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The Journal of Physiology logoLink to The Journal of Physiology
. 1998 Jun 15;509(Pt 3):895–907. doi: 10.1111/j.1469-7793.1998.895bm.x

Respiratory modulation of carotid and aortic body reflex left ventricular inotropic responses in the cat

M de Burgh Daly 1, James F X Jones 1
PMCID: PMC2230997  PMID: 9596808

Abstract

  1. The reflex changes in the inotropic state of the left ventricle, measured as the dP/dtmax (maximum rate of change of pressure), occurring in response to selective stimulation of the carotid and aortic body chemoreceptors by sodium cyanide, were studied in the cat anaesthetized with a mixture of chloralose and urethane.

  2. The animals were artificially ventilated with an open pneumothorax. The heart rate and mean arterial blood pressure were maintained constant.

  3. With on-going central respiratory activity, stimulation of the carotid bodies caused an increase in respiratory movements. Variable changes in left ventricular dP/dtmax occurred, the predominant response being an increase. The mean change was 8.3 ± 2.9 % from a control value of 6850 ± 450 mmHg s−1. Stimulation of the aortic bodies resulted in a smaller increase in respiration or no effect, but a significant increase occurred in left ventricular dP/dtmax of 19.6 ± 2.9 % from a control value of 6136 ± 228 mmHg s−1. No significant changes in left ventricular end-diastolic pressure occurred in response to stimulation of either group of chemoreceptors.

  4. Tests of chemoreceptor stimulations were repeated during temporary suppression of the secondary respiratory mechanisms: the central respiratory drive was suppressed reflexly by electrical stimulation of the central cut ends of both superior laryngeal nerves and lung stretch afferent activity was minimized by stopping artificial respiration. Carotid body stimulation again evoked variable responses, the predominant now being a reduction in left ventricular dP/dtmax of 3.1 % from a control value of 5720 ± 320 mmHg s−1, which was significantly different to that occurring during on-going spontaneous respiration. Aortic body stimulation caused an increase in left ventricular dP/dtmax similar to the response during on-going spontaneous respiration.

  5. The positive inotropic responses were mediated via the sympathetic nervous system, as indicated by their abolition as a result of intravenous injections of the β-adrenoceptor blocking agent, propranolol.

  6. It is concluded that the carotid bodies exert a small variable effect on left ventricular dP/dtmax, the predominant positive inotropic response being due to the concomitant neurogenic effects of the increase in respiration. In contrast, the positive inotropic response to excitation of the aortic chemoreceptors is not respiratory modulated.

Several studies have demonstrated that the cardiac chronotropic responses to selective stimulation of the carotid body chemoreceptors are respiratory modulated. The reflex bradycardia of vagal origin is greater when the excitatory stimuli are delivered in the expiratory phase of the respiratory cycle than when delivered in the inspiratory phase (Haymet & McCloskey, 1975; see also Spyer, 1990). This is accounted for by the excitability of the cardiac vagal preganglionic motoneurones near the nucleus ambiguus varying with the phase of respiration: they become refractory to incoming excitatory stimuli during the inspiratory phase of the respiratory cycle, the excitability of the neurones returning during expiration. Two neurogenic mechanisms are responsible for this refractoriness: first, activity of the central inspiratory neurones mediated by a cholinergic pathway, and second, increased activity of slowly adapting pulmonary stretch receptors driven by lung inflation (see Spyer, 1990; Richter & Spyer, 1990; Daly 1997). This means that the magnitude of the cardioinhibitory response elicited by stimulation of the carotid chemoreceptors is determined by the degree of refractoriness of the cardiac vagal motoneurones evoked by the secondary respiratory mechanisms. Stimulation of the carotid bodies in the cat also causes a vagally mediated negative dromotropic response, that is, an increase in atrio-ventricular conduction time (Downing, Remensnyder & Mitchell, 1962), which is similarly respiratory modulated: the conduction time was augmented when respiration was inhibited in the phase of expiration (Jones & Daly, 1997).

Reflex inotropic responses resulting from stimulation of the carotid chemoreceptors were investigated previously (Downing et al. 1962). These authors demonstrated in the vagotomized dog a decrease of ventricular contractility in about two-thirds of the tests, as indicated by a decrease in left ventricular stroke work at any given left ventricular end-diastolic pressure. No change was seen in the remaining tests. There must be doubt about whether this response represents a direct reflex from the carotid bodies because although heart rate was maintained constant by electrical pacing, there was an accompanying reflex increase in systemic vascular resistance. This increased resistance to ventricular injection per se is known to increase ventricular contractility (Anrep, 1912). Furthermore any rise in arterial blood pressure would, through an arterial baroreceptor reflex, exert the opposite effect on contractility (Hainsworth & Karim, 1972, 1973; Ward, Daly & Wood, 1995). De Geest, Levy & Zieske (1965) also reported that stimulation of the carotid bodies had a negative inotropic effect on the left ventricle but they attributed it to an increase in vagal activity. It is difficult to reconcile this finding of a reflex-mediated vagal negative inotropic response with those of others who found that electrical stimulation of the vagus had little or no direct inotropic effect (see review by Linden & Snow, 1973), a result in keeping with there being no known vagal efferent nerve supply to the mammalian ventricle (Nonidez, 1939). Other studies, too, have led to conflicting results concerning the reflex control of left ventricular function by the carotid bodies, probably as a result of inadequate localization of the stimulus to the carotid bodies (Salem, Penna & Aviado, 1964) or to inadequate control of heart rate and/or arterial blood pressure (Kahler, Goldblatt & Braunwald, 1962; Stern & Rapaport, 1967; Pace, 1970). Hainsworth, Karim & Sofola (1979), re-examining this problem in the dog using preparations with controlled heart rate and aortic pressure, also found that stimulation of the carotid bodies resulted in a reflex negative inotropic response, but that it was mediated via cardiac sympathetic efferent fibres. Subsequently, in a study of the reflexes from stimulation of the aortic bodies, the opposite effect was observed, that is, a positive inotropic response, and this, too, was dependent on the integrity of the sympathetic supply to the heart (Karim, Hainsworth, Sofola & Wood, 1980). These contrasting responses to stimulation of the two groups of chemoreceptors occurred in the same animals, but there is still doubt about the explanation for these differing effects.

One aspect of the reflex control of left ventricular function by the peripheral arterial chemoreceptors, which has hitherto received no attention, is the possibility that mechanisms secondary to the concomitant stimulation of respiration might play a role in determining the direction and magnitude of the inotropic responses. In this connection studies already cited above have shown that reflex vagally mediated cardiac chronotropic and dromotropic responses are respiratory modulated. Other studies concerned with the reflex sympathetic cardiac chronotropic and peripheral vascular responses evoked by stimulation of carotid chemoreceptors and baroreceptors are similarly affected by changes in pulmonary ventilation (Daly & Ungar, 1966; Seller, Langhorst, Richter & Koepchen, 1968; Richter, Keck & Seller, 1970; Davis, McCloskey & Potter, 1977).

The present study was undertaken to re-examine the left ventricular inotropic reflex responses to separate stimulations of the carotid and aortic bodies in the cat with the main aim of finding out whether they undergo respiratory modulation. Some of our findings have been reported briefly elsewhere (Daly & Jones, 1997).

METHODS

Cats of either sex were used, their weights being recorded in Table 1. They were anaesthetized with a mixture of 2 %α-chloralose (52 mg kg−1; Sigma) and 20 % urethane (520 mg kg−1; British Drug Houses Ltd) dissolved in 85 parts sodium chloride (120 mM) and 15 parts polyethylene glycol (molecular weight, 200; Carbowax; Union Carbide Ltd, Rickmansworth, UK). The initial dose was injected intraperitoneally, 2.6 ml kg−1 of the mixture, and supplementary doses of 0.2 ml kg−1 were administered intravenously when necessary. All injections were made at 37°C. At the end of the experiments, the animals were killed by switching off the respiration pump combined with exsanguination.

Table 1.

Initial control values (means ± S.D.) at the start of the experimental period, and before blood pressure compensation or cardiac pacing, for blood gas, respiratory and cardiovascular variables

No. of animals 19
Body weight (kg) 2.71 ± 0.27
Tracheal pressure(mmHg)
   Lung inflation 6.8 ± 1.8
   Lung deflation 1.6 ± 0.74
Heart rate (beats min−1) 168.6 ± 41.2
Pulse interval (ms) 381.4 ± 116
Left ventricular
   systolic pressure (mmHg) 124.9 ± 14.7
   end-diastolic pressure (mmHg) 4.1 ± 3.1
   dP/dtmax (mmHg s−1) 5316 ± 1134
Arterial blood pressure (mmHg)
   Systolic 123.8 ± 17.9
   Diastolic 69.3 ± 16.2
   Mean 86.9 ± 16.0
Hindlimb mean perfusion pressure (mmHg) 110.4 ± 18.2
Arterial blood
   PO2 (mmHg) >100
   PCO2 (mmHg) 38.8 ± 9.1
   pH 7.413 ± 0.085
   Haematocrit (%) 35.6 ± 7.1
Rectal temperature (°C) 37.8 ± 0.59
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Rectal temperature was monitored throughout each experiment and maintained between 37 and 39°C. The bladder was continuously drained of urine via a catheter inserted suprapubically or sometimes per urethram to exclude reflexes from this organ.

In the course of some experiments the carotid sinus and/or the aortic nerves were cut bilaterally. The carotid sinus nerve was identified at its junction with the glossopharyngeal nerve, the aortic nerve at the junction between the superior laryngeal nerve and cervical vagus nerve.

The essential features of the experimental preparation are shown in Fig. 1.

Figure 1. Diagrammatic representation of the method used for stimulating the carotid and aortic bodies.

Figure 1

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Positive pressure ventilation (PPV) was applied, the chest being opened via a median sternotomy. Central respiratory movements were measured qualitatively as thoraco-abdominal movements by a pneumatic method. The heart was paced electrically, and a catheter-tip manometer was inserted into the left ventricle via the left atrial appendage for the measurements of left ventricular systolic and end-diastolic pressures and dP/dtmax. Arterial blood pressure (BP) was measured from the right brachial artery (ba) and was maintained constant by a compensator, the pressure in which was controlled by an air-leak bypass system. The blood pressure compensator was connected to cannulae inserted into the rostral ends of the two femoral arteries. The right hindlimb was vascularly isolated and perfused with blood at constant flow from the blood pressure compensator. The aortic chemoreceptors were stimulated by left atrial injections of sodium cyanide, the arrival of the agent at the carotid bodies being delayed by about 22 s by the insertion of a length of tubing (carotid artery loop) in the common carotid arteries. The carotid bodies were stimulated by cyanide injected into the distal end of the tubing (CCA inj.). Both superior laryngeal nerves were dissected and cut for electrical stimulation of their central ends (SLN stim.). All external sources of blood were water-jacketed (W-J), the water being circulated at a temperature of 37 °C. Measurements were made of: Pa and P¯a, phasic and mean arterial blood pressure; PI, pulse interval; Ptr, tracheal pressure; Plv, left ventricular systolic pressure; LVEDP, left ventricular end-diastolic pressure; LV (left ventricular) dP/dtmax; and Plimb, hindlimb mean perfusion pressure. For details, see text.

Respiration

The chest was opened in the midsternal line, positive pressure ventilation being applied by a Starling ‘Ideal’ pump (C. F. Palmer Ltd) at a rate of 20 cycles min−1. The tidal volume was adjusted to maintain the arterial PCO2 at 35-42 mmHg. An end-expiratory pressure of 1-3 cmH2O prevented collapse of the lungs. In all experiments, oxygen-enriched air was administered (inspired O2 fraction approximately 0.4). Respiratory movements were measured qualitatively by recording the pressure changes in an air-filled balloon system placed over the thoraco-abdominal region. These recorded movements were central in origin and not mechanical due to phasic changes in lung volume as indicated by their abolition during an induced state of hypocapnia.

Some tests of stimulation of the carotid and aortic bodies were carried out during cessation of all respiratory movements. The central cut ends of both superior laryngeal nerves were stimulated electrically by pulses of 0.3-2.8 V, 2 ms pulse duration at a frequency of 30 Hz (Grass S88 stimulator through a stimulus-isolation unit (S88); Grass Medical Instruments), combined with temporary cessation of artificial respiration, the lungs being held at their end-expiratory level.

Arterial blood pressure

Blood pressure was measured from a brachial artery and was maintained constant by connecting a pressurized reservoir of blood to the animal's systemic circulation via cannulae in the two femoral arteries pointing rostrally. The perfusion pump (Fig. 1) drew blood from the reservoir which ensured that continuous mixing of blood took place between the reservoir and the animal. Fine adjustments to the reservoir pressure were made by means of an air-leak bypass system. The reservoir was enclosed in a water-jacket maintained at 37°C. The blood used to prime the extracorporeal system was obtained from a donor animal taken up to 7 days previously, stored at a temperature of 2-4°C until used, and treated as follows: to each 100 ml of arterialized blood, heparin (1000 i.u.; Monoparin, C.P. Pharmaceuticals Ltd) and penicillin (250 000 i.u.; Crystapen; benzylpenicillin sodium, BP) were added initially, the doses being repeated every 2 days. Immediately before use, the blood was warmed to 37°C, and filtered through two layers of gauze (organdie, organza, 120 μm mesh). In a few experiments the compensator was filled with the animal's own blood, the equivalent volume of Gelafusine (B. Braun Medical Ltd, Switzerland) being administered intravenously.

Cardiac pacing

Heart rate was maintained constant by electrical pacing through platinum wire electrodes applied to the left atrial appendage, the stimulus parameters being 9-11 V, 2 ms pulse duration at a frequency slightly higher than that of the natural heart frequency during control and the test periods (Grass S88 stimulator).

Measurement of maximum rate of change in left ventricular pressure (dP/dtmax)

A catheter-tip manometer (implantable pressure transducer, type 12 er/4F; Gaeltec Ltd, Dunvegan, Isle of Skye, Scotland) was inserted into the left ventricle via an introducer tied into the left atrial appendage for the measurement of left ventricular pressure and, separately, left ventricular end-diastolic pressure. The output of the amplifier was differentiated electrically to record left ventricular dP/dtmax. The manometer was calibrated statically against a mercury manometer. Its frequency response was determined from the results of applying a square-wave transient as described by Fry (1960) and was found to be flat ( ± 5 %) to 400 Hz. A switched precision calibrator built into the amplifier- differentiator circuit enabled steady ramp functions to be applied to the differentiator to give calibration signals of 2000, 5000 and 10 000 mmHg s−1. The frequency response of the differentiator was assessed by applying a sine-wave input voltage from a signal generator and gave a linear response ( ± 5 %) up to 130 Hz.

Perfusion of the right hindlimb

The vascularly isolated right hindlimb was perfused through the femoral artery at constant flow with blood from the blood pressure compensator by means of an occlusive roller pump (type MHRE 200, Watson-Marlow Ltd, Falmouth, Cornwall, UK), as described previously (Daly & Kirkman, 1988). Changes in hindlimb vascular resistance were indicated by changes in mean femoral arterial perfusion pressure. Alterations in femoral venous pressure were minimal compared with those in arterial perfusion pressure, and were not, therefore, taken into account.

Measurements of variables

All variables were recorded on a multichannel high resolution thermal print-head recorder (model PAR2000B, TDM Tape Services Ltd, Nottingham, UK) and included: intratracheal pressure, central respiratory movements, hindlimb perfusion pressure, and arterial blood pressures (phasic and integrated mean) using strain gauge manometers (Model P23Gb, Statham Instruments), and pulse interval triggered from the ascending phase of the anacrotic wave of the arterial blood pressure. The frequency response of the catheter-manometer system used for the measurement of arterial pressure was determined as described by Fry (1960), and was flat ( ± 5 %) up to 12 Hz. Zero reference pressures were obtained post mortem with the catheter tips exposed to air in situ.

Stimulation of arterial chemoreceptors

The aortic bodies were stimulated by sodium cyanide (0.1 % w/v) injected into the left atrium via a catheter tied into the left atrial appendage. Effects on the carotid bodies were excluded by delaying the arrival of the agent at the carotid bifurcation regions by about 22 s by inserting into the common carotid arteries a length of tubing which was water-jacketed at 37°C (Fig. 1). The pressure gradient between the aorta and carotid bifurcation regions was 2-3 mmHg. Alternatively, the carotid sinus nerves were cut to exclude carotid chemoreceptor reflexes. For stimulation of both carotid bodies simultaneously, sodium cyanide (0.01 % w/v) was injected into the distal ends of the tubing. The injection volumes were always less than 0.15 ml, the injection period being about 0.3 s. No attempt was made to carry out the injections at a particular phase of the respiratory cycle because the sites of the injections were not close enough to the receptor sites to predict the arrival time of the stimuli.

Blood gas analysis

At intervals during each experiment, the arterial blood PO2, PCO2, pH and haematocrit were determined. Metabolic acidosis was corrected with an intravenous infusion of 1 M sodium bicarbonate solution.

Drugs

The following drugs were used: sodium cyanide (British Drug Houses Ltd), atropine sulphate (BDH Chemicals Ltd), propranolol hydrochloride (Inderal; Imperial Chemical Industries Ltd) and isoprenaline sulphate (Martindale Pharmaceuticals, Romford, UK).

After completion of the surgical procedures and before connecting the extracorporeal circuits, heparin (Monoparin; C.P. Pharmaceuticals, Ltd, 1000 i.u. kg−1i.v.) was administered to render the blood incoagulable.

Analysis of results

All values are expressed as means ± s.e.m. unless otherwise stated. Student's t test or repeated measures ANOVA with Tukey-Kramer multiple comparisons test, as appropriate, was used to evaluate the significance of the difference between sets of paired observations. Values were taken as being significantly different if P < 0.05. The data for the carotid chemoreceptors were analysed separately from the data for the aortic chemoreceptors. The reflexes from the two groups of chemoreceptors were not compared as this would be inappropriate given the different doses of cyanide required for their elicitation.

Experimental procedure

In all tests made to evaluate left ventricular inotropic responses, heart rate and mean systemic arterial pressure were maintained constant. To evaluate any possible respiratory modulation of the responses to stimulation of the carotid and aortic bodies, a series of tests was carried out in three stages: first, in the presence of on-going spontaneous respiratory activity and positive-pressure artificial respiration. The magnitude of the respiratory movements of the thorax and abdomen was adjusted initially by eye to a level similar to that occurring in the closed-chest spontaneously breathing animal. This was achieved by setting the arterial PCO2 at an appropriate value by altering the stroke of the respiratory pump. The measured cardiovascular responses to stimulation of the carotid or aortic bodies was obtained as the difference between the peak value during stimulation and the control. In the second stage, the responses to temporary suppression of the secondary respiratory mechanisms alone were evaluated. Inhibition of the central inspiratory drive was produced by electrical stimulation of both superior laryngeal nerves. This central apnoea was combined with cessation of artificial respiration, the lungs being held in their end-expiratory position (positive end-expiratory pressure of 1-3 cmH2O) to minimize and hold constant the activity of slowly adapting pulmonary stretch receptors. This condition was maintained for about 20 s. In the third stage, stimulation of the carotid or aortic bodies was carried out during the period of suppression of the secondary respiratory mechanisms (second stage), the test injections of cyanide being made 5 s into the period. The cardiovascular responses to excitation of the carotid or aortic bodies were then calculated as the difference between the peak values obtained on the injections of cyanide during cessation of respiration with the control value taken as that occurring during cessation of respiration alone (second stage) using time-matched points.

RESULTS

The weights of the animals and the initial control values for the respiratory and cardiovascular variables and arterial blood gases are shown in Table 1. In all experiments, the arterial O2 pressure (PO2) was greater than 100 mmHg.

In all tests of stimulation of the carotid and aortic bodies described below, the heart was electrically paced at constant frequency, and the mean arterial pressure was held constant.

Stimulation of carotid bodies

During on-going spontaneous respiratory movements

Stimulations with sodium cyanide, 4.0 ± 0.23 μg kg−1, injected into the distal end of the carotid bypass tubing invariably caused an increase in respiratory movements, but overall there was no change in left ventricular dP/dtmax (control value of 6850 ± 450 mmHg s−1; experimental value, 7370 ± 490 mmHg s−1; P > 0.05). An increase was the predominant response occurring in nine animals, with a reduction in two and no change in the remaining two. The hindlimb perfusion pressure was raised by 33.1 ± 4.9 mmHg from the control value of 117.9 ± 4.8 mmHg. This represents an increase in vascular resistance of 28.1 % (P < 0.001; n = 13). On average the left ventricular end-diastolic pressure did not change (P > 0.95). An example of one test is shown in Fig. 2 (first three panels), and the results are summarized in Fig. 3.

Figure 2. The effects of stimulation of the carotid bodies (panels CB) by sodium cyanide, 3.1 μg kg−1, injected into the distal end of the common carotid delay tubing (see Fig. 1).

Figure 2

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First three panels, stimulation during on-going spontaneous respiratory movements; last three panels, stimulation during cessation of central respiratory drive evoked by electrical stimulation of the central cut ends of the superior laryngeal nerves (SLN) and cessation of artificial respiration, the lungs being held at their end-expiratory position. Panels labelled C, control records. Records from above downwards: Plimb, hindlimb mean perfusion pressure; LV (left ventricular) dP/dtmax; Ptr, tracheal pressure; LVEDP, left ventricular end-diastolic pressure; P¯a, mean arterial perfusion pressure; PI, pulse interval; Pa, phasic arterial blood pressure; Resp., respiratory (thoraco-abdominal) movements (inspiration upwards); Plv, left ventricular pressure. Time calibrations, 1 s and 5 s. Note that CB stimulation causes an increase in LV dP/dtmax (2nd panels versus 1st and 3rd panels) which is reversed during cessation of respiratory movements (5th panel versus 4th and 6th panels), while the increase in hindlimb perfusion pressure is enhanced.

Figure 3. Summary of the effects of selective stimulations of the carotid bodies (CB) and aortic bodies (AB) alone and during electrical stimulation of the central cut ends of both superior laryngeal nerves (SLN) (CB or AB during SLN).

Figure 3

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SLN, electrical stimulation of the superior laryngeal nerves alone. During stimulation of the SLN alone and during excitation of the CB or AB during SLN, central respiratory movements ceased; also artificial respiration was temporarily interrupted. Heart was electrically paced and mean arterial blood pressure maintained constant. •, control values; ○, experimental values. Variables from above downwards: ΔPI, change in pulse interval; LV (left ventricular) dP/dtmax; LVEDP, left ventricular end-diastolic pressure; P¯a, mean arterial blood pressure; Plimb, hindlimb mean perfusion pressure. Values are the means ± s.e.m. from 13 tests in 7 animals for the CB series and 22 tests in 11 animals for the AB series. Where no standard error bar is given, the value is less than the size of the symbol. Statistical analyses (ANOVA with Tukey-Kramer multiple comparisons test): *P < 0.05; **P < 0.01; ***P < 0.001.

Pulse interval averaged 273.9 ± 12.1 ms, and was maintained unchanged in individual experiments. Arterial blood pressure did not change (control 98.7 ± 4.2 mmHg; experimental value, 100.8 ± 3.8 mmHg; 0.1 > P > 0.05).

During cessation of respiration

Suppression of the secondary respiratory effects of central respiratory drive and lung inflation was carried out by electrical stimulation of the central cut ends of the superior laryngeal nerves combined with cessation of artificial respiration for three or four respiratory pump cycles. This caused central apnoea, a reduction in left ventricular dP/dtmax of 908 ± 122 mmHg s−1, control value 6620 ± 300 mmHg s−1 (P < 0.05), but no change in hindlimb perfusion pressure, control value 122.2 ± 4.3 mmHg (P > 0.1), nor in left ventricular end-diastolic pressure, control value 3.0 ± 0.7 mmHg (P > 0.4) (Fig. 3).

Stimulation of the carotid bodies during the period of central apnoea combined with cessation of artificial respiration had no effect on respiration confirming previous observations (Angell-James & Daly, 1975; see also Daly, 1997), but resulted in some variability in the response of the left ventricular dP/dtmax; it was reduced in six animals (Fig. 2, last three panels), increased in five and unaffected in the remaining two. Overall there was no change in left ventricular dP/dtmax (control value 5720 ± 320 mmHg s−1 during suppression of respiration alone; experimental value, 5540 ± 250 mmHg s−1; P > 0.3; Fig. 3).

Comparison of the effects of stimulation of the carotid bodies under the two sets of conditions indicates that the responses occurring during on-going respiration were significantly reduced by suppressing the secondary respiratory mechanisms (P < 0.05).

The hindlimb perfusion pressure increased by 51.8 ± 6.8 mmHg from a control of 128.9 ± 5.7 mmHg on stimulation of the carotid bodies (P < 0.001), a response which was significantly greater than that evoked during on-going spontaneous respiration (P < 0.05; Figs 2, last three panels and 3). The responses to stimulations of the carotid bodies and superior laryngeal nerves in combination were significantly greater than the algebraic sum of their separate effects (P < 0.01).

Left ventricular diastolic pressure did not change significantly from its control value of 3.2 ± 0.8 mmHg (P > 0.7; Fig. 3), nor did the arterial blood pressure (P > 0.3; Fig. 3).

Stimulation of the aortic bodies

During on-going spontaneous respiration

Left atrial injections of sodium cyanide, 43.7 ± 3.2 μg kg−1, carried out to stimulate the aortic chemoreceptors, caused an increase in respiration (rate and depth) in eleven of sixteen animals, an increase in rate only in one, and no effect in the remaining four animals. The left ventricular dP/dtmax increased by 1127 ± 144 mmHg s−1 from a control value of 6136 ± 228 mmHg s−1, or by 19.6 % (P < 0.001). A typical response is shown in Fig. 4 (first three panels). The hindlimb perfusion pressure increased by 40.8 ± 4.4 mmHg, or by 35.3 %, from a control value of 115.3 ± 3.4 mmHg (n = 16; P < 0.001; Fig. 4, first three panels).

Figure 4. The effects of stimulation of the aortic bodies (panels AB) by sodium cyanide, 35 μg kg−1, injected into the left atrium.

Figure 4

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First three panels, stimulation during on-going spontaneous respiratory movements; last three panels, stimulation during cessation of central respiratory drive evoked by electrical stimulation of the central cut ends of the superior laryngeal nerves (SLN) and interruption of artificial respiration, the lungs being held at their end-expiratory position. Panels labelled C, control records. Records from above downwards are the same as in Fig. 2. Time calibration, 1 s. Note that AB stimulation causes an increase in LV dP/dtmax (2nd panel versus 1st and 3rd panels), a response which is still present, albeit reduced in size, during cessation of respiratory movements (5th panel versus 4th and 6th panels). The increase in hindlimb perfusion pressure is enhanced.

The left ventricular end-diastolic pressure did not change significantly from its control value of 3.8 ± 0.6 mmHg (P > 0.7; Figs 3 and 4). The pulse interval, which was maintained constant in each experiment, averaged 269.7 ± 6.0 ms for all the tests. The averaged mean arterial blood pressure remained unchanged (control value 92.2 ± 3.4 mmHg; P > 0.7; Fig. 3).

During cessation of respiration

Suppression of the secondary respiratory mechanisms alone caused a fall in left ventricular dP/dtmax of 736 ± 143 mmHg s−1 from a control value of 6200 ± 290 mmHg s−1 (n = 23; P < 0.01), but no change in hindlimb perfusion pressure (control value of 121.4 ± 3.3 mmHg). Nor was there any change in left ventricular end-diastolic pressure (control value of 3.9 ± 0.8 mmHg) (Fig. 3).

Stimulations of the aortic chemoreceptors during suppression of the secondary respiratory mechanisms had no effect on respiration but resulted in an increase in left ventricular dP/dtmax in twenty of twenty-two tests (fourteen animals; Fig. 4, last three panels), a reduction occurring in the remaining two tests (two animals). Overall, there was an increase of 959 ± 210 mmHg s−1 from a control value of 5400 ± 225 mmHg, which was statistically significant (P < 0.001) (Fig. 3). This response was not significantly different from that evoked by stimulation of the aortic bodies under conditions of on-going spontaneous respiration (P > 0.5; Fig. 3).

During suppression of the secondary respiratory mechanisms, stimulation of the aortic bodies caused an increase in hindlimb perfusion pressure of 51.3 ± 6.9 mmHg from a control value of 129.7 ± 3.7 mmHg (P < 0.001; Figs 3 and 4, last three panels). This change in pressure, however, was not statistically different from the value of 40.8 ± 4.4 mmHg for the increase in pressure observed during aortic body stimulation during on-going spontaneous respiration (P > 0.1). However, the response to stimulations of the aortic bodies and superior laryngeal nerves in combination was significantly greater than the algebraic sum of their separate effects (P < 0.02).

The left ventricular end-diastolic pressure on stimulation of the aortic bodies did not change (control value 4.2 ± 0.8 mmHg; P > 0.2; Fig. 3), nor did the arterial blood pressure (control value 93.8 ± 3.4 mmHg; P > 0.9).

Reflex nature of responses

Afferent pathways

In three experiments, division of the carotid sinus nerves markedly reduced or abolished the left ventricular inotropic and hindlimb vascular responses to stimulation of the carotid bodies during on-going spontaneous respiration and during the period of elimination of the secondary respiratory mechanisms (Fig. 5). In two of these experiments subsequent stimulations of the aortic bodies during the phase of on-going spontaneous respiration evoked responses which were not dissimilar to those with intact carotid sinus nerves. This demonstrates the effectiveness of the temporal separation of the responses to aortic body stimulation from those of excitation of the carotid chemoreceptors provided by the extracorporeal carotid artery loop (Fig. 1).

Figure 5. The effects of division of the carotid sinus (CSN) and aortic nerves (AN) on the cardiovascular responses to stimulation of the carotid and aortic bodies, respectively, by sodium cyanide.

Figure 5

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Heart electrically paced. Mean blood pressure maintained constant by a compensator (Fig. 1). Filled symbols, control values; open symbols, experimental values during stimulations. Circles, responses to stimulations during on-going spontaneous respiration; triangles, responses to stimulations carried out during apnoea evoked by combined electrical stimulation of the superior laryngeal nerves and temporary cessation of artificial respiration. Variables are left ventricular dP/dtmax and Plimb, hindlimb mean perfusion pressure.

In five experiments, division of the aortic nerves reduced or abolished the responses to stimulation of the aortic bodies (Fig. 5). Subsequent division of the cervical vagosympathetic nerves abolished the residual left ventricular dP/dtmax and hindlimb vascular responses suggesting that afferent aortic chemoreceptor fibres also run in the vagus nerves (Neil, Redwood & Schweitzer, 1949).

Efferent pathways

The β-adrenoceptor blocking agent propranolol was used in doses of 0.5 mg kg−1i.v. which blocked the positive inotropic effect of isoprenaline, 1-2 μg kg−1i.v. The baseline dP/dtmax decreased after propranolol, indicating loss of tonic adrenergic drive to the left ventricle (Fig. 6). The increases in left ventricular dP/dtmax occurring on stimulation of the carotid bodies were abolished by propranolol in two of three experiments; in a third, it was reduced (Fig. 6). In tests carried out under conditions of suppression of the secondary respiratory mechanisms, the control responses to stimulation of the carotid bodies were small and variable (Fig. 3), as were those after propranolol (Fig. 6).

Figure 6. The effects of propranolol, 0.5 mg kg−1i.v., on the cardiovascular responses to separate stimulations of the carotid and aortic bodies by sodium cyanide.

Figure 6

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Heart electrically paced. Mean blood pressure maintained constant by a compensator (Fig. 1). Filled symbols, control values; open symbols, experimental values during stimulations. Circles, responses to stimulations during on-going spontaneous respiration; triangles, responses to stimulations carried out during apnoea evoked by combined electrical stimulation of the superior laryngeal nerves and temporary cessation of artificial respiration. Variables are left ventricular dP/dtmax and Plimb, hindlimb mean perfusion pressure.

Stimulation of the aortic bodies during on-going respiration increased left ventricular dP/dtmax in six experiments. After propranolol, the response was abolished in one experiment, markedly reduced in size in three, and reversed to a decrease in two (Fig. 6). Responses obtained during suppression of the secondary respiratory mechanisms were similarly affected by propranolol. An increase in left ventricular dP/dtmax occurred in six experiments before propranolol; after blockade, the response was abolished in two tests, reduced in two, and converted to a fall in two (Fig. 6). In all those tests after propranolol giving rise to a reduction in dP/dtmax, the responses were ephemeral and could not therefore be analysed further. The increases in hindlimb perfusion pressure resulting from stimulation of both groups of chemoreceptors were unaffected by propranolol (Fig. 6).

DISCUSSION

The present experiments demonstrate that there are striking differences between the left ventricular inotropic responses evoked by stimulation of the carotid and aortic bodies. Stimulation of the carotid bodies evoked consistent increases in respiration but variable inotropic responses, with a trend, which was not statistically significant, towards an increase in dP/dtmax. When the stimulations were repeated under conditions in which the central respiratory activity was suppressed at the same time as activity of lung stretch afferents was maintained constant at a minimal level, again, the inotropic responses were variable, but now there was a trend towards a reduction in left ventricular dP/dtmax. The difference in the responses in the two experimental states was statistically significant indicating that mechanisms arising from the associated increase in respiration were contributing towards evoking a positive inotropic effect. The absence of a significant response under conditions in which the secondary respiratory mechanisms were eliminated means that the carotid bodies do not have any primary or direct left ventricular inotropic action. On the other hand, stimulation of the aortic bodies in the absence of secondary respiratory mechanisms evoked a brisk positive inotropic response which represents therefore the primary effect. Interestingly, this response was found not to be respiratory modulated.

Left ventricular dP/dtmax was used in our experiments as a sensitive and quantitative index of left ventricular contractility (Furnival, Linden & Snow, 1970). However, simultaneous changes in other variables, notably heart rate and arterial blood pressure can also affect left ventricular dP/dtmax directly (Bowditch, 1871; Anrep, 1912; Starling, 1918; Sarnoff, Mitchell, Gilmore & Remensnyder, 1960; Furnival et al. 1970), and, therefore, if not controlled can vitiate the interpretation of any reflex changes resulting from stimulation of the arterial chemoreceptors. Furthermore, changes in blood pressure can reflexly affect left ventricular contractility through an arterial baroreceptor reflex (Hainsworth & Karim, 1972, 1973; Ward et al. 1995). By carrying out the present study under conditions in which the heart was electrically paced and the arterial blood pressure was maintained constant, the secondary effects on left ventricle dP/dtmax of changes in heart rate, arterial blood pressure and arterial baroreceptor activity were eliminated. Left ventricular dP/dtmax is insensitive to moderate changes in left ventricular end-diastolic pressure, and in any case, there was, overall, no statistically significant alteration in this variable to stimulation of either group of chemoreceptors.

The choice of sodium cyanide to stimulate the carotid and aortic bodies was taken for several reasons. It is reasonably selective for arterial chemoreceptors and has no actions on autonomic ganglia compared, for instance, with nicotine or lobeline. Furthermore, there was no evidence either from experiments in which the left ventricular inotropic responses were abolished by cutting the carotid sinus and aortic nerves or by use of propranolol that cyanide in the doses used had any direct effect on ventricular contractility. The method, however, did require temporal separation of the responses of the carotid bodies from those of the aortic bodies when left atrial injections of cyanide were used to excite the aortic chemoreceptors. The insertion of a long-circuit bypass in the common carotid arteries lowered the mean pressure in the carotid bifurcation areas due to the resistance of the carotid cannulae and bypass tubing. This raises the possibility therefore that some cyanide injected into the left atrium may have reached the carotid bodies via a natural short circuit, such as the vertebral-occipital artery anastomoses, so that the responses evoked by the aortic bodies would be complicated by simultaneous effects on the carotid chemoreceptors. We obtained no evidence that this was so. The mean pressure gradient between the aortic arch and carotid bifurcation regions was only 2-3 mmHg. Furthermore, the responses to left atrial injections were abolished by cutting the aortic and cervical vago-sympathetic nerves so that the carotid chemoreceptors could not have made any contribution. In other experiments, the immediate responses to left atrial injections of cyanide were not modified by subsequent division of the carotid sinus nerves. We are confident therefore that temporal separation of the responses from the two groups of chemoreceptors was complete.

An alternative method of stimulating the arterial chemoreceptors was considered, namely that used in the dog, in which the two main groups of chemoreceptors situated in both carotid bifurcation regions and the region of the aortic arch were vascularly isolated and separately perfused with blood, stimulation of the chemoreceptors being carried out by hypoxic blood (Daly & Ungar, 1966; Karim et al. 1980). The use of this method was excluded, however, largely because perfusion of the vascular region in the thorax did not include all known groups of aortic bodies (Coleridge, Coleridge & Howe, 1970) and would not have done so in the cat without considerable modification. The method we adopted therefore not only involved less surgery, thereby minimizing trauma, and the use of smaller quantities of blood for priming extracorporeal circuits, but allowed the full complement of groups of aortic bodies to be excited selectively and separately from the carotid bodies. The method also had the advantage of allowing stimulations of the carotid and aortic chemoreceptors to be made in the same animal so that any qualitative differences in the observed reflex responses are real and not due to differences of experimental conditions such as would occur when the reflexes from each group are studied in separate animals. However, the blood concentration of cyanide reaching the carotid and aortic bodies by injections into the carotid arteries and left atrium, respectively, is not known, so that the reflex responses from the two groups of receptors cannot be compared quantitatively.

In the present experiments, measurements of the changes in pressure in the vascularly isolated perfused hindlimb were included routinely. The reason for this was that stimulations of the carotid and aortic bodies invariably cause increases in vascular resistance as primary reflex vascular responses (Daly & Ungar, 1966; see also Daly, 1997, chapters 9 and 10). Thus, these vascular responses provide a valuable means of monitoring the viability of preparations when the response of the main variable under consideration is weak or ephemeral, as for instance, in the study of the left ventricular inotropic responses occurring on distension of the urinary bladder (Ward et al. 1995). In the present experiments, responses of the hindlimb, apart from providing information on the reflex activity of the preparations when the left ventricular inotropic effects of stimulation of the arterial chemoreceptors were abolished by propranolol, also acted as a guide as to the doses of the chemical agent to be used for exciting the two groups of chemoreceptors. In addition, measurements of the hindlimb vascular responses to stimulation of the arterial chemoreceptors yielded results that suggested that the presumed sympathetic effects can also undergo respiratory modulation. The hindlimb vasoconstrictor responses to excitation of the carotid bodies were potentiated when the secondary respiratory mechanisms were suppressed. Thus the effects of combined stimulation of the carotid bodies and superior laryngeal nerves were greater than the algebraic sum of the individual responses, as was observed previously in the cat (Daly & Kirkman, 1988) and monkey (Daly, Korner, Angell-James & Oliver, 1978). A similar more than additive effect was seen on excitation of the aortic bodies in the present study.

The changes in left ventricular dP/dtmax to stimulation of both groups of chemoreceptors are reflex in origin being abolished by cutting the afferent nerve supply. They are mediated via the sympathetic nervous system as indicated by their abolition by propranolol. As the responses normally occurred immediately, allowing for the transit time of the cyanide to the chemoreceptors, they are most likely to be mediated by increased activity in sympathetic nerves to the heart, although a possible contribution of an increased secretion of suprarenal catecholamines to later parts of the responses cannot be excluded.

Bearing on the finding that the carotid chemoreceptors have no primary or direct reflex inotropic effect are the results of Davis et al. (1977). They studied the effects of stimulation of the carotid bodies on heart rate in vagotomized dogs and demonstrated a small slowing of the heart due to decreased sympathetic tone which was more marked when stimuli were given in expiration than the same stimuli given in inspiration. On this basis it might be expected that in the present experiments stimulation of the carotid chemoreceptors would elicit as a primary effect a decrease in dP/dtmax through a reduction in sympathetic activity. It could be argued that the reason why this was not seen routinely was that there was already a very low background level of cardiac sympathetic activity present under conditions of suppression of respiration. Our evidence indicates that this is an unlikely explanation. Carotid chemoreceptor stimuli were given when the background left ventricular dP/dtmax was, on average, 5720 ± 320 mmHg s−1; this is a value much higher than that of 3000 ± 184 mmHg s−1 observed after blocking the effects of all cardiac sympathetic activity with propranolol. In this connection, however, Hainsworth et al. (1979) and Karim et al. (1980) observed a reflex reduction in left ventricular dP/dtmax on stimulation of the carotid bodies, but in the present context their results are difficult to interpret in the absence of information on the concomitant respiratory responses in their experiments.

There are two implications arising from our results. The first concerns the central control of the cardiovascular system by the peripheral arterial chemoreceptors. It is evident that many of the presympathetic neurones in the subretrofacial nucleus in the rostral ventrolateral medulla project to specific target organs via preganglionic cells in the intermediolateral cell column (Dampney, Goodchild & Tan, 1985; McAllen, 1986). In this way excitation of different groups of cardiovascular receptors at a supraspinal level can evoke, through the sympathetic nervous system, varying patterns of reflex responses affecting the heart and different vascular beds on a differential basis (Spyer, 1990). In keeping with the idea that these presympathetic neurones can produce widespread actions on cardiovascular effectors are the findings that stimulation of the carotid bodies evokes different effects on the sympathetic outflow: withdrawal of sympathetic activity causing slowing of the heart (Daly & Scott, 1958; Davis et al. 1977), increasing activity to the peripheral vascular bed resulting in vasoconstriction (this paper; see also Daly, 1997), or no change in activity in respect of the left ventricular inotropism (this paper). On the other hand, stimulation of the aortic chemoreceptors exerts sympathetic excitatory effects on both left ventricular inotropism (this paper) and peripheral blood vessels (Daly & Ungar, 1966). Second, the rostral ventrolateral medulla constitutes one of the main sites responsible for the respiratory modulation of reflex sympathetic responses, mapping studies indicating that a group of respiratory neurones reside close to, but separate from, neurones with a vascular function within the subretrofacial nucleus (Dampney et al. 1985). Neurones themselves in the rostral ventrolateral medulla and/or antecedent interneurones appear to be involved in the reflexes arising from stimulation of the carotid bodies (McAllen, 1987; Koshiya & Guyenet, 1996). Neurones in the same region subserving heart rate and left ventricular inotropism may also be the ones responsible for their respiratory modulation. On the other hand, the inotropic response evoked by aortic chemoreceptor stimulation is only minimally affected by changes in respiration. Thus, the groups of medullary presympathetic neurones with inputs from the carotid and aortic bodies show considerable differentiation in the way they undergo respiratory modulation.

Our results are also pertinent to the relative importance of the two groups of chemoreceptors in the control of blood pressure. It is now evident that the responses of the carotid and aortic bodies to various natural stimuli differ quantitatively (see Daly, 1997, chapter 3). For example, the aortic bodies are considerably more sensitive than the carotid bodies to anaemia, to reductions in O2 saturation, and therefore to O2 flow, and are consequently more important in detecting changes, particularly reductions in arterial blood pressure. Thus, relatively small reductions in blood pressure will result in a reflex increase in systemic vascular resistance through stimulation of the aortic chemoreceptors and by doing so will act synergistically with the reflex vasoconstrictor response to unloading the arterial baroreceptors in helping to maintain the arterial blood pressure. Similarly, the reflex left ventricular positive inotropic response evoked by stimulation of the aortic bodies will complement that of unloading the arterial baroreceptors (Hainsworth & Karim, 1972). The carotid chemoreceptors, on the other hand, would not be expected to contribute in the same way to the haemodynamic changes resulting from small degrees of hypotension because they have no primary reflex inotropic effect (this paper) and their excitation is delayed until the arterial blood pressure is lowered to around 60 mmHg (Eyzaguirre & Lewin, 1961; see also Daly, 1997).

Acknowledgments

We wish to express our thanks to Miss Joanne Davies for expert technical assistance. The work was supported by a grant from the British Heart Foundation (to M. de B. Daly and K. M. Spyer). J. F. X. Jones was supported by The Wellcome Trust.

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