Brain Research, 87 (1975) 293-303

293

© ElsevierScientificPublishingCompany,Amsterdam- Printed in The Netherlands

REFLEX AUTONOMIC CONTROL OF HEART RATE AND PERIPHERAL BLOOD FLOW

P. I. K O R N E R *

AND J. B. U T H E R

Department of Medicine, University of Sydney, and Hallstrom Institute of Cardiology, Royal Prince Alfred Hospital, Sydney 2050 (Australia)

A number of environmental disturbances can alter the blood flow distribution to the different circulatory target organs and produce changes in heart rate and in cardiac output20,21,32,36. The circulatory responses evoked by a particular stress are distinctive and result from interaction of the reflex autonomic effects with direct local and non-autonomic humoral effects on the heart and vasculature5,22,24. Analysis of a variety of reflex circulatory responses have suggested that the sympathetic neural discharge to the various regions is often differentiated, with increasing constrictor tone in some beds and decreasing tone in others 4-v,~z,24,29,sS. These conclusions based on haemodynamic studies have recently been confirmed and extended in the elegant studies of Iriki and colleagues 15-17 in animals, by Wallin et al. 3s in man and by others 19 using direct recording of the regional efferent sympathetic neural discharge. The various studies of reflex responses extend our previous knowledge which showed that highly differentiated sympathetic neural patterns could be evoked by emotional stimuli or by muscular exercise8,12,30,32,s3,36. It is now well established that some of the central nervous mechanisms which mediate the differentiated patterns of sympathetic nerve discharge during emotional stress, muscular exercise or changes in temperature are located in the hypothalamus and cerebral hemispheresS,8,12,36. However, it has only become recognized relatively recently that suprapontine autpnomic mechanisms receive projections from baroreceptors, chemoreceptors and many other afferent inputs 1a,2°. Recent studies suggest that the participation of the suprapontine mechanisms in reflex circulatory activity is far greater than was previously thought8AS,z5,26,~8,31,37. The present paper reviews the contribution of the suprapontine and bulbospinal autonomic mechanisms on the reflex response to arterial hypoxia in the unanaesthetized rabbit. This response is an example of a highly differentiated reflex autonomic pattern in the development of which suprapontine autonomic control mechanisms play an important role22,24,25, a7. The unanaesthetized neurological preparations studied were sham-operated * Present address: Baker Medical Research Institute, Melbourne, Victoria 3181, Australia.

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Fig. 1. Mean results obtained before, during and after severe arterial hypoxia (Pao~ 26-34 mm Hg; heavy bar on time scale) in sham-operated rabbits with intact autonomic effectorsand in 'de-efferented' rabbits. Variables measured were ear artery pressure (B.P., turn Hg); heart rate (H.R., beats]rain); portal vein blood flow (ml/min); renal blood flow (ml/min/kidney); muscle blood flow (ml/min/hindlimb) and ear skin blood flow (ml/min/100 g). The number of animals studied for each variable are given in the legend of Fig. 4. The vertical bar equals :k 1 standard error of the difference (S.E.D.) from control of the mean of a single time interval during hypoxia. rabbits; thalamic rabbits, where the cerebral hemispheres were removed but thalamus and hypothalamus remained intact and pontine rabbits subjected to infracollicular decerebration. The ablation procedures were performed under halothane anaesthesia using a suction diathermy technique which minimized blood loss to 3-5 ml, and resulted in relatively few non-specific effects on somatic, autonomic and respiratory function due to the neurosurgery25, 37. Each animal was studied before, during and after a 48 rain period of severe arterial hypoxia (Pao2 approximately 30 mm Hg) (Fig. 1)37. Changes in arterial pressure and heart rate were measured, and also changes in portal, renal and iliac vein blood flows, which were measured by means of a local thermodilution technique 39. A calibrated thermal conductivity method was used to measure ankle skin and ear skin blood flows 4. Iliac vein blood flow was partitioned into hindlimb muscle and skin blood flows, with ankle skin regarded as being representative of hindlimb cutaneous blood flow 22. In each experiment 25 sets of measurements of each variable were obtained (5 resting, 16 hypoxia, 4 recovery)37. In some of the preparations the response to arterial hypoxia was studied in animals in which some or all of their autonomic effectors had been inactivated. This allowed assessment of the role of neural, adrenal and direct local effects on the heart

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Fig. 6. Mean changes from resting in vascular resistance (averaged over entire treatment period) in sham-operated, thalamic and pontine rabbits. The number of animals studied in relation to each variable is given in Fig. 4 for sham-operated rabbits, and is given below in parentheses for the other groups in the order intact and adrenalectomized preparations; for these groups the 'de-efferented' results shown for reference were obtained from animals with intact CNS. Thalamic" portal (5,4); renal (5,-); muscle (4,4); limb skin (5,4) and ear skin (5,4). Pontine: portal (6,5); renal (5,-); muscle (4,4); limb skin (6,5) and ear skin (6,5). Notation as in Fig. 4.

normal rise in portal vascular resistance, minimal changes in the renal bed, absence of ear skin vasodilatation but a reflex vasodilatation in the muscle bed. The heart rate response was mainly due to cardiac sympathetic excitation, contrasting with the cardiac sympathetic inhibition of sham-operated rabbits (Fig. 2). Furthermore, at the beginning of hypoxia there was excitation in both the cardiac sympathetic and the vagus (Fig. 2, results with propranolol), each producing opposite effects on heart rate contrasting with the synergistic action of both effectors when the higher autonomic mechanisms were intact. The adrenals' contribution to the pontine animal's reflex response was even greater than in sham-operated rabbits (Figs. 6 and 7). As in the latter group adrenal secretions accounted for about half the net autonomic resistance rise in the portal bed, and also for the vasodilatation in muscle. However, in adrenalectomized pontine animals the muscle bed vasodilator effect was abolished rather than reversed into a constrictor effect, suggesting that hypoxia evokes only minimal sympathetic neural constrictor effects in this bed. The findings indicate that the pontine rabbit's autono-

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mic response is less extensive and relatively undifferentiated when compared with thalamic and sham-operated preparations. The sympathetic neural effects increased in only heart and the portal bed for the whole period of hypoxia, and there was no evidence of sympathetic inhibition in any outflow. Metabolic cost of different control mechanisms. In the 'de-efferented' rabbit 32 min of exposure to severe arterial hypoxia was associated with a respiratory alkalosis, whilst in sham-operated animals with intact autonomic effectors there was a small fall in p H from the resting value (Fig. 7). The difference between the groups indicates the cost of autonomic control in terms of H + ion production. The H + ions were produced owing to fl-adrenergic receptor stimulation by adrenal catecholamines, and such an effect was absent in adrenalectomized rabbits or after treatment with propranolol. In pontine rabbits the adrenally mediated metabolic production of H ÷ ion was greater than in sham-operated rabbits (Fig. 7). In thalamic animals H ÷ ion production was also increased, but in this preparation it was not dependent on increased adrenal catecholamine production, since the high rate of production occurred in adrenalectomized thalamic rabbits (Fig. 7). It probably depended on the more pronounced neurally mediated sympathetic constrictor effects observed in this preparation in several beds, particularly in muscle. It is likely that the greater acidosis in these preparations may enhance the local vasodilator effects of hypoxia. The reflex autonomic responses to arterial hypoxia in the rabbit illustrate the different efferent and central mechanisms underlying a highly differentiated autonomic response to environmental stress. The differentiated pattern of sympathetic neural outflow is at variance with Cannon's original view that the sympathetic nerves were a

301 system for mediating mass discharges to all the organs of the body 19. The differentiation in sympathetic neural outflow is no less marked than during emotional stimuli s,l~, a6, and the importance of the adrenal catecholamines in the response is probably related to the prolonged nature of the stress. Adrenal catecholamine secretion produces additional peripheral modulation Of the sympathetic neural discharge through a- and fl-adrenoreceptor stimulation, the relative importance of which differs in the various peripheral beds. The differentiated sympathetic neural response pattern, the rate of adrenal secretions and the vagal excitation evoked by hypoxia all depend on the integrity of the suprapontine control mechanisms of the cerebral hemispheres and diencephalon. Thalamic and pontine preparations develop different patterns of autonomic control compared with rabbits with intact nervous system. The latter group has the greatest differentiation in autonomic effector pattern and shows the greatest range of blood flow responses associated with the smallest rate of metabolic H + ion production. The thalamic rabbit shows much of the differentiation in sympathetic neural effector pattern observed in sham-operated animals, but does not apparently increase its rate of adrenal catecholamine secretion in hypoxia. In pontine rabbits, in which only bulbospinal mechanisms are intact, the sympathetic neural constrictor effects are less wide-spread, suggesting inadequate excitation of some motoneurone pools by the disturbance, and there is much control through increased catecholamine secretion. In this preparation the reflex tachycardia due to sympathetic excitation contrasts with the sham-operated rabbits sympatho-inhibitory response. It might be thought that the tachycardia is an artefact related to non-specific damage following the ablation procedure 25. This seems unlikely in view of the fact that mild arterial hypoxia evokes a tachycardia of similar time course and magnitude in sham-operated and pontine preparations, but produces reflex bradycardia in rhinencephalic (limbic) and thalamic rabbits 25. Probably there is suppression by cortical mechanisms of limbic and diencephalic mechanisms subserving cardiac slowing allowing the bulbospinally mediated reflex tachycardia to become manifest ~0,25. The concept that suprapontine mechanisms modulate the size of reflex autonomic responses is well supported by results from several studies demonstrating changes in the magnitude of baroreceptor-evoked responses during electrical stimulation of various suprapontine structures 1,~,6,~°,~1,~4. In a complex disturbance such as arterial hypoxia there are changes in activity of several afferent receptor groups, i.e. arterial and cardiac baroreceptors, chemoreceptors and lung inflation receptors20,2a. There is now some evidence that all of the above, as well as the somatic afferents send projections to the suprapontine region concerned with cardiovascular controP3,1s,zo,~l,~6,2s,34,36. The highly differentiated autonomic response pattern in this disturbance probably involves differential activation of a number of suprapontine and bulbospinal pathways, by different components of the afferent input profile20,23,25. The present results support the view that the various cortical, limbic, diencephalic, bulbar and spinal autonomic mechanisms are all part of a single central autonomic control system rather than a series of different 'centres' each subserving a special function. Excitatory and inhibitory interactions occur between different components

302 o f this system as a result o f differential activation o f the various p a t h w a y s by changes in afferent input, or sui generis t h r o u g h psychic stimuli. Because o f this the role o f some p a t h w a y s m a y a p p e a r to be p r e - e m i n e n t in the p r o d u c t i o n o f a p a r t i c u l a r a u t o n o m i c effector p a t t e r n (e.g. 'defence' reaction8). However, when we investigate the central mechanisms involved in the d e v e l o p m e n t o f the differentiated reflex response p a t t e r n to a disturbance such as h y p o x i a there is little d o u b t t h a t the characteristic p a t t e r n results f r o m changes in activity in virtually all the central a u t o n o m i c p a t h w a y s o f the intact animal. This w o r k was s u p p o r t e d by grants f r o m the N a t i o n a l H e a r t F o u n d a t i o n o f A u s t r a l i a , the Life Insurance M e d i c a l Research F u n d o f A u s t r a l i a a n d New Z e a l a n d , the N a t i o n a l H e a l t h a n d M e d i c a l Research Council, a n d the P o s t g r a d u a t e C o m m i t t e e in Medicine, University o f Sydney.

1 BAGSHAW,R. J., IIZUKA,M., AND PETERSON, L. H., Effect of interaction of the hypothalamus an d

the carotid sinus mechanoreceptor system on renal hemodynamics in the anaesthetized dog, Circulat. Res., 29 (1971) 569-585. 2 BRONK, D. W., LEWY, F. H., AND LARRABEE, M. G., The hypothalamic control of sympathetic rhythms, Amer. J. Physiol., 116 (1936) 15-16. 3 CALARESU, F. R., AND MOGENSON, G. J., Cardiovascular responses to electrical stimulation of the septum in the rat, Arner. J. Physiol., 223 (1972) 777-782. 4 CHALMERS,J. P., AND KORNER, P. I., Effects of arterial hypoxia on the cutaneous circulation of the rabbit, J. Physiol. (Lond.), 184 (1966) 685-697. 5 CHALMERS,J. P., KORNER, P. I., AND WHITE, S. W., Local and reflex factors affecting the distribution of the peripheral blood flow during arterial hypoxia in the rabbit, J. Physiol. (Lond.), 192 (1967) 537-548. 6 DJOJOSUGITO,A. M., FOLKOW, B., KYLSTRA, P. H., L1SANDER,B., AND TUTTLE, R. S., Differentiated interactions between the hypothalamic defence reaction and baroreceptor reflexes, Acta physiol, scand., 78 (1970) 376-385. 7 FOLKOW,B., JOHANSSON,B., AND LOrVING, B., Aspects of functional differentiation of the sympatho-adrenergic control of the cardiovascular system, Med. Exp., 4 (1961) 321-328. 8 FOLKOW,B., AND NEIL, E., Nervous control of the circulation: cortico-hypothalamic influences. In Circulation, Oxford Univ. Press, London, 1971, pp. 340-363. 9 FUKODA, T., ANn KOBAYASHI, T., On the relation of chemoreceptor stimulation to epinephrine secretion in anoxemia, Jap. J. Physiol., 167 (1963) 268-279. 10 GEBBER,G. L., ANDKLEVANS,L. R., Central nervous system modulation of cardiovascular reflexes, Fed. Proc., 31 (1972) 1245-1252. 11 GEBBER, G. L., AND SNYDER, D. W., Hypothalamic control of baroreceptor reflexes, Amer. J. Physiol., 218 (1970) 124-131. 12 HILTON,S. M., Hypothalamic control of the cardiovascular responses in fear and rage, Lect. Sci. Basis Med., (1965) 217-238. 13 HILTON,S. M., ANn SPYER,K. M., Participation of the anterior hypothalamus in the baroreceptor reflex, J. Physiol. (Lond.), 218 (1971) 271-293. 14 HOCKMAN, C. a . , TALESNIK, J., AND LIVINGSTON, K. E., Central nervous modulation of baroreceptor reflexes, Amer. J. PhysioL, 217 (1969) 1681-1689. 15 IRIKI, M., PLESCHKA, K., WALTHER, O. E., AND SIMON, E., Hypoxia and hypercapnia in asphyctic differentiation in reginal sympathetic activity in the anesthetized rabbit, Pfliigers Arch. ges. Physiol., 328 (1971) 91-102. 16 ]RIKI, M., RIEDEL, W., AND SIMON, E., Regional differentiation of sympathetic activity during hypothalamic heating and cooling in anesthetized rabbits, Pfliigers Arch. ges. Physiol., 328 (1971) 320-331. 17 IRIKI, M., ANt) SIMON,E., Differential autonomic control of regional circulatory reflexes evoked by thermal stimulation and by hypoxia, Aust. J. exp. Biol. med. Sci., 51 (1973) 283-293.

303 18 KENT, B. B., DRANE, J. W., AND MANNING,J. W., Suprapontine contributions to the carotid sinus reflex in the cat, Circular. Res., 29 (1971) 534-541. 19 KolzoMI, K., AND BROOKS,C. M., The integration of autonomic system reactions : a discussion of autonomic reflexes, their control and their association with somatic reflexes, Ergebn. Physiol., 67 (1972) 2-68. 20 KORNER, P. I., Integrative neural cardiovascular control, Physiol. Rev., 51 (1971) 312-367. 21 KORNER,P. I., Control of blood flow to special vascular areas: brain, kidney, muscle, skin, liver and intestine. In A. C. GUYTON AND C. E. JON~S(Eds.), M.T.P. International Review of Science, Physiology, Series I, Vol. 1, Cardiovascular Physiology, Butterworths, London, 1974, pp. 124-162. 22 KORNER P. I., AND UTHER, J. B., Dynamic characteristics of the cardiovascular autonomic effects during severe arterial hypoxia in the unanesthetized rabbit, Circulat. Res., 24 (1969) 671-687. 23 KORNER P. I., AND UTHER, J. B., Stimulus cardiorespiratory effector response profile during arterial hypoxia in the unanaesthetized rabbit, Aust. J. exp. Biol. reed. Sci., 48 (1970) 663-685. 24 KORNER P. I., CHALMERS,J. P., AND WHITE, S. W., Some mechanisms of reflex control of the circulation by the sympatho-adrenal system, Circular. Res., Suppl. III 20, 21 (1967) 157-172. 25 KORNER P. I., UTHER, J. B., AND WHITE, S. W., Central nervous integration of the circulatory and respiratory responses to arterial hypoxemia in the rabbit, Circulat. Res., 24 (1969) 757-776. 26 KORNER P. I., SHAW,J., WEST, M. J., AND OLIVER,J. R., Central nervous control ofbaroreceptorheart rate reflexes in the rabbit, Circulot. Res., 31 (1972) 637-652. 27 KORNER P. I., STOKES,G. S., WHITE, S. W., AND CHALMERS,J. P., Role of the autonomic nervous system in the renal vasoconstriction response to hemorrhage in the rabbit, Circulat. Res., 20 (1967) 676-685. 28 KORNER,P. I., SHAW,J., WEST, M. J., OLIVER,J. R., ANn HILDER, R. G., Integrative reflex control of the heart rate of the rabbit in hypoxia and hyperventilation, Circulat. Res., 33 (1973) 43-58. 29 L6FVING, B., Differential vascular adjustments reflexly induced by changes in the carotid barnand chemo-receptor activity and by asphyxia, Med. Exp., 4 (1961) 307-312. 30 MILLER, N. E., Learning of visceral and glandular responses, Science, 163 (1969) 43 A, 4a.5. 31 REIS, D. J., AND CUENOD, M., Central neural regulation of carotid baroreceptor reflexes in the cat, Amer. J. Physiol., 209 (1965) 1267-1277. 32 ROWELL, L. B., Human cardiovascular adjustments to exercise and thermal stress, Physiol. Rev., 54 (1974) 75-159. 33 RUSHMER,R. F., AND SMITH, O. A., JR., Cardiac control, Physiol. Rev., 39 (1959) 41-68. 34 SATO,A., KAUFMAN,m., KOIZUMI, K., AND BROOKS,C. McC., Afferent nerve groups and sympathetic reflex pathways, Brain Research, 14 (1969) 575-587. 35 SCHONUNG,W., WAGNER, H., JESSEN,C., AND SIMON, E., Differentiation of cutaneous and intestinal blood flow during hypothalamic heating and cooling in anesthetized dogs, Pfliigers Arch. ges. Physiol., 328 (1971) 145-154. 36 SMITH,O. A., Reflex and central mechanisms involved in the control of the heart and circulation, Ann. Rev. Physiol., 36 (1974) 93-123. 37 UTHER, J. B., HUNYOR, S. N., SHAW, J., AND KORNER, P. I., Bulbar and suprabulbar control of the cardiovascular autonomic effects during arterial hypoxia in the rabbit, Circular. Res., 26 (1970) 491-506. 38 WALLIN, B. G., DELIUS, W., AND HAGBARTH, K.-E., Comparison of sympathetic nerve activity in normotensive and hypertensive subjects, Circular. Res., 33 (1973) 9-21. 39 WHITE, S. W., CHALMERS,J. P., H ILDER, R., AND KORNER, P. I., Local thermodilution method for measuring blood flow in the portal and renal veins of the unanaesthetized rabbit, Aust. J. exp. Biol. reed. Sci., 45 (1967) 453--468.