Observations on the hypoxic depression of sympathetic discharge in sinsaortic-denervated cats

CHARLES V. WOHEZCEK AND CANIO POLOSA~

Department of Physiology, McGilb University, 3655 Drummond Street, Montrkal, Qu&. , Canada H3G I Y6

Received September 14, 1987

ROHLICEK, C. V., and POLOSA, C. 1988. Observations on the hypoxic depression of sympathetic discharge in sinoaesrtic- denervated cats. Can. J . Physiol. P h m a c o l . 66: 41 3-4 18.

The effect of graded isocapnic hypoxia on the mass activity of the cervical sympathetic tmnk and of the phrenic nerve was studied in sinoaortic-denervated, pentobarbital-anaesthetid cats. Under control conditions (nomoxia, normocapnia) sympathetic discharge showed (i) a burst of action potentials synchronous with the phrenic nerve burst, which was selectively abolished by procedures suppressing inspiratory neuron activity (inspiration synchronous sympathetic activity, ISSA); and ( i i ) a lower level of sympathetic activity during expiration (tonic sympathetic activity, TSA). The effects of graded hypoxia on these two components of the sympathetic discharge were different. ISSA showed depression only, which began at inspired Po2 (Pin, 02) of 58 2 10 (mean 2 SEM) m d g (1 m H g = 133.3 Pa), became progressively more marked as PinSp o2 decreased further, and was paralleled by depression of phrenic nerve activity. Both ISSA and phrenic nerve activity were suppressed at PI,,,

g. TSA increased progressively with the lowering of Pin,, 02, beginning at a Pin,, o2 significantly lower than that at which ISSA depression began (50 + 13 m H g , p < 0.01). In the range of PI,,, 02 values intermediate between the t h s h s l d s for ISSA depression and for TSA increase, some animals showed a depression of TSA that reversed to an increase as Pi,,, o2 decreased further. During brief (duration B .% 2 0.2 min) episodes of cerebral ischemia produced by occlusion of the brachiocephalic and left subclavian artery, the two components of sympathetic discharge showed responses similar to those observed in hypoxia, namely depression of ISSA as well as depression md enhancement of 2'SA. These findings show that CNS hypoxia influences sympathetic activity by several mechanisms and that all components of the response to systemic hypoxia can be generated supraspinally. The hypoxic depression of ISSA is presumably due to withdrawal of facilitatory input to sympathetic preganglionic neurons from brainstem inspiratory neurons.

ROMLICEK, C. V., et POLOSA, C. 1988. Observations on the hypoxic depression of sympathetic discharge in sinoaortic- denervated cats. Can. J . Physiol . P h m a c o l . 66 : 4 13 -4 1 8.

k9effet d'un hypxie isocapnique graduelle sur l'activit6 de rnasse du tronc sympathique cervical et du nerf phrknique a CtC exmink chez des chats avec Cnervation sino-aartique, anesthesiks au pentobarbital. Dans des conditions tCmoins (normoxie, nomocapnie), la dCcharge sympathique a rnontr6 (i) une bouffCe de potentiels d'action, synchrones avec la RouffCe nerveuse phCnique, qui a Ctd sklectivement abolie par des interventions supprimant l'activitt neuronale inspiratoire (activitk sympathique synchrone inspiratoire, ASSI); et (ii) un taux plus faible d'activit6 sympathique durant l'expiration (activite sympathique towique, AST). Les effets d'une hypaxie graduelle sur ces deux cornposantes de la dCcharge sympathique ont diffCr6. L'ASSB n'a montre qu'une diminution, qui a comencC h une PoZ inspiree (Panspo2) de 58 + 10 (moyenne -k ET) m N g (1 m N g = 133.3 Pa), devewant progressivement plus marquCe mesure que la Pin,, 0 2 dirminuait de pair avec la diminution dQactivitC du nerf phknique. L9ASSI et I'activid du nerf phrknique ont CtC supprimkes h une Pin,, 02 de 46 + 9 m d g . L'AST a augment6 progressivement avec la diminution de Pinspo2. commensant a une Pins, 02 significativement plus faible que celle laquelle I'ASSI a c s m e n c t dirninuer (50 + 13 m d g , p < 0.01). Dans la gamme des valeurs de Pin,, 0 2 intemCdiaires entre les seuils pour la diminution d'ASSI et pour ]'augmentation d'AST, certains animux ant montrk une inversion de eomportement de I'AST, c .-h.-d. une augmentation d' AST avec la diminution de Pin,, 02. Durant de brkves pCriodes (durke de 1,5 zk 0,2 min) B9isch6mie ctrdbrale, provoquke par une occlusion de I'art6re brachiocCphalique et sous-clavikre gauche, les deux composantes de la dtcharge sympathique ont montrt des reponses similaires a celles observkes durnat l'hypoxie, c'est-a-dire une diminution d9ASSI ainsi qu9une diminution et une augmentation d'AST. Ces rksultats montrent qu'une hypoxie du SNC influence 1'activitC sympathique par plusieurs rnCcanismes et que toutes les composantes de la rdpsnse a B'hypoxie systkmique peuvent &re produites de rnanikre supraspinale. La diminution hypoxique d' ASSI serait vraisembfablernent due a un absence d'entrke facilitatrice aux neurones prkganglionnaires syrnpathiques des neurones inspirateurs du tronc cCrkbral.

[Traduit par Ba revue]

Introduction Hra the sinoaofaic denervated (SAD) animal with intact CNS,

systemic hypoxia can cause a neurogenic increase in cardiac output, ventricular contractility, and heart rate (Korner 1959, 197 B ; Krasney and KoehHer 1980) as well as in the firing rate of sympathetic postganglionic neurons innervating myocardium, skeletal muscle, kidney, abdominal viscera, and skin (Gregor and Janig 1977; Iriki and Kszawa 1975; vsn KehreB et al. 1962). However, we have previously shown (Rohlicek et al. 1984; Rohlicek and Polosa 1983~) that during graded isocapnic hypoxia in SAD animals, sympathetic preganglionic neuron (SPN) firing as well as the neurogenic component of hindlimb

' ~ u t h o s for correspondence.

vascular resistance decrease at moderate levels of hypxia (Paoz in the range of 68-35 mmHg) (1 mmWg - 133.3 Pa) and increase only at more severe levels of hypcexia (Bas2 in the range of 35-20 mmHg). The finding that the hypsxic syqatho- depression occurs in the range of Pao2 values in which depression of phrenic nerve activity also occurs (Wohlicek and Polosa 1983a) suggests the possibility of a relation between these two phenomena. Since hypoxia has a depressant effect on the activity of brainstem inspkatsry neurons (Van Beek et aB. 1984) and these neurons provide a considerable fraction of the input generating the background discharge of SPNs (Bachoo and Polosa 19859, the hypoxic depression of sympathetic activity m y be tentatively explained by the withdrawal of this input. However, from the data available it is not possible to

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414 C.4N. J . PHYSIOL. PHHAWMACOL. VOE. 66, 1988

eliminate the possibility of depression by hypoxia of the SPNs themselves or of synaptic input to the SBNs unrelated to respiration.

The purpose of the present investigation was to further analyze the properties of the hypoxic depression of sympathetic activity. Since it is possible to distinguish in the discharge of a sympathetic nerve a component that is inspiration-related and another that is not (Bachoo and Polosa 1985), it was of interest to detemine whether or not both components were affected by hypoxia, what was the temporal relation between hypoxic changes in sympathetic and phrenic nerve activity, and whether or not there was depression of sympathetic activity when the inspiration-related activity was absent, e. g . , in hypscapnia. To determine whether or not the hypoxic depression of sympathetic activity is due to a supraspinal mechanism, we examined the response sf sympathetic discharge to cerebral ischemia. Since it is known that in the SAD cat, systemic hypercapnia-acidosis has an excitatory effect mediated by the ventrolateral medulla on sympathetic neurons (Hanna et al. 19811), any depression of sympathetic activity that might be observed during cerebral ischemia would presumably be the result of brain hypoxia.

Methods The experiments were conducted on adult cats of either sex (3-4.5

kg) under pentobarbital anaesthesia (35 mg/kg i,p. followed by a maintenance dose of 9 mg/kg i.v. every 3 h). The animals were paralyzed with pmcmrsniurn bromide (initial dose, 0.25 mg/kg i.v., followed by maintenance doses of 0.1 mg/kg i.v. every 2-3 h when the effect of the previous dose had w m off, as evidenced by the appearance of spontamesus breathing movements, and after testing for the level of anesthesia) and ventilated with positive pressure to maintain end-tidal Pco2 constant between 30 and 40 mmHg. Core temperature was maintained between 36 and 38°C by means of infrared heat lamps.

h e r i a l chemoreceptors and baroreceptors were denewated by bilateral section of the carotid sinus, aortic, and vagus nerves. Effective $enervation of the arterial chemoreceptors was demonstrated by the loss, after nerve section, sf the increase in phrenic nerve activity caused by systemic hypoxia (ventilation with 10% O2 in NZ) or by i.v. injection of a bolus of KCN (58ylg/kg, D u d e et al. 1941). A cervical sympathetic trunk and phrenic nerve were desheathed and kept submerged in paraffin oil in a pml made of the skin flaps. The electrical activity of both nerves was recorded monophasically with silver hook electrodes, amplified (Grass P5 1 1 pre-amplifier, 11% amplitude band- pass 30-3000 Hz), and displayed on a storage oscilloscope. The amplified signals were also integrated, after half-wave rectification, using a resistance-capacitance circuit with a 100-ms time constant and displayed on a Grass model 7 polygraph. Sympathetic discharge was characterized in control conditions by two components: a burst of action potentids synchronous with the phrenic nerve burst, md a lower level of discharge during expiration (Bachoo and Bolosa 1985). These two components are referred to in this paper as the inspiration synchronous component of sympathetic activity (ISSA) and the tonic component of sympathetic activity (TSA), respectively. The ISSA cam be selectively eliminated by hypocapnia or superior Iqngeal nerve stimulation (Bachoo and Polosa 1985). Both components show fluctuations at frequencies faster than the respiratory frequency (Polosa 1984). The zero level sf activity in the cervical sympathetic trunk was determined by cutting the nerve proximal to the recording electrodes.

Systemic arterial pressure ((SAP) was monitored from a cannula in the femoral artery using a Statham pressure transducer. End-tidal Peo2 and inspired Poz were monitored with a B e c h a n EB-2 abwd OM- 15 gas analyzer, respectively. These variables were ccontinuously displayed on the plygraph.

Systemic hypxia was produced by gradually decreasing the proportion of inspired Po2 (Pins, 02) to N2 from nomoxia (1 60 m H g ) to a maximally hypoxic level of 26 a 3 (mean 2 SE) m H g at a meam

rate of 18 2 1 mHg/min . Cerebral ischemia was produced by occlusion of the brachiocephalic and left subclavian artery for periods d 1-2.7 rnin (1.5 1 0.2 min). An interval of at least I0 rnin elapsed between successive hypoxic or ischemic trials.

Differences between means were tested for statistical significance with the Wilcsxon signed-rank test (Rmmke and De Jonge 1964). p values of less than 0.01 were considered to be significant. Means listed in the text we given with their accompanying standard error.

Results The effect of progressive systemic hypoxia on cervical

sympathetic tmmk (CST) and phrenic nerve activity was observed in 17 trials in eight animals. Three different effects on sympathetic activity, which appeared at different Hevels of hypoxia, were identified: (i) a depression of ISSA closely associated with depression of phrenic nerve activity, (ii) a decrease in TSA, and (iii) an increase in TSA.

In all the experiments the effect that appeared first as Pinsp 02

began to decrease was the depression of phrenic nerve activity and sf ISSA (Fig. 1, record at PinspoZ of 50 mmHg). On average, the ISSA was first noticeably depressed at an inspired Po2 of 58 k 10 mmHg . With a further decrease in inspired Po2 , complete suppression of phrenic nerve activity and ISSA occumed at an average inspired Po2 of 46 9 9 mmHg (Fig. I , record at Pinsp 02 of 40 mmHg).

In all experiments TSA started to increase when Pirasp 8 2

reached a level lower than that at which the depression sf ISSA began (50 t 13 mmHg compared with 58 -& 10 mmHg; p < OeO1). As inspired Po2 was lowered further, TSA progressively increased reaching a maximum level at the lowest Pa2 tested (26 * 3 mmHg) (Fig. 1 , record at Pi,,, 02 of 30 mmHg). At the lowest Bins, 02 the TSA level averaged 2280 i~ 28% of the level in nomoxia.

In five of the eight animals only the two responses described above were observed. In three of these five animals TSA remained approximately constant over a small range of decreas- ing Pi,,, 02 values after the disappearance of ISSA and prior to the increase in TSA (Fig. 1, record at Pins, 02 of 40 m d g ) . Thus, in these animals there was a clear separation in time, and therefore Po2 , sf the two responses. In the two remaining animals TSA started to increase while ISSA was still present and becoming progressively smaller.

An additional type of depression of sympathetic discharge during systemic hypoxia was observed in the remaining three animals. In these preparations a depression of TSA occurred at levels of hypoxia sufficient to depress or abolish phrenic nerve discharge and ISSA but less severe than those associated with the increase in TSA. The threshold for this depression was in the Pi,,, o2 range of 50-40 mmHg and the peak (at 228-50% of the c o n ~ l TSA level) in the Pi,,, 02 range of 35-20 rnmHg. This decrease in TSA during systemic hypoxia was also present when phrenic nerve discharge and ISSA were first eliminated as a result of kypocapnia produced by hyperventilation (Fig. 2).

The effect of cerebral ischemia on the activity of the CST and phrenic nerve was recorded in six animals. In all the animals there was depression of phrenic nerve activity and of ISSA. In some preparations this depression was preceded by a transient increase in phrenic nerve discharge and ISSA (two animals). In five of the six animals an increase in TSA was observed concomitantly with or following the depression sf ISSA, while in the remaining animal TSA did not change. In two animals a decrease in TSA was also observed following the initial increase in TSA. As in the experiments involving systemic hypoxia, this decrease in TSA was &so present following elimination of

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WOWLICEK AND POLOSA

~ i n s p 0 2 (mHg) 1 60 65 50 40 30 4

Integrated 3 Sympathetic (CST) Activity 2 (units) I

Integrated 3 Phrenic n. 2 Activity I

(units) o

Systemic Arterial 100 Pressure so m

FIG. I . Sinoaortic-denervated cat. End-tidal P C C P ~ , 37 mrnHg. Response of cervical sympathetic trunk (CST) and phrenic nerve discharge to progressive systemic hypxia (average Pi,,, Q2 for the 15-s record shown in each panel is indicated on top of panel). Notice parallel depression of inspkation-synchonous sympathetic discharge and phrenic nerve discharge. At Pi,,, o2 of 40 mmHg, both are suppressed. Tonic sympathetic activity increases at 30 m H g . Record at extreme right shows cut-nerve base line for cervical sympathetic trunk record.

Integrated ' Sympathetic 3 (CST) Activity a (units) 1

Csr cut 0 -

Integrated 2

Phrenic n. 1

Activity 8 - - b w l l p ~ d a q - -

(units)

FIG. 2. Sitmaortic-denemated cat. Response of sympathetic activity to progressive systemic kypoxia. End-tidal Pes2, 15 m H g . At this Pro2 level inspiration-synchronous sympathetic discharge and phrenic nerve discharge are absent. Notice depression of tonic sympathetic activity at

g, followed by increase at 15 m d g . Record at extreme right shows cut-nerve base line for cervical sympathetic trunk (CST).

phrenic nerve discharge and ISSA, prior to cerebral ischemia, from a control value of 138 zk 8 mmHg to a value s f 53 & 3 by hyperventilation producing h y p a p n i a . Examples s f differ- mmHg at the peak hypoxic level (Pi,,, o2 of 26 & 3 mmHg). ent response patterns of CST mQ phrenic nerve discharge during Similar results have been observed in previous studies (Bemthal cerebral ischemia are shown in Fig. 3. and Woodcock 195%; Bouckaega et al. 1941; Gellham and

During systemic h y p x i a SAP decreased in all the animals Lambed 1939; Rohlicek and Polosa 1983~; Rohlicek et al.

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CAN. J . PHYSHOL. PHAWMACQL. VOL. 64, 1988

Integrated Sy rnpathetic (CST) Activity

t ntegrated Phrenic w. Activity

On tegrated Sy rnpathetic (CST) Activity

Integrated Phrenic w. Activity

Integrated Sympathetic (@ST) Activity

lntegrated Phrenic w. Activity

FIG. 3. Effects of cerebral ischemia on cervical sympathetic trunk and phrenic nerve discharge. (a-c) Records from thee different sinoaortic-denewated cats. The cats of panels a and b were nomo- capnie. In the cab of panel c , phrenic nerve and inspiration-synchonous sympathetic discharges were eliminated by hyperventilation in air (end-tidal Pco~, 20 g). Between mows: occlusisn s f the brachiocephalic and left subclavian xtery.

1984). The fall in SAP during hypoxia was smaller in some animals compared with others (c. f. Figs. 1 and 2). Tkis may have been due to a greater level of circulating vasopressor agents during hypoxia in some preparations (Ashack et al . 1 985;

ss et ;pH* 1977; Rose et al. 1983). During occlusion of the iocephalic and left subclavian arteries there was a marked

pressor response (67 2 9 mmHg increase from a control level sf g) . Similar results have been obtained previously

(Guyton 1948; Sagawa et al. 1961; Downing et al. 1963; Takeuchi et al. 1969; Barnpney and Moon 1980; Wshlicek and

83b). It does not appear that the changes in SAP with systemic hypoxia or cerebral ischemia were spnsible for the observed effects on sympathetic

activity9 as a decrease in rnem SAP to 43 f 7 (n = 3) mmHg produced by rapid hemorrhage or an increase in mean SAP to

15 m H g as a result of bolus i.v. injection of , n = 3) from control level of 1 B 5 2 13

mmHg did not have an appreciable effect on sympathetic activity.

Diseussian The SPN response to systemic hypoxia in the CNS-intact

SAD preparation is more complex than previously thought ohficek and Pslosa 1983 a). e have identified thee c s m p -

nents of this response with different Po2 thresholds: a decrease in the ISSA, an increase in TSA, and a decrease in TSA.

The loss of ISSA during systemic hypoxia can be attributed to withdrawal of the phasic facilitatory input to SPNs provided by brainstem inspiratory neurons achoo and Polosa 19851, which are depressed by hypoxia ( n Beek et al. 1984) because (i) the time course of the depression of ISSA paralleled the time course of the depression of phrenic nerve discharge as inspired Po2 was gradually decreased, and (ii) ISSA was depressed independently of changes in TSA. The latter observation rules out the possibility that the depression of ISSA was due to a depressant action of systemic hypoxia on SPNs or on tonic facilitatory inputs to these neurons, because if this was the case TSA also would be depressed over the same range of inspired Po2. Instead, in a number of experiments the level of TSA was unchanged or increasing when ISSA was depressed. Further support for the view that the depression of ISSA during hypoxia is a result of the withdrawal of excitatory input to sympathetic preganglionic neurons from brainstem inspiratory neurons is provided by the observation that ISSA is also de cerebral ischemia. As during systemic hypxia, during brain ischemia ISSA was depressed concomitantly with the phrenic nerve discharge, while TSA showed either no change or an increase. This effect of cerebral ischemia can be attributed to m action of brain hypoxia becasue CNS hypercapnia and acidosis, which also result from cerebral ischemia (Ljunggren et al. 1974), appear to have only excitatory effects on sympathetic and respiratory activity (Hanna et al. 1981; Berkenbosch et al. 19791, while brain hypsxia is known to depress respiration regardless of these simultaneously occurring excitatory effects (Monill et al. 6975).

A second component of the CST nse to systemic hypoxia was an increase in TSA. This is likely of both spinal and supraspinal origin since previous work has shown that severe hypsxia in the 1 animal has sympathoexcitatory effects (Alexander 1945; cek and Polosa 198 1, % 986) as does cephalic perfusion with hypoxic blood (Downing et al. 1963; De Geest et al. 9965; McGillicudy et al. 1978). The increase in TSA during hypoxia ma e due to increased excitability of SPNs or of antecedent nal and supraspinal excitatory neurons as well as to a dec in tonic sympatho- inhibitory influences.

A third component of the CST response to systemic hypoxia was a decrease in TSA. A reason why this component was not seen in all the animals may be that the range of Po2 over which this effect appears overlaps with that producing the increase in TSA. The h p x i c depression of TSA seems to be of supraspinal origin, since it is absent in the C1 spinal animal ( Polosa 1981, 6986), but it was seen during cerebral ischemia. In the latter case, for the reasons given above, the depression can be attributed to the effects of cerebral hypoxia. The hypoxic depression of TSA does not appear to be related to the hypsxic decrease in central respiratory activity, since it was also seen in the absence of phrenic rnotoneuron discharge resulting from hypocapnia. The hypoxic decrease in TSA may result from depression by hypoxia of supraspinal mechanisms involved in the generation of tonic sympathetic activity or from the activation of sympathoinhibitory pathways.

g denenation sf the arterial chemoreceptors, there wn remaining peripher chemsensory structures the lack of Q2 with ex action on sympathetic

neurons. Therefore, changes in sympathetic preganglionie neuron activity d u ~ g systemic hypoxia in the SAD preparation

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WOHLICEK AND POLOSA 417

can be attributed to central actions of O2 depletion. CNS hypxia has depolarizing (Lorente de No 1947; Lundberg and Bscarsson 1953; Kolmodin and Skoglund 1959; Collewi~n and Van Hmeveld 1866; Eccles et al. 1966; Chalazonitis 1963; Segal 1970) or hyperpolarizing (Hansen et al., 1982; Glotzner and Grusser 1967) effects on neuron membrane as well as a depressant effect on synaptic transmission (Hansen 1985). Depolarization of sympathetic preganglionic neurons or of ante- cedent excitatory neurons, or decreased efficacy of tonically active sympathoinhibitory pathways as a result of depressed synaptic transmission or hyperpolarization of neurons in such a pathway, could lead to increased sympathetic activity. Similarly depolsuization of inhibitory neurons antecedent to sympathetic preganglionic neurons or decreased efficacy of tonically active sympathoexcitatory pathways could lead to decreased sympa- thetic activity.

The mechanism of the hypoxic depression of brainstem inspiratory neurons, which is suggested as the cause of the depression of ISSA during hypoxia, is not known. A direct effect on central respiratory neurons has been suggested (Cherniack et d. 197 1). A mediation by adenosine (Millhorn et al. 1984) or GABA (Yamada et al. 1981) has also been proposed.

These central sympathodepressant and sympathoexcitatory effects of systemic hypoxia may be physiologically significant. It is Bikely that these excitatory and depressant effects interact with the input to sympathetic neurons from the arterial chemo- receptors (Trzebski 1983) to produce the overall sympathetic response to systemic hypoxia in the intact animal. Krasney and co-workers have suggested that central sympathetic effects of hypoxia are particularly important in neurogenic cardiovascular adjustments during acute systemic hypoxia (Koehler et al. 1980; Krasney and Koehler 1877). Changes in sympathetic activity resulting from CNS hypoxia may modulate arterial chemo- receptor output as a result of the sympathetic innervation of the carotid sinus (B'Regan and Majcherczyk 1983). The central sympathoexcitatory effects of hypoxia may explain the increased pressor effect of carotid baroreceptor unloading during systemic hypoxia (Bagshaw et al. 1986). Finally, central hypoxic sympathodepressant effects may explain the decrease in neuro- genic vasoconstrictor tone sometimes seen during systemic hypotension produced by hemorrhage (Corazza et aH. 1963; Gootman and Cohen 1970; Lundgren et al. 1964; Rothe et al. 1%3).

Acknowledgements The financial support of the Medical Research Council of

Canada is gratefully acknowledged. C. Rohlicek was supported by a Medical Scientist Award of the Canadian Heart Foundation. We thank Sandra James and Christine Pmplin for typing the manuscript.

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