afferents in the adventitia. How-

ever, only one ®bre of each type was examined, so it is

unknown whether the location of the C-®bre ending was

representative or exceptional. If C-®bres are activated by

compression, it may explain why they are less reset than

A-®bres in chronic hypertension (Jones & Thoren 1977,

Thoren et al. 1983). When the aorta becomes less dis-

tensible, endings in the adventitia are thought to reset

owing to the increased stiffness of the vessel wall.

However, endings in the media may be compressed at

higher pressures, so they would not reset as much. This

may contribute to why barore¯ex control of sympathetic

out¯ow (in contrast to heart rate) is reportedly

unimpaired in hypertension (Angell-James & George

1980, Ricksten & Thoren 1981, Guo et al. 1983).

Physiological role

Another interesting consideration is what role C-®bres

play in neural control of the circulation. As shown here

and in previous studies, C-®bres are generally quiescent

at normal and hypotensive pressures and thus are

probably not involved in correcting changes in mean

pressure at these levels. Additionally, they are not likely

to be of major importance in the re¯ex response to

rapid pressure transients, as their inherent variability in

discharge would not faithfully signal ¯uctuations in the

pulse pressure waveform. It seems more likely, given

their typically high pressure thresholds, that C-®bres are

probably involved primarily in re¯ex responses at

hypertensive pressures.

Although C-®bres exhibit slow irregular activity

compared with A-®bres, their cardiovascular effects may

be signi®cant. For instance, stimulating baroreceptor

afferent nerves using parameters that selectively activate

C-®bres results in depression of heart rate and peripheral

resistance (Kardon et al. 1975). Their importance also

seems implied by the relatively high number of C-®bres

compared with A-®bres in some baroreceptor afferent

nerves (Brown et al. 1976). In addition, recent data

(Seagard et al. 1993) indicate that blocking of aortic A-

®bres results in a signi®cant decrease in barore¯ex sen-

sitivity without a re¯ex change in baseline levels of

arterial pressure. In contrast, blocking of thinner ®bres

resulted also in a signi®cant elevation of arterial pressure,

indicating a loss of tonic control.

The characteristic differences between A- and

C-®bre diameter±frequency curves should suggest cau-

tion when evaluating the effects of various drugs on

baroreceptor afferents, particularly vasoactive agents.

C-®bres operate at relatively high pressures where

changes in smooth muscle tone have little effect on the

diameter (Munch et al. 1987). Logically, C-®bres should

be unresponsive to vasoactive agents because smooth

muscle tone has little effect on the diameter at these

pressures. A-®bres, on the other hand, may have signi-

®cant responses to the same agents because they operate

at normotensive pressures where changes in tone have a

substantially greater effect on diameter (Munch et al.

1987, Munch 1994). The lack of a mechanical response

may also unmask potential direct chemical effects on the

nerve endings, such that C-®bres appear more chemi-

cally sensitive to some drugs than A-®bres. Such a direct

chemical effect might explain earlier work by Landgren

(1952), Akre & Aars (1977) and Yao & Thoren (1983b)

showing a stimulating effect on baroreceptor C-®bre

activity of adrenergic stimulation.

In conclusion, we recorded the activity of single

aortic baroreceptor C-®bres in rabbits and rats together

with changes in aortic pressure and diameter. The

C-®bre activity showed no obvious relation to aortic

diameter. We suggest that C-®bres afferents might

sense stress rather than strain of the vessel wall, or that

they may be coupled primarily to collagen ®laments that

are slack at normotensive pressures. Alternatively,

C-®bres may be situated in the medial layers of the

aortic wall where they are activated by compression.

This work was performed at the Department of Physiology and

Biophysics, University of Texas Medical Branch, Galveston, Texas

77550, USA. The study was supported by grant 4764 from the

Swedish Medical Research Council and by grants HL-16657 and

HL-44675 from the US National Institute of Health.

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