J Physiol Volume 515, Number 2, 543-554, March 1, 1999
The Journal of Physiology (1999), 515.2, pp. 543-554
© Copyright 1999 The Physiological Society
Trigeminal and carotid body inputs controlling vascular resistance in muscle during post-contraction hyperaemia in cats
M. de Burgh Daly and M. N. Cook
Department of Physiology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
MS 8714 Received 14 September 1998; accepted after revision 24 November 1998.
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ABSTRACT |
- In anaesthetized cats, the effects of stimulation of the receptors in the nasal mucosa and carotid body chemoreceptors on vascular resistance in hindlimb skeletal muscle were studied to see whether the responses were the same in active as in resting muscle. The measurements of vascular resistance were taken, first, in resting muscle, and second, in the immediate post-contraction hyperaemic phase that followed a 30 s period of isometric contractions.
- Stimulation of the receptors in the nasal mucosa caused reflex apnoea and vasoconstriction in muscle. The latter response was attenuated when the test was repeated during post-contraction hyperaemia.
- Stimulations of the carotid bodies were made during a period of apnoea evoked reflexly by electrical stimulation of both superior laryngeal nerves. This apnoea prevented any effects of changes in respiration on the carotid body reflex vascular responses. Stimulation of the carotid bodies evoked hindlimb muscle vasoconstriction. In the post-contraction hyperaemic period, the response was reduced or abolished. A similar attenuation of the reflex vasoconstrictor responses occurred in decentralized muscles stimulated through their motor roots in the cauda equina.
- Evidence is presented that the attenuation of the vasoconstrictor responses evoked by the two reflexes is a phenomenon localized to the contracting muscles themselves resulting from an interaction between sympathetic neuronal activity and the local production of metabolites.
- The results are discussed in relation to the metabolic needs of tissues in relation to asphyxial defence mechanisms such as occur in the diving response.
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INTRODUCTION |
Previous work has shown that stimulation of facial skin receptors and of the carotid body chemoreceptors evokes reflex vasoconstriction in skeletal muscle through an increase in noradrenergic sympathetic activity (Daly & Scott, 1962; Blumberg et al. 1980; Elsner & Gooden, 1983). Both these reflexes participate in the so-called 'diving response' which is a pattern of responses consisting of apnoea, respiration usually ceasing in the expiratory position, bradycardia and selective peripheral vasoconstriction. The diving response is a defence mechanism against asphyxia and occurs in different conditions including breath-hold diving (see Elsner & Gooden, 1983; Daly, 1984, 1986, 1997). There is a redistribution of the reduced cardiac output away from organs of the body, including skeletal muscle, that can survive by anaerobic metabolic processes, to more vital ones such as the brain. For survival, this permits periods of apnoea longer than would otherwise be the case.
In breath-hold diving, the mechanism that initiates the vasoconstriction is a reflex arising from stimulation of receptors in the skin of the face (see Elsner & Gooden, 1983), a response that is mimicked by excitation of trigeminal receptors in the nasal mucosa (Angell-James & Daly, 1972).
The state of apnoeic asphyxia stimulates the carotid body chemoreceptors, and in the dog, the aortic bodies as well, resulting in an increase in systemic vascular resistance due to a predominance of vasoconstriction (Angell James & Daly, 1969) in several vascular beds including skeletal muscle (Daly & Scott, 1962). This chemoreceptor reflex is dependent on the co-existence of apnoea, since an increase in respiration results in augmented activity of slowly adapting pulmonary stretch receptors and of central inspiratory neuronal activity which are known to suppress this vasoconstrictor response.
In the experiments mentioned above the skeletal musculature was studied in the resting state. The question arises, therefore, of whether the responses are attenuated in active muscle, since local products of metabolism in active muscle result in a functional sympatholysis (Rein, 1931; Remensnyder et al. 1962; Kjellmer, 1965; Costin & Skinner, 1971). If so, this integration between neural and metabolic activities may be important in meeting the metabolic demands of tissues.
The present experiments were done to determine if the reflex vasoconstrictor responses occurring in resting skeletal muscle with stimulation of the trigeminal receptors and carotid chemoreceptors are modified by simulated exercise. The trigeminal receptors stimulated were those in the nasal mucosa; these receptors give rise to more reproducible responses than those in the skin of the face but evoke similar respiratory and cardiovascular responses (see Daly, 1997). To exclude the mechanical effects of increased intramuscular pressure on muscle vascular resistance, all observations were made in the immediate post-contraction hyperaemic period. The cat was chosen as a convenient model for this study because the components of the diving response and the mechanisms underlying the interactions between the respiratory and cardiovascular systems are similar to those in other terrestrial animals and in a marine mammal, the harbour seal (Phoca vitulina richardsi) (Daly et al. 1977; Elsner et al. 1977; also see Daly, 1997). Some of our results have been reported briefly elsewhere (Daly & Cook, 1993).
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METHODS |
Cats of either sex (2·7-4·6 kg) were anaesthetized with a mixture of 2 % 
-chloralose (52 mg kg-1; Sigma Chemical Co.) and 20 % urethane (520 mg kg-1; Sigma-Aldrich Co. Ltd, Poole, UK) dissolved in 85 parts of sodium chloride solution (120 mM) and 15 parts of polyethylene glycol (molecular weight 200; 'Carbowax', Union Carbide Ltd, Rickmansworth, UK). The initial dose was 2·6 ml kg-1 of the mixture (I.P.); supplementary doses of 0·2 ml kg-1 were administered I.V. when necessary, as indicated by a rise in background level of respiration, heart rate and blood pressure, and by testing the withdrawal reflex on pinching an Achilles tendon. All experiments were carried out in accordance with the Animals (Scientific Procedures) Act, 1986.
Rectal temperature was maintained between 37·5 and 39°C. The urinary bladder was routinely catheterized suprapubically to prevent reflexes arising from this organ. After surgery, heparin (1000 i.u. (kg body weight)-1 I.V.) was administered to prevent coagulation.
Respiration
A tracheostomy tube was inserted just rostral to the sternum and connected to a Fleisch pneumotachograph (Godart-Stratham BV) for the measurement of tidal volume (VT), respiratory frequency (Rf) and respiratory minute volume (E). In some experiments, positive pressure ventilation was applied by means of a Starling 'Ideal' pump at a rate of 19 cycles min-1, the stroke volume being adjusted to maintain the arterial partial pressure of CO2 (Pa,CO2) at 36-43 mmHg. An open pneumothorax was created, the lungs collapsing against an expiratory pressure of 2-4 cmH2O. In all experiments oxygen-enriched air was breathed (inspired O2 fraction (FI,O2) approximately 0·4). Thoraco-abdominal movements were measured qualitatively as an index of central respiratory activity by recording the pressure changes in a balloon situated over the xiphisternum.
Stimulation of receptors in the nasal mucosa
Stimulation was carried out by perfusion of a mixture (1:1 by volume) of air and water at room temperature over the nasal mucosa. A cuffed catheter was inserted rostrally through the trachea at a point rostral to the respiratory cannula into the posterior nasal fossa (Angell-James & Daly, 1972). After positioning the tip of the catheter, the cuff was inflated permanently thereby restricting the perfusate to the nasal cavity. The effluent left via the external nares. Both superior laryngeal nerves (SLN) were cut to denervate the larynx.
Stimulation of the carotid body chemoreceptors
The common carotid arteries were tied and blood flow to the carotid bifurcation regions was restored by cannulating the cut ends of the arteries with polythene tubing (priming volume approximately 2 ml). The rostral connection was by way of a Y-piece which allowed a single bolus injection of sodium cyanide (0·01 % w/v) of less than 0·2 ml to reach both carotid bodies simultaneously. All stimulations of the carotid body chemoreceptors were done during respiratory inhibition induced by simultaneous electrical stimulation of the central cut ends of both SLN using rectangular pulses (0·25-3·0 V, 2 ms duration at a frequency of 20-30 Hz (Grass stimulator)) through a stimulus-isolation unit. The strength of stimulus was that which would maintain an apnoeic period for 20 s.
Perfusion of hindlimb muscle
Vascular resistance changes in muscle were determined in the skinned hindlimb, the paw circulation being occluded at the ankle joint by applying a tight ligature. The right skinned hindlimb was perfused with blood through the femoral artery at constant flow by means of an occlusive roller pump (Type MHRE 200, Watson Marlow Ltd, Falmouth, UK). The pump was fed with blood from the abdominal aorta via a catheter inserted into the ipsilateral femoral artery. The right profunda artery was tied to minimize collateral flow to the limb; this provided an adequate degree of vascular isolation (Daly & Kirkman, 1988). At the start of perfusion, femoral blood flow was adjusted so that the mean perfusion pressure was approximately the same as the mean arterial pressure. Changes in vascular resistance were those in mean femoral arterial perfusion pressure minus inferior vena caval pressure from control values to the peak of the response during the stimulus.
In two experiments, changes in the perfusion pressure-blood flow relationship was determined by a modification of the method of Angell-James & Daly (1972). Blood flow was progressively increased by augmenting the output of the pump, thereby enabling coincidental points for perfusion pressure and flow to be plotted. Each pressure-flow curve made in the control and at the peak experimental states took about 10 s to construct, normal flow being restored on completion of the procedure.
In some experiments the left hindlimb also was skinned, vascularly isolated and perfused with blood at constant flow with a second pump, the pump being fed with blood from the aorta via the ipsilateral femoral artery.
Stimulation of skeletal muscle
Periods of isometric contractions of the muscles of the right immobilized hindlimb were evoked electrically by simultaneous stimulation via needle electrodes of the quadriceps, hamstring and gastrocnemius muscles. In some experiments, the ventral roots L6, L7 and S1 were exposed in the cauda equina, cut, and the caudal ends stimulated. The corresponding dorsal roots were cut as well to deafferentate the limb. Electrical stimuli (voltage, pulse duration and frequency) were set to provide submaximal contractions, and were maintained constant throughout each period unless otherwise stated. Since the flexor and extensor muscles, were excited simultaneously, it was not possible to determine quantitatively the maximum contractions. Submaximal contractions were therefore assessed arbitrarily from the reduction of hindlimb perfusion pressure in the immediate post-contraction period under controlled conditions. The stimulus to evoke a submaximal response was taken as that which produced a change of pressure approximately 70 % of the maximum.
In some experiments the contractions of muscle evoked by electrical stimulation of the ventral roots were prevented by administration of the neuromuscular blocking agent vecuronium bromide (300 mg kg-1 I.V.), supplementary doses of 100 mg kg-1 I.V. being given as necessary. Anaesthesia was maintained by supplementary doses of the mixture of -chloralose and urethane at regular intervals determined in experiments in which no blocking agent was given.
Measurement of pressures
Pressures were measured in the aorta, inferior or superior vena cava (via a brachial vein), and trachea, via catheters attached to Statham strain-gauge transducers (model P23Gb). The frequency response of the aortic catheter-manometer system was flat (± 5 %) up to 12 Hz. Each mean pressure (aortic, inferior venal caval and femoral arterial perfusion) was recorded separately and obtained electrically by passing the output of the amplifier through a simple R-C network (time constant of 1 s). Zero pressures were established postmortem by exposing the tips of the catheters to air in situ.
All variables, including pulse interval, were recorded on a multichannel high resolution thermal print-head recorder (model PAR2000B; TDM Tape Services Ltd, Nottingham, UK).
Blood gas analysis
Samples of arterial blood were analysed immediately for PO2, PCO2 and pH using a calibrated electrode system (model 158, Corning Medical Scientific) at a temperature of 37·5°C. Metabolic acidosis was corrected by infusion of 1 M sodium bicarbonate solution. Packed cell volume was determined by centrifuging samples of blood in capillary haematocrit tubes.
Drugs
The following drugs were used: sodium cyanide (BDH Ltd), vecuronium bromide ('Norcuron', Organon Teknika, Cambridge, UK), heparin (Monoparin, CP Pharmaceuticals Ltd, Wrexham, UK) and guanethidine monosulphate (Ismelin, Ciba).
Experimental procedures
The peak cardiovascular responses to stimulation of the nasal receptors were measured. Since apnoea invariably occurred (see Introduction), any modulation of the cardiovascular responses induced by muscular contractions cannot be due to changes in respiration.
Stimulations of the carotid bodies were made 5 s after the beginning of a 20 s period of apnoea evoked by electrical stimulation of the superior laryngeal nerves. Thus in spontaneously breathing animals, the primary cardiac and vasomotor responses, bradycardia and vasoconstriction, seen after stimulating the carotid bodies were uncomplicated by alterations in respiration (see Daly 1984, 1997). In those animals in which ventilation was maintained artificially, chemoreceptor stimuli were applied during stimulation of the superior laryngeal nerves to produce central apnoea, but in addition, the respiratory pump was switched off for the same duration. The lungs were held at their end-expiratory pressure, both to minimize and hold constant activity in lung stretch afferents. In all cases the strength of the stimulus applied to the superior laryngeal nerves was adjusted so that the accompanying cardiac and vasomotor responses were minimal (Daly & Kirkman, 1989; Daly, 1991). The peak responses to carotid body stimulation were compared with the control values at the time of the injection of cyanide.
Three tests of stimulations of the nasal mucosa and carotid chemoreceptors were made: (1) under control conditions before stimulation of the hindlimb muscles; (2) immediately after a 30 s period of contractions of the right hindlimb muscles; and (3) after the effects of the hyperaemia had worn off completely (30-90 s). However, it was important to rule out the mechanical effects of muscular contractions on hindlimb vascular resistance and hence on perfusion pressure. Therefore excitations of the nasal mucosal receptors and chemoreceptors were carried out 10 s after cessation of the stimulus to the muscles, that is, during the early part of the post-contraction hyperaemic phase. Since in some cases stimulation of the nasal mucosal receptors and carotid chemoreceptors were done against a background of recovery from the post-contraction hyperaemia, the values before and after the tests were averaged. The data from the last control test of stimulation of the nasal mucosal receptors or carotid chemoreceptors was averaged with the first.
The animals were killed by exsanguination combined with a bilateral pneumothorax in spontaneously breathing animals or by switching off the respiration pump in those with pneumothorax.
Analysis of results
All values are expressed as means ± S.E.M. unless otherwise stated. Student's t test 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.
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RESULTS |
The control values for respiratory, cardiovascular and arterial blood gases at the start of the recording period in spontaneously breathing and artificially ventilated animals are shown in Table 1. In all experiments Pa,O2 > 100 mmHg.
Table 1. Initial control values for respiratory, cardiovascular and blood gas variables
| | Spontaneous
respiration | Artificial
respiration |
| No. of animals | 9 | 10 |
| Body weight (kg) | 2·95 ± 0·28 | 3·49 ± 0·55 |
| VT (ml) | 40 ± 4·9 | - |
| Rf (breaths min-1) | 22·1 ± 6·3 | - |
| E (l min-1 kg-1) | 0·302 ± 0·105 | - |
| Ptr (mmHg) |
| Lung inflation | - | 6·8 ± 16·6 |
| Lung deflation | - | 1·4 ± 0·6 |
| Heart rate (beats min-1)* | 235·3 ± 21·3 | 224·2 ± 16·6 |
| Pulse interval (ms)* | 257 ± 22·4 | 269 ± 20·2 |
| Arterial blood pressure |
| Systolic | 164·1 ± 22·2 | 165·5 ± 28·0 |
| Diastolic | 104·4 ± 13·7 | 99·2 ± 17·3 |
| Mean | 124·3 ± 15·2 | 121·3 ± 19·3 |
| PIVC (mmHg) | 5·3 ± 2·7 | 5·3 ± 2·1 |
| Plimb (mmHg) | 106 ± 5·4 | 115·2 ± 8·8 |
| Arterial blood |
| PO2 (mmHg) | >100 | >100 |
| PCO2 (mmHg) | 39·8 ± 6·5 | 41·9 ± 4·0 |
| pH | 7·398 ± 0·057 | 7·379 ± 0·059 |
| Haematocrit (%) | 41·1 ± 2·6 | 43·6 ± 4·5 |
Values are means ± S.D. VT, tidal volume; Rf, respiratory frequency; E, respiratory minute volume; PIVC, inferior vena caval pressure; Plimb, hindlimb mean perfusion pressure; Ptr, tracheal mean pressure. *Averaged over a 10 s period.
Stimulation of receptors in nasal mucosa
Stimulation of the nasal mucosa in six spontaneously breathing animals caused reflex apnoea, bradycardia and vasoconstriction in skeletal muscle as indicated by a rise in perfusion pressure at constant flow. Pulse interval increased 83·3 ± 19·8 ms from a control value of 244·2 ± 9·2 ms (34 %, P < 0·01), the mean arterial blood pressure did not change (P > 0·6), but the hindlimb perfusion pressure rose by 30·7 ± 4·8 mmHg from 98·7 ± 4·8 mmHg (31·1 %, P < 0·001) (Fig. 1, left-hand panel).
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Figure 1. The effects of stimulation of nasal mucosal receptors (Nasal stim., circles), stimulation of hindlimb muscle for 30 s (Mus. stim., triangles), and stimulation of nasal mucosal receptors again during the period of the post-contraction hyperaemia in spontaneously breathing animals
C (open symbols), control values; E (filled symbols), experimental values. Stimulation of the nasal receptors invariably resulted in apnoea. Other variables:  limb, hindlimb mean perfusion pressure; a, mean arterial blood pressure; PI, pulse interval. Values are the means ± S.E.M. (n = 6). Where the S.E.M. bar is absent, the value for S.E.M. is less than the size of the symbol. Note the hindlimb vasoconstrictor response to stimulation of the nasal mucosa (left-hand panel) is abolished during the post-contraction hyperaemic period, without any change in the responses of blood pressure and pulse interval. *P < 0·01; **P < 0·001.
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Direct electrical stimulation of the hindlimb muscles at a frequency of 10 Hz caused a fall in perfusion pressure of 32·5 ± 8·5 mmHg, measured after cessation of the contractions, but was without effect on mean arterial pressure or pulse interval (Fig. 1, right-hand panel). When stimulation of the nasal mucosa was repeated during the period of post-contraction hyperaemia, the increase in hindlimb perfusion pressure was either reduced (three animals) or abolished (three animals). The hindlimb perfusion pressure rose only 1·7 ± 0·8 mmHg (P > 0·1), which was statistically different from the value of 30·7 ± 4·8 mmHg in unstimulated muscle (P < 0·005; Fig. 1, right-hand panel). The changes in blood pressure and pulse interval under the two conditions were not significantly different (P > 0·6 and P > 0·3, respectively) (Fig. 1).
Effects of stimulation of the carotid bodies
Spontaneously breathing animals
The carotid body chemoreceptors were stimulated during apnoea in the end-expiratory position evoked by electrical stimulation of the superior laryngeal nerves (Fig. 2A).
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Figure 2. The effects of stimulation of the carotid bodies with intracarotid injections of cyanide with and without prior contraction of the hindlimbs during a 20 s period of apnoea evoked by electrical stimulation of the superior laryngeal nerves
Spontaneous respiration; both hindlimbs skinned, vascularly isolated and separately perfused at constant blood flow. Cyanide (CN) dose, 5 µg kg-1; SLN stimulation protocol, 2·5 V, 2 ms duration, 20 Hz. In A and C, stimulations of SLN and carotid bodies were carried out without prior contractions of the right hindlimb muscles. In B, the carotid body stimulations were carried out after a 30 s period of direct electrical stimulation of the right hindlimb muscles at 12 Hz (Mus., bar) which commenced in the left-hand panel and continued during a 30 s break in the records. Recording in the right-hand panel commenced 5 s after cessation of the stimulus to the muscles. Records from above downwards: rt.limb and lt.limb, right and left hindlimb mean perfusion pressures; bv, brachial vein mean pressure; VT, tidal volume (inspiration upwards); a and Pa, mean and phasic arterial pressure; PI, pulse interval. Time calibration, 10 s. Note, in B, (1) the reduction in right hindlimb perfusion pressure, indicating vasodilatation, due to electrical stimulation of the muscle (the left and right hindlimb traces cross during the interval between the two panels), and (2) the striking reduction in the vasoconstrictor response in the stimulated right hindlimb versus that in the unstimulated left hindlimb in response to stimulation of the carotid bodies in the immediate post-contraction hyperaemic period.
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In fourteen tests in eight animals, carotid body stimulation had no effect on respiration in contrast to the increase in pulmonary ventilation associated with normal on-going breathing, confirming previous observations (Angell-James & Daly, 1975; see also reviews by Daly, 1984, 1997). Pulse interval increased by 237·1 ± 29·0 ms from control values of 235·7 ± 11·1 ms (100·6 %; P < 0·001), hindlimb perfusion pressure rose by 27·9 ± 2·5 mmHg from control values of 99·8 ± 1·8 mmHg (30·0 %; P < 0·001), and the mean arterial blood pressure fell 10·4 ± 3·6 mmHg from control values of 131·9 ± 3·0 mmHg (-7·9 %; P < 0·01). There was no change in brachial vein pressure. Typical responses are shown in Fig. 2A and C and all the results are summarized in Fig. 3A.
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Figure 3. The effects of stimulation of the carotid body (CB) chemoreceptors in a group of spontaneously breathing animals (A) and artificially ventilated animals with open pneumothorax (B)
Stimulations were carried out during apnoea evoked by electrical stimulation of the superior laryngeal nerves (0·5-1·5 V, 2 ms, 30 Hz). In B, the respiratory pump was switched off at the same time (see Methods). A and B each show: (1) the effects of stimulation of the carotid bodies (CB stim., circles), (2) a 30 s period of stimulation of the right hindlimb muscles (Mus. stim., triangles) (2·5-5 V, 2 ms, 10 Hz for 30 s), and (3) stimulation of the carotid bodies during the post-contraction hyperaemic period commencing 10 s after cessation of the contractions. C (open symbols), control values; E (filled symbols), experimental values. limb, skinned hindlimb mean perfusion pressure; a, mean arterial blood pressure; PI, pulse interval. Values are means ± S.E.M. (n = 14 in A; n = 11 in B). Where the S.E.M. bar is absent, the value for S.E.M. is less than the size of the symbol. *P < 0·02; **P < 0·01; ***P < 0·001.
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Direct electrical stimulation of the skeletal muscle of the hindlimb at a frequency of 10 Hz resulted in a small rise in perfusion pressure at the start of the tetanus, followed by a fall (Fig. 2B). On cessation of the stimulus, the pressure fell further and was then maintained for at least 15 s. The perfusion pressure fell from its initial control value of 102·7 ± 2·7 mmHg to a post-contraction value of 83·8 ± 4·1 mmHg (P < 0·001). Mean arterial blood pressure and pulse interval were unchanged (P > 0·38 and P > 0·1, respectively) (Figs 2B and 3A).
Excitation of the carotid bodies was then repeated under the same apnoeic conditions but in the immediate post-contraction hyperaemic period commencing about 10 s after cessation of the tetanus. The typical response is shown in Fig. 2B and the averaged results are presented in Fig. 3A. The rise in hindlimb perfusion pressure in unstimulated muscle was either strikingly reduced (eleven tests; Fig. 2B, cf. Fig. 2A and C) or abolished (three tests). On average the perfusion pressure increased by 4·4 ± 1·3 mmHg (P < 0·01) compared with 27·9 ± 2·5 mmHg in the same unstimulated muscles. This difference is statistically significant (P < 0·001). The blood pressure fell 10·4 ± 4·0 mmHg (P < 0·02) while the pulse interval rose 290·7 ± 38·5 ms (P < 0·001), responses which were not significantly different from those occurring in the control state (P > 0·9 and P > 0·1, respectively).
The attenuation of the vasoconstrictor response to carotid body stimulation in the post-contraction hyperaemic phase was not at the same time seen in the unstimulated contralateral limb. This is evident in Fig. 2, taken from one of three experiments in which both skinned hindlimbs were simultaneously, but separately perfused with blood (cf. Fig. 2B with Fig. 2A and C).
Artificially ventilated animals
Essentially similar results were obtained in eleven paired tests in a group of six artificially ventilated animals with open pneumothorax. In these experiments the carotid bodies were stimulated during the period of inhibition of central inspiratory drive produced by electrical excitation of the superior laryngeal nerves. For the same period of time (20 s) artificial respiration was stopped at the end-expiratory position. These conditions mimicked, therefore, those in the spontaneously breathing animals in which apnoea was evoked solely by electrical stimulation of the superior laryngeal nerves.
The results are summarized in Fig. 3B. The increase in hindlimb perfusion pressure resulting from excitation of the carotid body chemoreceptors in unstimulated muscle was again considerably attenuated when the stimulation was carried out during the post-contraction hyperaemic period, the values being 24·2 ± 2·0 and 6·0 ± 1·7 mmHg, respectively (P < 0·001). The changes in blood pressure and pulse interval under the two conditions were not significantly different (P > 0·5 and P > 0·3, respectively).
Effects of maintaining constant hindlimb perfusion pressure. The blunting of the carotid body vasoconstrictor response occurring during the post-contraction hyperaemic phase was not the result of the reduction in hindlimb perfusion pressure evoked by the contractions of the muscle. A similar blunting of the response was also seen under conditions in which the perfusion pressure was maintained constant, by adjustments to the output of the perfusion pump, during the period of contractions and in the immediate post-contraction period up to the time of application of the chemoreceptor stimulus. This finding was substantiated further by the results of studies of the effects on the pressure-flow characteristics of the hindlimb muscle vascular bed. Four series of observations in two animals gave similar results; those in one of the animals are shown in Fig. 4. This figure demonstrates, first, that the pressure-flow curves obtained during the immediate post-contraction period (M) are shifted to the left of those for unstimulated muscle (C), indicating vasodilatation, and second, that, whereas in unstimulated muscle excitation of the carotid bodies during an induced apnoea caused a shift of the curve to the right (C 
CB), indicating vasoconstriction, the same stimulus to the chemoreceptors carried out in the post-contraction period was without effect (M M + CB). The extent to which the normal carotid body vasoconstrictor response is modulated in the post-contraction period can be seen by comparing the curve labelled 'CB' with that labelled 'M + CB' in each panel in Fig. 4.
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Figure 4. Two series of pressure-flow curves in the right skinned hindlimb carried out during the apnoeic period evoked by stimulation of the superior laryngeal nerves
Natural respiration, closed chest. The curves were obtained in the following order: (1) control (C), (2) during stimulation of the carotid bodies (CB), (3) in the immediate post-contraction hyperaemic period (M), and (4) during stimulation of the carotid bodies in the post-contraction hyperaemic period (M + CB). The sequences carried out in the left- and right-hand panels were separated by a period of 20 min. Note that the shift of the curve on stimulation of the carotid bodies in resting muscle (C CB), indicating vasoconstriction, is absent when the chemoreceptors are excited during the hyperaemic period following a 30 s period of electrical stimulation of the muscles (M M + CB).
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Effects of electrical stimulation of motor supply to limb muscles at different frequencies. In five animals contractions of the right hindlimb muscles were evoked by electrical stimulation of the caudal cut ends of the ventral roots L6, L7 and S1 in the cauda equina, using randomly selected stimulus frequencies from 0·5 to 16 Hz for a period of 30 s. The corresponding dorsal roots were cut as well. The stimulations caused a progressive reduction in hindlimb perfusion pressure measured in the post-contraction hyperaemic period 10 s after cessation of the stimulus, the size of the response being related to the stimulus frequency (Fig. 5A, 
). Compared with the control level in unstimulated muscle (0 Hz), the pressure at a stimulus frequency of 16 Hz was reduced by 42·8 ± 12·7 mmHg (n = 5; P < 0·01). There were no differences in the blood pressure and pulse interval at the two frequencies (P > 0·8 and P > 0·7, respectively).
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Figure 5. The effects of increasing the frequency of electrical stimulation of hindlimb muscles applied through their motor roots in the cauda equina for a period of 30 s on the vasoconstrictor responses to stimulation of the carotid body chemoreceptors
Chemoreceptor stimulations were carried out during the apnoeic period evoked by excitation of the superior laryngeal nerves. Between A and B, vecuronium was given at 300 mg kg-1 I.V. together with application of artificial respiration. Chemoreceptor responses in B were carried out during excitation of the superior laryngeal nerves combined with temporary cessation of artificial respiration (see Methods). , responses to stimulation of the motor roots to hindlimb muscles;  , responses to superimposition of stimulation of the carotid bodies. Note (1) the progressive hindlimb vasodilator effects of increasing frequency of electrical stimulation of the motor roots, present in A, but absent in B following neuromuscular blockade, (2) the chemoreceptor vasoconstrictor response, the size of which progressively declines with increasing frequency of muscle stimulation (A), which does not occur when muscle contractions are absent (B), and (3) the absence of changes in arterial blood pressure. limb, hindlimb mean perfusion pressure; a, mean arterial pressure.
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Superimposition of tests of stimulation of the carotid body chemoreceptors at each stimulus frequency caused a rise in perfusion pressure, the size of the response diminishing as the stimulus frequency applied to the motor roots was increased (Fig. 5A, ). The values for the increases in perfusion pressure without prior stimulation of the hindlimb muscles, and with stimulation at a frequency of 16 Hz, were 26·4 ± 3·0 and 6·3 ± 2·0 mmHg, respectively, the difference being statistically significant (n = 5; P < 0·01). The blood pressure and pulse interval in the two situations did not change (P > 0·8 and P > 0·08, respectively).
After injection of the neuromuscular blocking agent vecuronium (300 mg I.V.), stimulation of the motor roots failed, as expected, to cause contraction of the hindlimb muscles or to evoke a post-stimulus hyperaemic response (Fig. 5B, ). On the other hand, superimposition of tests of stimulation of the carotid chemoreceptors resulted in an increase in hindlimb perfusion pressure, the size of the response being similar at all frequencies of electrical stimulation of the motor roots (Fig. 5B, ). The differences in the chemoreceptor responses carried out without nerve stimulation (0 Hz) and when stimulated at a frequency of 16 Hz were not significant (n = 6; P > 0·4), nor were those of blood pressure (P > 0·4) and pulse interval (P > 0·9).
Effects of electrical stimulation of motor supply to limb muscles for different periods of time. The degree of suppression of the carotid chemoreceptor vasoconstrictor response in skeletal muscle was also dependent on the duration of the period of contractions. Figure 6 shows that as the duration was increased, maintaining the parameters of electrical stimulation constant, there was a progressive reduction in the hindlimb perfusion pressure from 98·9 ± 2·7 mmHg in unstimulated muscle to 67·1 ± 5·1 mmHg when the muscle was stimulated for a period of 30 s (P < 0·005). The size of the pressor response to stimulation of the carotid bodies was also progressively reduced, the corresponding values being 26·5 ± 2·7 and 5·2 ± 1·1 mmHg, respectively, the difference being statistically significant (P < 0·001) (Fig. 6). The mean arterial blood pressure and pulse interval were unaffected by stimulating the ventral roots and the carotid chemoreceptors (Fig. 6).
Effects of guanethidine. In five animals guanethidine (10 mg kg-1 I.V.) led to a small fall in arterial blood pressure from 126·4 ± 7·2 mmHg to 115·0 ± 3·2 mmHg (P > 0·1). Blood pressure did not change when excitation of the carotid bodies was carried out under conditions of unstimulated muscle nor in the post-contraction hyperaemic state, either before or after guanethidine (P > 0·2 to > 0·9, respectively).
Regarding the effects on the hindlimb perfusion pressure, guanethidine invariably caused a fall, the mean reduction being 32·0 ± 9·1 mmHg. It also abolished the increase in perfusion pressure that occurred on stimulation of the carotid bodies, the responses before and after administration of the blocking agent being 22·8 ± 3·3 and -1·8 ± 1·6 mmHg, respectively, the difference being statistically significant (P < 0·001). The reflex vasoconstrictor responses to stimulation of the carotid bodies occurring in the hyperaemic period of muscle contraction were suppressed by guanethidine, the increases in perfusion pressure before and after administration being 5·0 ± 1·8 and 1·0 ± 0·5 mmHg, respectively (P < 0·05).
|
DISCUSSION |
The new results reported here indicate that the reflex vasoconstrictor responses occurring in resting skeletal muscle on stimulation of receptors in the nasal mucosa and carotid body chemoreceptors (see Daly, 1997) are attenuated during the hyperaemic period of contraction of the muscle. Although most observations were carried out in the immediate post-contraction hyperaemic phase, similar results were obtained when the tests of stimulation of the carotid chemoreceptors were made during the latter part of the period of the active contractions. In the latter case, however, the observed changes in vascular resistance were difficult to interpret as it was not always possible to separate events associated with hyperaemia from the mechanical effects of muscle contraction. These results are therefore not reported.
We have been able to localize the site of the integration of the attenuation of the reflex nasal and carotid chemoreceptor vasoconstrictor responses occurring in contracting muscle to the active muscles themselves. The evidence for this is as follows. Firstly, the attenuated responses occurring in the contracting muscles of one limb did not at the same time affect the reflex vasoconstrictor responses in unstimulated muscles of the contralateral limb. This rules out a central nervous mechanism; nor were there any effects on respiration, pulse interval or blood pressure. Secondly, the attenuation of the reflexes still occurred in experiments in which the active muscles were decentralized by division of their sensory innervation at the level of the cauda equina, thus eliminating any reflex effects arising from receptors in the hindlimb (see Mitchell & Schmidt, 1983). Finally, when the muscles were paralysed, excitation of the motor roots in the cauda equina failed, as expected, to cause contraction. Then attenuation of the vasoconstrictor response to carotid body stimulation did not occur. While these observations indicate the importance of a peripheral site of integration between reflexes from the nasal mucosa and carotid bodies and the local events resulting from activity of skeletal muscle, they do not rule out the possibility that under normal circumstances such reflexes might be modulated by chemo- and mechanoreflexes arising from the active muscles themselves.
Sympathetic noradrenergic fibres are known to be involved in the vasoconstrictor responses in muscle as a result of stimulation of receptors in the nasal mucosa (Angell-James & Daly, 1972) and carotid chemoreceptors (Daly & Scott, 1962; Blumberg et al. 1980; this paper). Thus our finding that the reflex sympathetic vasoconstrictor responses are attenuated in active muscle falls into line with that of others who found that the vasomotor effects of direct electrical stimulation of sympathetic fibres to muscle were diminished in contracting muscle (Rein, 1931; Remensnyder et al. 1962; Kjellmer, 1965). Furthermore, it has been shown that local metabolic factors concerned in the vasodilator response in active muscle can oppose the vasoconstrictor response of augmented sympathetic nerve activity evoked reflexly by unloading the arterial baroreceptors (Remensnyder et al. 1962; Kjellmer, 1965), applying a subatmospheric pressure to the lower part of the body in humans (Strandell & Shepherd, 1967), tilting recumbent subjects to 45 deg in the feet down position (Fewings et al. 1965), changing from a supine to a standing position (Joyner et al. 1990) and inducing systemic hypoxia (Costin & Skinner, 1971). The final response depends on the magnitude of the two opposing mechanisms.
The mechanisms responsible for the local modulation of the noradrenergic neuroeffector system have been discussed in detail elsewhere (Vanhoutte et al. 1981; Shepherd, 1983). These include ionic modulation, metabolic acidosis, local hypoxia, hyperosmolarity of the extracellular fluid, and changes in interstitial concentration of potassium, adenosine and adenine nucleotides. All exert their effects largely by depressing the contractile response of vascular smooth muscle and/or inhibiting the release of noradrenaline. In the present experiments in which contractions of the muscle were produced by direct electrical stimuli, the possibility was considered that the attenuation of the nasal receptor and carotid chemoreceptor reflex vasoconstrictor responses in contracting muscle might be due to the electrical stimuli exciting the sympathetic postganglionic nerves in the muscle, leading to exhaustion of the postganglionic transmitter. Although this cannot be completely ruled out, it is not the sole cause, since a similar attenuation of the responses was obtained when contractions of the muscle were evoked by electrical stimulation of the ventral roots in the cauda equina which are outside the pathway of sympathetic fibres to the hindlimbs.
It was not the purpose of the present experiments to study what local mechanisms are involved in the attenuation of reflex vasoconstrictor responses in muscle during the post-contraction period. Nevertheless, some of our observations are pertinent to this problem as they indicated that events directly related to the activity of the contracting muscles probably play a role. It was found that the degree of attenuation was not only directly related to the frequency of contractions of the muscle, the duration of the contractions being maintained constant, but also to the length of the period of contractions, the parameters of electrical stimulation being the same. Furthermore no attenuation of the reflex responses was seen in unstimulated muscles of the contralateral hindlimb. In this connection Remensnyder et al. (1962) showed that the attenuation of the vasoconstrictor response to direct stimulation of sympathetic fibres to the limb was related to an increase in arterio-venous oxygen difference across the contracting muscle. Whatever the details of the mechanism, it is evident that in the control of muscle vascular resistance there is an interaction between, on the one hand, inputs from the carotid chemoreceptors, and possibly the trigeminal receptors as well, acting reflexly via the sympathetic efferent fibres, and on the other, local mechanisms acting on blood vessels and resulting from contractile processes in skeletal muscle. Our evidence for this is that the size of the reflex vascular responses to excitation of the carotid bodies decreased progressively as the activity of skeletal muscle contraction was raised, whether by increasing the frequency of electrical stimulation (Fig. 5A) or the length of the period of stimulation (Fig. 6). Furthermore, after paralysing the muscles, these differences in the size of the responses disappeared and the vasoconstrictor response to excitation of the carotid bodies occurring in resting muscle remained the same at all levels of electrical stimulation of the motor roots (Fig. 5B).
The results of the present experiments have a bearing on the potential mechanisms involved in the diving response. The diving response constitutes a defence mechanism against asphyxia of the whole organism, whereby oxygen is conserved and the reduced cardiac output is redistributed towards the brain. On the other hand, exercise during breath-hold diving requires an increase in oxygen utilization over and above that at rest, albeit the increase is very low, at least in some marine animals (Castellini, 1991), so that there must presumably be mechanisms by which a balance is achieved between the metabolic demands of these two situations.
It has been shown that the vascular component of the diving response can be modulated by situations where the presence of asphyxia is associated with some other challenge which itself would normally exhibit priority (Elsner & Gooden, 1983). In this connection our results may have a bearing on the vascular responses in those skeletal muscles that are involved in locomotion when diving is accompanied by exercise. It has been shown in humans that there is an antagonism between, on the one hand, the vasoconstrictor response occurring in muscle on apnoeic face immersion in water and, on the other, the immediate post-contraction response in calf muscle (Elsner et al. 1966) and the reactive hyperaemic response of temporary circulatory arrest in the forearm (Elsner & Gooden, 1970). Thus apnoeic face immersion, which caused a reduction in limb muscle blood flow of presumed sympathetic origin (Fagius & Sundlöf, 1986), resulted in a delay in the usual post-exercise hyperaemia until the subject removed his head from the water (Elsner et al. 1966), and in a reduction in reactive hyperaemia (Elsner & Gooden, 1970).
In marine mammals, the majority of free-ranging dives (75-92 %) constitute short duration dives which are only a fraction of the maximum of which they are capable. For example, in Weddell seals (Leptonychotes weddelli), about 77 % of dives take place within the aerobic dive limit, that is, the time limit imposed by oxygen stores and the estimated rate of oxygen consumption. This corresponds to dive durations of up to about 20 min, compared with longer dives of up to 82 min in which accumulation of lactate and a dependence on anaerobic metabolism occurred (Kooyman et al. 1980, 1983; Guppy et al. 1986). In short duration dives, bradycardia occurs but it is less marked than in forced dives (Elsner, 1965; Kooyman & Campbell, 1973). It is presumed that selective peripheral vasoconstriction also takes place including the potential, at least, for sympathetic vasoconstriction in skeletal muscle (Elsner et al. 1964). Kooyman (1989) postulated that because anaerobic metabolism is not important during short dives (Guppy et al. 1986; Castellini et al. 1988), the circulation to muscle must be either open continuously or oscillate periodically to provide additional oxygen to those tissues, such as active skeletal muscle, with depleted oxygen stores. Similarly, in the coronary circulation of conscious seals (Phoca vitulina richardsi and Phoca vitulina largha), slow oscillations in blood flow occur not only in the non-diving state, but also during simulated dives when the mean blood flow is considerably reduced. These blood flow oscillations are independent of changes in arterial blood pressure and heart rate, and probably result from a competition between sympathetic vasoconstriction and metabolic vasodilatation (Elsner et al. 1985).
It is suggested that the peripheral interaction between neural and local metabolic activities in skeletal muscle is a potential mechanism operating in the diving response, whereby some control of the local tissue metabolic needs of skeletal muscle can be achieved in the presence of defence mechanisms against asphyxia of the whole organism during normal swimming movements and during bursts of increased activity. The coronary circulation could be controlled, in part at least, by the same interactive mechanism. It must be pointed out, however, that the main aim of the present experiments was to determine whether the hindlimb vasoconstrictor responses evoked by separate stimulations of the trigeminal receptor and carotid chemoreceptor inputs were the same in active as in resting skeletal muscle. In the diving response, such as occurs in breath-hold diving, both inputs might be excited together, particularly during the progressive asphyxial stage of a dive (see Daly, 1997). The combined response may give rise to greater activation of sympathetic activity than either input separately. Furthermore, in naturally occurring situations, additional drives to the sympathetic outflow to active skeletal muscles may be provided by central commands (e.g. Buckwalter et al. 1997) and by feedback from muscle afferents (Alam & Smirk, 1937). The combination of these various potential vasoconstrictor mechanisms may more strongly oppose the local metabolic vasodilator effects in some circumstances. Even so, the effectiveness of such augmented sympathetic activity could also be considerably attenuated (Rein, 1931) by what Remensnyder et al. (1962) termed 'functional sympatholysis', and this is confirmed in the present study.
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Acknowledgements
This work was supported by a grant from the British Heart Foundation.
Corresponding author
M de Burgh Daly: Department of Physiology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
Email: fleitao{at}rfhsm.ac.uk
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Introduction
, control values before stimulation of the hindlimb muscles; 
