Medical Hyporheses Q Longman Group
(1990) 32,91-99 UK Ltd 1990
The Autonomic Nervous System is not a Purely Efferent System L. FREIRE-MAIA
and A. D. AZEVEDO”
Departamento de Farmacologia and “Departamento de Fisiologia e Biofihca, lnstituto de Citkcias Bioldgicas, Universidade Federal de Minas Gerais, Caixa Postal 2486, 30.161 - Belo Horizonte, MG-Brasil (Reprint requests to L F-M)
Abstract - The concept of the autonomic nervous system as purely efferent does not seem to describe satisfactorily the patterns of its actions and mobilizing mechanisms. It is herein suggested that the autonomic nervous system should be rather considered as composed of functional modules comprising the visceral afferents, the integrating centers and the visceral efferents (sympathetic and parasympathetic).
physiological since it would leave neurons stranded without innervation’. Actually, Langley (24) mentions, specifically on page 13, the central connections of the ANS in the following statement: ‘Both autonomic and somatic systems consist of central and peripheral parts’. However, the central connections of the ANS were imperfectly known, and for this reason the description of the system was mainly related to preganglionic and postanglionic nerve connections. Why did Langley (24) not include the afferent fibers as part of the ANS? Perhaps because the physiology of these fibers was not well known when he wrote his book, in 1921. Actually, only 11 years later Bronk and Stela (9) recorded, by the first time, action potentials in afferent fibers of the carotid nerve.
Introduction There are controversies among the authors on the concept of autonomic nervous system (ANS). The majority of the investigators and authors of Textbooks of Physiology state that the ANS is a purely efferent and peripheral system, because of the old concept of ANS described by Langley (24). This concept of a purely efferent system is clearly defined by Langle_y (24) on page 1 of his book, where he states: ‘The autonomic nervous system consists of the nerve cells and nerve fibres, by means of which efferent impulses pass to the tissues other than multinuclear striated muscie’. In accordance with Fulton (16) this has been interpreted ‘as meaning that one cannot extend the concept of autonomic system farther into the nervous system than the cell body of its preganglionic fibers; but such limitation is un91
92 Objectives
MEDICAL HYPOTHESES
of the article
We will try to show in this article that the ANS is composed not only of efferent visceral fibers, but also of centers of integration and afferent visceral fibers.
8
Efferent part of the ANS
Since the classical work of Langley (24), many investigators around the world have studied in detail the morphological, physiological, and pharmacological aspects of the efferent part of the ANS (sympathetic and parasympathetic systems) and for this reason, we will not discuss them in this article. Afferent part and central connections ANS
of the
For the purpose of this paper we will rather analyse several experiments performed by different authors, which give an idea of the role played by afferent fibers and the central connections in the control of complex physiological phenomena.
Vagal glucoreceptors and the insulin release. Mei (31) has shown that in anesthetized cats the activity of sensory vagal neurones, recorded in nodose ganglia .by means of extracellular glass microelectrodes, was stimulated by perfusion of the small intestine with glucose. The neurones were of the C type and were slowly adapting. Figure 1 (A) shows an example of a glucoreceptor discharge after perfusion with glucose of the small intestine, and the slow adaptation of discharge (Figure 1, B, C, and D). In a subsequent paper Mei et al (32) showed that glucose perfusion of the small intestine in anesthetized cats and rats produced a fast increase of insulin secretion which preceded the variation of glycemia (Fig. 2) and could be explained as a reflex effect evoked by stimulation of intestinal glucoreceptors. The afferent pathway of this reflex is represented by vagal fibers coming from the intestinal glucoreceptors and the efferent pathway involves chiefly parasympathetic fibers, but also sympathetic fibers. As far as the centers involved in the neural insulin regulation, data from several authors indicate that the ventromedial nucleus (VM) and the lateral hypothalamus (LH) may be implicated (32, 40). Figure 3 shows a schematic representation of the pathways involved in the nervous regulation of insulin release. This is a
Fig. 1 Activity of sensory vagal neurones, recorded in nodose ganglia of an anesthetized cat, after administration of glucose solution (10 g/l) in the small intestine. A, immediately after the end of injection (all the receptors were silent before the perfusion). B, C, and D, after 15 min., 30 min. and 60 min. respectively. According to Mei (31).
nice example of regulation of an important metabolic function, which involves afferent fibers, centers of integration and efferent fibers of the ANS. Vagal afferent fibers and the control of the circulation. Since the thirties several authors have been
studying the projections of sensory receptors into the central nervous system by means of electrophysiological techniques. bore recently, the horseradish peroxidase technique (7, 26) and deoxyglucose technique (36, 37) have been used to localize precisely the centers of integration of the ANS in the medulla, hypothalamus, cortex etc. Kostreva and coworkers used the deoxyglucose technique and obtained very interesting results, demonstrating that the stimulation of afferent vagal fibers and afferent fibers of carotid sinus evoke an increase in the metabolism of specific areas in the central nervous system, mainly in the region of the nucleus tractus solitarius. In a review article, Kostreva (21) summarizes several of the results obtained by his group in the following way: A. The authors stimulated the left cut central end of the vagus in an anesthetized dog, after section of the contralateral vagus nerve, and observed an increased glucose utilization by the left
THE AUTONOMIC
93
NERVOUS SYSTEM IS NOT A PURELY EFFERENT SYSTEM
VAGAL NERVES
&2_+,a Fig. 2 Rise of insulin and glucose blood levels after intestinal perfusion with glucose solution (100 g/l) in anesthetized rats (A) and cats (B). C, and C, control values; the arrow indicates the end of glucose perfusion. Note that the insulin levels (a---*) start to rise before the elevation of glucose levels (o----a). According to Mei et al. (32).
NTS. They also showed that the medial subnuclei of the left NTS was metabolically the most active part of the NTS, and that the inferior olivary nuclei and the external cuneate nuclei were also activated. However, the contralateral NTS did not increase its glucose utilization after the left vagus stimulation. B. The authors stimulated the left carotid sinus nerve in cats and dogs, and found that the projections into the CNS were different for these species. Thus, for the cat the structures involved were the ipsilateral dorsolateral NTS, the external cuneate nuclei bilaterally and the medial subnuclei of the NTS more rostrally, while for the dog the structures involved were the dorsolateral NTS, bilaterally, with the ipsilateral NTS presenting greater i_ncrease in activity. C. ‘Sympathetic’ afferents: the electrical stimulation of the central end of the left T3 white
1
INSULINRELEASE
Fig. 3 Schematic representation of afferent fibers, central connections and efferent fibers involved in the nervous regulation of insulin release. a, afferent vagal fiber; b, efferent vagal fiber; c, efferent splanhnic fiber; 1, absorption of glucose from the small intestine into the blood circulation; 2, direct effect of glucose on cells of the pancreas. VMH, ventromedial hypothalamus; LA, lateral hypothalamus. According to Mei et at. (32).
increased the glucose rami communicantes utilization in the ipsilateral lateral NTS, portions of the external cuneate nuclei, and portions of the inferior olivary nuclei. The data show that different parts of the NTS region are metabolically activated by different afferent stimulation. On the other hand, other investigators (26, 35) have demonstrated, in cats and rats, that the NTS sends efferent fibers both to inferior and superior levels, such as the spinal cord, the hypothalamus, amygdala and other forebrain structures, which, we assume, are involved in complex autonomic and behavioral patterns. Figure 4 shows a schematic diagram of the afferent and efferent projections of the NTS.
94
MEDICAL
AFFERENT A 5 GUSTATORY
E
TASTE
INPUT CELL
AFFERENTS
\
TO NTS
EFFERENT
OUTPUT
HYPOTHESES
FROM NTS
GROUP RESPIRATORY
/ FASTIGIAL
N.
N.AMBIGUUS
FOREBRAIN AMYGDALOID
N.
PERIVENTRICULAR N. THALAMUS
BARORECEPTORS BARORECEPTORS CEREBRAL
CAROTID
SINUS
CAHOTlD
CORTEX
PREOPTIC AREA
BARORECEPTORS
CHEMORECEPTORSA
4 Schematic representation Modified from Kostreva (21).
Fig.
MEDIAL
LPARAVENTRICULAR HYPOTHAL.
of afferent
FLOCCULUSof CEREBELLUM N,
input
VENTROLATERAL RETICULAR FORMATION
to Nucleus
Electrical stimulation of the carotid sinus nerve also evoked an increase in the utilization of glucose in the parabrachial regions of the pons, paraventricular nuclei of the hypothalamus and insular cortex, whereas stimulation of ‘sympathetic’ afferents also induced an activation of the preoptic and paraventricular nuclei of the hypothalamus. These data seem to indicate that integration of cardiovascular reflexes in the CNS is complex in nature, with activation of areas of medulla, pons, hypothalamus and cortex. Mapping of sympathetic ganglia: Many authors have shown that the sympathetic ganglia can mediate visceral reflexes without connection with the CNS. Thus, electrical stimulation of the vagal trunk, in deafferented ganglia preparations, evoked an increase in the glucose utilization in the middle, cervical and stellate ganglia, in an anesthetized dog. These data indicate that the decentralized ganglia are activated by cardiopulstimulation monary afferent (22). These experiments strongly suggest that the sympathetic ganglia are not a part of a purely efferent system and that they can mediate visceral reflexes, evoking an increase in the glucose utilization of specific areas of the heart. On the other hand the application of horseradish peroxidase to the central cut end of the carotid sinus nerve produces labeling of efferent neurons in the nucleus parvocellularis and the
Tractus
Solitatuis
(NTS)
BED
and efferent
NUCLEUSof TERMINALIS
output
STRlA
from NTS
retrofacial nucleus in the medulla, which would act as preganglionic parasympathetic neurons to carotid body (7, 15). These investigations indicate that the Autonomic Nervous System (ANS) is composed of afferent fibers, complex centers of integration and efferent fibers. An example of central integration of the ANS: the baroreceptor reflex
In a review article Spyer (38) studied the central nervous integration of autonomic functions. The baroreceptor influence on cardiac vagal motoneurones (CVM) is conducted by afferent fibers of the sinus and the aortic nerves, and is mediated by the nucleus tractus solitarius (NTS), as is shown in Figure 5. This Figure also shows an inhibitory influence of inspiratory neurones and hypothalamic defense area on the CVM. The defense area could inhibit also the transmission from NTS to CVM. Therefore, an increase in arterial blood pressure will evoke action potentials in afferent fibers, with projection to NTS in the medulla and activation of CVM, with a consequent bradycardia. This reflex can be blocked by hypothalamic defence area stimulation. On the other hand, it has been shown (11) that the neurons in the ventrolateral medulla receive chemoreceptor and baroreceptor afferents and in turn influence vasoconstrictor and cardioac-
THE AUTONOMIC
NERVOUS
SYSTEM IS NOT A PURELY
EFFERENT
Fig. 5
Schematic representation of the control of the baroreceptor input to cardiac vagal motoneurones (CVM). lnspiratory neurones (I) exert and inhibitory control (-) of CVM. The hypothalamic defence area may inhibit CVM activity (-) and block their baroreceptor input through this mechanism, but also by an alternative mechanism i.v., by inhibition - of the activity of Nucleus Tractus Solitarius (NTS). Modified from Spyer (38).
celeratory neurons in the intermediolateral nucleus of the upper thoracic cord. These data confirm the concept that the ANS is composed of afferent fibers (chemoreceptor and baroreceptor fibers), centers of integration (medulla) and efferent fibers (sympathetic). Are the afferent fibers part of the ANS?
According to Koizumi and Brooks (20), although afferent fibers ‘are included in autonomic nerve trunks, these afferents serve the somatic as well as the autonomic system, except in a few cases _ . .’ For this reason, the afferent fibers are not considered as a part of the ANS. However, the visceral afferent fibers have their cell bodies located in the sensory ganglia of cranial nerves, e.g., the nodose ganglion of the vagus nerves, and in the dorsal root ganglia of the spinal nerves. If we consider these afferent fibers as part of the ANS, it would be easier to explain many autonomic reflexes, such as those involved in the control of circulation (baroreceptor reflex, Bainbridge reflex, Bezold-Jarisch reflex etc), in the physiology of the gastrointestinal tract (gastric secretion, vomiting, defecation etc.) But, if the afferent fibers are part of the ANS a question arises: is it possible that a visceral afferent evoke a somatic response? It has been often shown that this occurs many times. When a newborn child sucks milk there is a gastrocolic reflex,
SYSTEM
9.5
that is, a mass movement in the colon forces the fecal material into the rectum, where the defecation reflex occurs. It seems that this is a ‘pure’ autonomic reflex but the child ‘learns’ how to control the external anal sphincter and defecation becomes a complex behavior, involving contractions of the voluntary muscles (diaphragm and muscles of the abdominal wall) terminating in relaxation of the external anal sphincter. The same type of reasoning can be applied to other such as vomiting, micturicomplex behaviors, tion. copulation etc. Another interesting example is related to J receptors. These receptors are located in the lungs, in the interstitium between the epithelium and the endothelium (34). Stimulation of these receptors by an increase in pulmonary flow or by drugs (e.g. phenyldiguanide) evoke autonomic responses (bradycardia and hypotension) but, also, respiratory changes mediated by skeletal muscles. Injection of veratridine directly into the left ventricle or into a coronary artery evokes an autonomic reflex (Bezold-Jarisch reflex) characand hypotension; terized by bradycardia moreover, respiratory responses are also observed (apnea or tachypnea). Bilateral vagotomy prevents the autonomic and respiratory responses, indicating that both are reflex by nature (12, 23). The stimulation of baroreceptors by an acute increase of arterial pressure evokes bradycardia (due to an increase in vagal activity) and hypotension (due to both a decrease in sympathetic activity and in increase of cardiac vagal activity) but also a change in the respiratory system, such as an apnea (4). The Bainbridge reflex, caused by an increase in pressure in the atria, is expressed as tachycardia (25). The afferent fibers are in the vagus and the efferent fibers in the cardiac sympathetic nerves. An increase in the atria1 pressure also causes a diuretic effect which is not due to stimulation of efferent fibers of the Autonomic Nervous System. The afferent fibers are also located in the vagus but the diuresis is due, at least in part, to a decrease in the release of the antidiuretic hormone by the neurohypophysis ( 18). All these data clearly show that visceral reflexes evoke, also, complex physiological responses. In other words, the autonomic refiexes are not ‘pure’ in the sense that only autonomic fibers are stimulated. Another interesting question is whether a non-
96 visceral stimulus could evoke an autonomic response. There is no doubt about this and one of the best examples is the defense reaction (1, 3, 5, 19). Thus, visual or auditory stimulation can evoke complex autonomic and somatic responses (changes in blood pressure and heart rate; muscle vasodilatation, midriasis, hyperventilation, limb movements etc). Therefore, a visceral stimulus can evoke a somatic response, and a non-visceral stimulus can also elicit an autonomic effect. These facts would be explained by the absence of ‘pure centers’ for the control of autonomic and somatic systems. Actually, this association is desirable inasmuch the autonomic changes have to support the behavioral patterns. Central integration of ANS
Even the authors who consider the ANS as a pure efferent outflow system, accept that there is an important central control on it (10, 14, 20). For this reason, there is no point of discussion on this subject and we will only cite examples of central integration of the ANS: 1. Spinal cord: defecation and micturition in the newborn baby; 2. Medulla: ‘vasomotor center’, vomiting center, cardiac center, salivary center: hypoten3. Hypothalamus: Hypertension, muscle sron, cholinergic vasodilation, tachycardia, bradycardia, micturition, defecation etc; changes ac4. Limbic system: autonomic companying emotional behaviour (tachycardia, midriasis etc) 5. Reticular formation: an important example of integration in this area is the defense reaction, including behavioral cardiovascular and changes; 6. Cerebral cortex: cardiovascular changes (arterial pressure and heart rate), midriasis , gastric secretion etc. Some authors (20) state that the ANS is a pure efferent outflow system, which operates under the direction of higher centers. We think that these higher centers and the afferent visceral fibers are also parts of the ANS.
MEDICAL
HYPOTHESES
Another interesting question is whether higher centers always operate as a consequence of stimulus from afferent impulses, or are able to generate impulses by themselves. Is there autonomic discharge originated in the Central Nervous System?
The cardiac-related rhythm in sympathetic nerve discharge (2) had been considered by many investigators as a consequence of baroreceptor reflexes. But, other authors have shown that this rhythm is not generated in the spinal cord but rather in brainstem networks (6, 30). These data indicate that central networks are able to control the discharge. of preganglionic sympathetic neurones. But, what would be the action of the baroreceptors? Experiments indicate that the rhythm originated in the brainstem is entrained in 1: 1 relation to the cardiac cycle by the baroreceptor reflexes, which is highly suggestive that a cardiac nerve discharge is originated in the brainstem but is modulated by baroreceptor reflexes. This is another example of integration of the Autonomic Nervous System, with afferent fibers (baroreceptors), centers (brainstem) and efferent fibers (sympathetic discharge).
Concepts of the Autonomic Nervous System The Autonomic Nervous System (ANS) could be defined at least in four different ways (Table). 1. One group of investigators think of the ANS as a purely efferent system, being divided into 2 subsystems: sympathetic and parasympathetic. The visceral afferent fibers and the central control of the efferent fibers are not considered as parts of the ANS (10, 14, 20, 33). We think that this concept is not correct because it does not consider the afferent fibers as a part of the ANS. Recent data show that afferent fibers are very important to modulate release of hormones, such as insulin and glucagon, to regulate cardiovascular functions, such as heart rate, cardiac output and arterial pressure, to modify the renal function etc. 2. The ANS could be divided into 2 parts, the sympathetic and the parasympathetic, both of which composed of afferent and efferent fibers, besides the central integration for both systems (8, 28). This concept could be considered correct at a first glance but it is very difficult to change the mind of the majority of the investigators all
97
THE AUTONOMIC NERVOUS SYSTEM IS NOT A PURELY EFFERENT SYSTEM
Table Four different ways to define the Autonomic Nervous System Sympatheticsystem
1. AutonomicNervous System(efferent)
Parasympatheticsystem Afferent fibers
Sympathetic 2.
AutonomicNervousSystem
Efferent fibers Afferent fibers
Parasympathetic
Efferent
of Integration
3.
Visceral of Integration
4.
of Intergration
Autonomic or Neurovegetative
as purely as efferents,
at the of integration
as parts of the it seems to write or ‘parasympathetic to afferent
to say or
of the of Weiner
is a little different
in the
as it
to write or ‘parasympathetic 3. Another to define a mixture 1 and 2.
be to consider
of historical as only of sympathetic a more complex entity would arise, that is, the Visceral Nervous System, composed of of integration We it created a new concept of is different Autonomic 4. To us,
of As in
the the the
it as parts of a peripheral we should
nervous it viscerar In short be considered of the a central part, composed of of integration peripheral, composed of
of To us, a unique entity. to define
parts
of
be named in accordthe
or ‘efferent’. be splanchnic
is of integration
a
is a mixed nerve it should be described
98 by the names that identify each of the fiber groups included in the nerve. For example, the oculomotor nerve: 1 - somatic afferent or efferent fibers of the oculomotor nerve (eye movements); 2 parasympathetic fibers of the oculomotor nerve (pupillary constriction). In a mixed nerve such as the sciatic nerve, which also includes somatic and visceral fibers, the latter should be called sympathetic fibers of the sciatic nerve and visceral afferent fibers of the sciatic nerve. And last but not least, instead of “sympathetic afferent fibers” of the heart we should say afferent fibers of the cardiac nerves or even cardiac nerves afferents. Conclusions
We have shown in this article that the concept of the autonomic nervous system (ANS) as purely efferent does not seem to describe satisfactorily the patterns of its actions and mobilizing mechanisms. We suggest that the ANS should be rather considered as composed of functional modules comprising the visceral afferent components, the integrating centers and the visceral efferent components (sympathetic and parasympathetic). To avoid incorrect and confusing names such as the widely used terms “sympathetic afferents” and “parasympathetic afferents” the visceral fibers should be identified by adding @@rent or effrent to the particular nerves involved. Accordingly, afferents running in the splanchnic nerves, for example, should be termed splanchnic afferents, those conveying efferent impulses should be called splanchnic efferents and the corresponding fibers in the vagus nerves should be termed vagal afferents and vagal efferents, respectively. By the same token, the so called “sympathetic afferent fibers” of the heart should be better called cardiac nerves afferents. When more than one type of efferents run in a certain nerve, the adjectives sympathetic and parasympathetic should be added, such as in oculomotor nerve parasympathetic fibers and sciatic nerve sympathetic fibers. Acknowledgements The authors thank Prof. Cesar Timo-Iaria (USP, SHo Paulo), Prof. Ramon Cosenza (UFMG, Belo Horizonte) and Prof. Henriaue A. Futuro-Neto (UFES. Vit6ria) for their comments on a preliminary version of this manuscript and Mrs. Maria Celia da Silva Costa for typing the manuscript.
MEDICAL HYPOTHESES Research supported by FINEP (No. 43. 85. 0281.00) and CAFES (No. 047 UFMG) Brazil. The authors were recipients of CNPG fellowships.
References 1. Abrahams V C, Hilton S M, Zbrozyna A W. The role of active muscle vasodilatation in the alerting stage of the defence reaction. Journal of Phvsiolozv 171: 189-202. 1964. 2. Adrian E D, Bronk D W, Phillips G. Discharges in mammalian sympathetic nerves. Journal of Physiology 74: 115-133,1932. 3. Azevedo A D. The defence reaction in the rabbit. Ph.D. Thesis, University of Birmingham, England, 1981. 4. Azevedo A D, Cunha-Melo J R, Freire-Maia L. Arterial hypertension and pulmonary edema induced by catecholamines in unanesthetized rats. Pharmacological Research Communications 11: 157-167, 1979. 5. Azevedo A D. Hilton S M. Timms R J. The defence reaction elicited by midbrain and hypothalamic stimulation in the rabbit. Journal of Physiology 301: 56-57P, 1980. 6. Barman S M, Gebber G L. Sympathetic herve rhythm of brain stem origin. American Journal of Physiology 239 (Regulatory and Integrative Comparative Physiology 8): R 42-47, 1980. 7. Berger A J. The distribution of cat’s carotid sinus nerve afferent and efferent cell bodies using the horseradish peroxidase technique. Brain Research 190: 309-320, 1980. 8. Brobeck J R. Control of smooth muscle and exocrine glands. pg. 9.54-9.65 in Best and Taylor’s Physiological Basis of Medical Practice, 10th ed. (J R Brobeck, ed) Williams & Wilkins, Baltimore, 1979. 9. Bronk D W, Stella G. Afferent impulses in the carotid sinus nerve. Journal of Cellular and Comparative Physiology 1: 113-130, 1932. 10. Brooks C M. The autonomic nervous system, molder and integrator of function. Review of a concept. Brazilian Journal of Medical and Biological Research 14: 151-160, 1981. 11. Caverson M M, Ciriello J, Calaresu F R. Chemoreceptor and baroreceptor inputs to ventrolateral medullary neurons. American Journal of Physiology 247 (Regulatory and Integrative Comparative Physiology 16): R 872-R 879, 1984. 12. Chianca Jr.D, Cunha-Melo J R, Freire-Maia L. The Bezold-Jarisch-like effect induced by veratridine and its potentiation by scorpion toxin in the rat. Brazilian Journal of Medical and Biological Research 18: 237-248, 1982. 13. Coleridge H H, Coleridge J C G. Cardiovascular afferents involved in regulation of peripheral vessels. Annual Review of Physiology 42: 413-427, 1980. 14. Covian M R. Sistema nervoso autbnomo. pp 694-700 in Fisiologia Humana B A Houssay (V G Foglia, Coord. Geral), 5” ed. Tradu@o Brasileira (M R Covian), Rio de Janeiro, 1984. 15. De Groat W C, Nadelhaft I, Morgan C, Schauble T. The central origin of efferent pathways in the carotid sinus nerve of the cat. Science 205: 1017-1018, 1979. 16. Fulton J F. Levels of autonomic function in the, central nervous system. Livro de homenagem aos Prof. Alvaro e I.
THE AUTONOMIC
17.
18. 19. 20.
21. 22.
23 24. 25. 26.
27. 28. 29.
NERVOUS
SYSTEM IS NOT A PURELY
EFFERENT
Miguel Ozorio de Ahneida, Rio de Janeiro, pp. 257-270, 1939. Fulton J F. Autonomic Nervous System: central division. pp 241-254 in Howell’s Textbook of Physiology 15th ed. (J F Fulton, ed) W B Saunders, Philadelphia, 1946. Gauer 0 H, Henry J P. Circulatory basis of fluid volume control. Physiological Review 43: 423-481, 1963. Hilton S M. The defence-arousal system and its relevance for circulatory and respiratory control. Journal of experimental Biology 100: 1.59-174, 1982. Koizumi K, Brooks C M. The autonomic system and its role in controlling body functions. pp 893-922 in Medical Physiology. 14th ed. (V B Mountcastle, ed) The CV Mosby. St. Louis, 1980. Kostreva D R. Functional mapping of cardiovascular reflexes and the heart using 2- 4C Deoxyglucose. Physiologist 26: 333-350, 1983. Kostreva D R, Armour J A, Bosnjak I I. Metabolic mapping of a cardiac reflex mediated by sympathetic ganglia in dogs. American Journal of Physiology 249 (Regulatory Integrative and Comparative Physiology 18): R 317-R 322, 1985. Krayer 0. The history of the Bezold-Jarisch effect. Archiv fiir experimentelle Pathologie und Pharmakologie 240: 361-3681961. Langley J N. The autonomic nervous system. W. Heffer & Sons, Cambridge, 1921. Linden R J. Reflexes from the heart. Progress in cardiovascular diseases 18: 201-221, 1975. Loewy A D. Burton H. Nuclei of the solitary tract. Efferent projections to the lower brainstem and spinal cord of the cat. Journal of Comparative Neurology 181: 421450. 1978. Machado A B. Neuroanatomia Funcional. 1” ed. Atheneu, Rio de Janeiro, pp 105-123, 1974. Malliani A. Cardiovascular sympathetic afferent fibers. Review of Physiology, Biochemistry and Pharmacology 94: 11-74.1982. Malliani A, Recordati G, Schwartz P J. Nervous activity of afferent cardiac sympathetic fibers with atria1 and
30. 31. 32. 33. 34. 35.
36. 37.
38. 39.
40.
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ventricular endings. Journal of Physiology 229: 457-469, 1973. McCall R B, Gebber G L. Brain stem and spinal synchronization of sympathetic nervous discharge. Brain Research 89: 139-143, 1975. Mei N, Vagal glucoreceptors in the small intestine of the cat. Journal of Physiology 282: 485-506. 1978. Mei N. Arlhac A, Boyer A. Nervous regulation of insulin release by the intestinal vagal glucoreceptors. Journal of the Autonomic Nervous System 4: 351-363, 1981. Noback D R, Demarest R J. The Nervous System - Introduction and Review. 2nd ed. McGraw-Hill, New York, pp. 148-158, 1977. Paintal A S. A method of locating the receptors of visceral afferent fibers. Journal of Physiology 124: 166-172, 1954. Ricardo J A, Koh E T. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus. amygdala, and other forebrain structures in the rat. Brain Research 153: l-26, 1978. Sokoloff L. Relation between physiological function and energy metabolism in the central nervous system. Journal of Neurochemistry 29: 13-26, 1977. Sokoloff L, Reivich M. Kennedy C. Des Rosiers M H, Patlak C S, Pettisrew K D, Saturada 0. Shinohara M. The 14C deoxyglucose method for the measurements of local cerebral glucose utilization: theorv, procedure, and normal values-in the conscious and anesthetized albino rat. Journal of Neurochemistrv 28: 897-916. 1977. Spyer K M. Central nervous integration of cardiovascular control. Journal of Experimental Biology 100: 109-128, 1982. Weiner N, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. pp 66-99 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 7th ed. (A G Gilman, L S Goodman. T W Rail, F Murad. eds) Macmillan, New York, 1985. Woods, S C. Porte D. Neural control of the endocrine pancreas. Physiological Review 54: 596-619, 1974
(1990) 32,91-99 UK Ltd 1990
The Autonomic Nervous System is not a Purely Efferent System L. FREIRE-MAIA
and A. D. AZEVEDO”
Departamento de Farmacologia and “Departamento de Fisiologia e Biofihca, lnstituto de Citkcias Bioldgicas, Universidade Federal de Minas Gerais, Caixa Postal 2486, 30.161 - Belo Horizonte, MG-Brasil (Reprint requests to L F-M)
Abstract - The concept of the autonomic nervous system as purely efferent does not seem to describe satisfactorily the patterns of its actions and mobilizing mechanisms. It is herein suggested that the autonomic nervous system should be rather considered as composed of functional modules comprising the visceral afferents, the integrating centers and the visceral efferents (sympathetic and parasympathetic).
physiological since it would leave neurons stranded without innervation’. Actually, Langley (24) mentions, specifically on page 13, the central connections of the ANS in the following statement: ‘Both autonomic and somatic systems consist of central and peripheral parts’. However, the central connections of the ANS were imperfectly known, and for this reason the description of the system was mainly related to preganglionic and postanglionic nerve connections. Why did Langley (24) not include the afferent fibers as part of the ANS? Perhaps because the physiology of these fibers was not well known when he wrote his book, in 1921. Actually, only 11 years later Bronk and Stela (9) recorded, by the first time, action potentials in afferent fibers of the carotid nerve.
Introduction There are controversies among the authors on the concept of autonomic nervous system (ANS). The majority of the investigators and authors of Textbooks of Physiology state that the ANS is a purely efferent and peripheral system, because of the old concept of ANS described by Langley (24). This concept of a purely efferent system is clearly defined by Langle_y (24) on page 1 of his book, where he states: ‘The autonomic nervous system consists of the nerve cells and nerve fibres, by means of which efferent impulses pass to the tissues other than multinuclear striated muscie’. In accordance with Fulton (16) this has been interpreted ‘as meaning that one cannot extend the concept of autonomic system farther into the nervous system than the cell body of its preganglionic fibers; but such limitation is un91
92 Objectives
MEDICAL HYPOTHESES
of the article
We will try to show in this article that the ANS is composed not only of efferent visceral fibers, but also of centers of integration and afferent visceral fibers.
8
Efferent part of the ANS
Since the classical work of Langley (24), many investigators around the world have studied in detail the morphological, physiological, and pharmacological aspects of the efferent part of the ANS (sympathetic and parasympathetic systems) and for this reason, we will not discuss them in this article. Afferent part and central connections ANS
of the
For the purpose of this paper we will rather analyse several experiments performed by different authors, which give an idea of the role played by afferent fibers and the central connections in the control of complex physiological phenomena.
Vagal glucoreceptors and the insulin release. Mei (31) has shown that in anesthetized cats the activity of sensory vagal neurones, recorded in nodose ganglia .by means of extracellular glass microelectrodes, was stimulated by perfusion of the small intestine with glucose. The neurones were of the C type and were slowly adapting. Figure 1 (A) shows an example of a glucoreceptor discharge after perfusion with glucose of the small intestine, and the slow adaptation of discharge (Figure 1, B, C, and D). In a subsequent paper Mei et al (32) showed that glucose perfusion of the small intestine in anesthetized cats and rats produced a fast increase of insulin secretion which preceded the variation of glycemia (Fig. 2) and could be explained as a reflex effect evoked by stimulation of intestinal glucoreceptors. The afferent pathway of this reflex is represented by vagal fibers coming from the intestinal glucoreceptors and the efferent pathway involves chiefly parasympathetic fibers, but also sympathetic fibers. As far as the centers involved in the neural insulin regulation, data from several authors indicate that the ventromedial nucleus (VM) and the lateral hypothalamus (LH) may be implicated (32, 40). Figure 3 shows a schematic representation of the pathways involved in the nervous regulation of insulin release. This is a
Fig. 1 Activity of sensory vagal neurones, recorded in nodose ganglia of an anesthetized cat, after administration of glucose solution (10 g/l) in the small intestine. A, immediately after the end of injection (all the receptors were silent before the perfusion). B, C, and D, after 15 min., 30 min. and 60 min. respectively. According to Mei (31).
nice example of regulation of an important metabolic function, which involves afferent fibers, centers of integration and efferent fibers of the ANS. Vagal afferent fibers and the control of the circulation. Since the thirties several authors have been
studying the projections of sensory receptors into the central nervous system by means of electrophysiological techniques. bore recently, the horseradish peroxidase technique (7, 26) and deoxyglucose technique (36, 37) have been used to localize precisely the centers of integration of the ANS in the medulla, hypothalamus, cortex etc. Kostreva and coworkers used the deoxyglucose technique and obtained very interesting results, demonstrating that the stimulation of afferent vagal fibers and afferent fibers of carotid sinus evoke an increase in the metabolism of specific areas in the central nervous system, mainly in the region of the nucleus tractus solitarius. In a review article, Kostreva (21) summarizes several of the results obtained by his group in the following way: A. The authors stimulated the left cut central end of the vagus in an anesthetized dog, after section of the contralateral vagus nerve, and observed an increased glucose utilization by the left
THE AUTONOMIC
93
NERVOUS SYSTEM IS NOT A PURELY EFFERENT SYSTEM
VAGAL NERVES
&2_+,a Fig. 2 Rise of insulin and glucose blood levels after intestinal perfusion with glucose solution (100 g/l) in anesthetized rats (A) and cats (B). C, and C, control values; the arrow indicates the end of glucose perfusion. Note that the insulin levels (a---*) start to rise before the elevation of glucose levels (o----a). According to Mei et al. (32).
NTS. They also showed that the medial subnuclei of the left NTS was metabolically the most active part of the NTS, and that the inferior olivary nuclei and the external cuneate nuclei were also activated. However, the contralateral NTS did not increase its glucose utilization after the left vagus stimulation. B. The authors stimulated the left carotid sinus nerve in cats and dogs, and found that the projections into the CNS were different for these species. Thus, for the cat the structures involved were the ipsilateral dorsolateral NTS, the external cuneate nuclei bilaterally and the medial subnuclei of the NTS more rostrally, while for the dog the structures involved were the dorsolateral NTS, bilaterally, with the ipsilateral NTS presenting greater i_ncrease in activity. C. ‘Sympathetic’ afferents: the electrical stimulation of the central end of the left T3 white
1
INSULINRELEASE
Fig. 3 Schematic representation of afferent fibers, central connections and efferent fibers involved in the nervous regulation of insulin release. a, afferent vagal fiber; b, efferent vagal fiber; c, efferent splanhnic fiber; 1, absorption of glucose from the small intestine into the blood circulation; 2, direct effect of glucose on cells of the pancreas. VMH, ventromedial hypothalamus; LA, lateral hypothalamus. According to Mei et at. (32).
increased the glucose rami communicantes utilization in the ipsilateral lateral NTS, portions of the external cuneate nuclei, and portions of the inferior olivary nuclei. The data show that different parts of the NTS region are metabolically activated by different afferent stimulation. On the other hand, other investigators (26, 35) have demonstrated, in cats and rats, that the NTS sends efferent fibers both to inferior and superior levels, such as the spinal cord, the hypothalamus, amygdala and other forebrain structures, which, we assume, are involved in complex autonomic and behavioral patterns. Figure 4 shows a schematic diagram of the afferent and efferent projections of the NTS.
94
MEDICAL
AFFERENT A 5 GUSTATORY
E
TASTE
INPUT CELL
AFFERENTS
\
TO NTS
EFFERENT
OUTPUT
HYPOTHESES
FROM NTS
GROUP RESPIRATORY
/ FASTIGIAL
N.
N.AMBIGUUS
FOREBRAIN AMYGDALOID
N.
PERIVENTRICULAR N. THALAMUS
BARORECEPTORS BARORECEPTORS CEREBRAL
CAROTID
SINUS
CAHOTlD
CORTEX
PREOPTIC AREA
BARORECEPTORS
CHEMORECEPTORSA
4 Schematic representation Modified from Kostreva (21).
Fig.
MEDIAL
LPARAVENTRICULAR HYPOTHAL.
of afferent
FLOCCULUSof CEREBELLUM N,
input
VENTROLATERAL RETICULAR FORMATION
to Nucleus
Electrical stimulation of the carotid sinus nerve also evoked an increase in the utilization of glucose in the parabrachial regions of the pons, paraventricular nuclei of the hypothalamus and insular cortex, whereas stimulation of ‘sympathetic’ afferents also induced an activation of the preoptic and paraventricular nuclei of the hypothalamus. These data seem to indicate that integration of cardiovascular reflexes in the CNS is complex in nature, with activation of areas of medulla, pons, hypothalamus and cortex. Mapping of sympathetic ganglia: Many authors have shown that the sympathetic ganglia can mediate visceral reflexes without connection with the CNS. Thus, electrical stimulation of the vagal trunk, in deafferented ganglia preparations, evoked an increase in the glucose utilization in the middle, cervical and stellate ganglia, in an anesthetized dog. These data indicate that the decentralized ganglia are activated by cardiopulstimulation monary afferent (22). These experiments strongly suggest that the sympathetic ganglia are not a part of a purely efferent system and that they can mediate visceral reflexes, evoking an increase in the glucose utilization of specific areas of the heart. On the other hand the application of horseradish peroxidase to the central cut end of the carotid sinus nerve produces labeling of efferent neurons in the nucleus parvocellularis and the
Tractus
Solitatuis
(NTS)
BED
and efferent
NUCLEUSof TERMINALIS
output
STRlA
from NTS
retrofacial nucleus in the medulla, which would act as preganglionic parasympathetic neurons to carotid body (7, 15). These investigations indicate that the Autonomic Nervous System (ANS) is composed of afferent fibers, complex centers of integration and efferent fibers. An example of central integration of the ANS: the baroreceptor reflex
In a review article Spyer (38) studied the central nervous integration of autonomic functions. The baroreceptor influence on cardiac vagal motoneurones (CVM) is conducted by afferent fibers of the sinus and the aortic nerves, and is mediated by the nucleus tractus solitarius (NTS), as is shown in Figure 5. This Figure also shows an inhibitory influence of inspiratory neurones and hypothalamic defense area on the CVM. The defense area could inhibit also the transmission from NTS to CVM. Therefore, an increase in arterial blood pressure will evoke action potentials in afferent fibers, with projection to NTS in the medulla and activation of CVM, with a consequent bradycardia. This reflex can be blocked by hypothalamic defence area stimulation. On the other hand, it has been shown (11) that the neurons in the ventrolateral medulla receive chemoreceptor and baroreceptor afferents and in turn influence vasoconstrictor and cardioac-
THE AUTONOMIC
NERVOUS
SYSTEM IS NOT A PURELY
EFFERENT
Fig. 5
Schematic representation of the control of the baroreceptor input to cardiac vagal motoneurones (CVM). lnspiratory neurones (I) exert and inhibitory control (-) of CVM. The hypothalamic defence area may inhibit CVM activity (-) and block their baroreceptor input through this mechanism, but also by an alternative mechanism i.v., by inhibition - of the activity of Nucleus Tractus Solitarius (NTS). Modified from Spyer (38).
celeratory neurons in the intermediolateral nucleus of the upper thoracic cord. These data confirm the concept that the ANS is composed of afferent fibers (chemoreceptor and baroreceptor fibers), centers of integration (medulla) and efferent fibers (sympathetic). Are the afferent fibers part of the ANS?
According to Koizumi and Brooks (20), although afferent fibers ‘are included in autonomic nerve trunks, these afferents serve the somatic as well as the autonomic system, except in a few cases _ . .’ For this reason, the afferent fibers are not considered as a part of the ANS. However, the visceral afferent fibers have their cell bodies located in the sensory ganglia of cranial nerves, e.g., the nodose ganglion of the vagus nerves, and in the dorsal root ganglia of the spinal nerves. If we consider these afferent fibers as part of the ANS, it would be easier to explain many autonomic reflexes, such as those involved in the control of circulation (baroreceptor reflex, Bainbridge reflex, Bezold-Jarisch reflex etc), in the physiology of the gastrointestinal tract (gastric secretion, vomiting, defecation etc.) But, if the afferent fibers are part of the ANS a question arises: is it possible that a visceral afferent evoke a somatic response? It has been often shown that this occurs many times. When a newborn child sucks milk there is a gastrocolic reflex,
SYSTEM
9.5
that is, a mass movement in the colon forces the fecal material into the rectum, where the defecation reflex occurs. It seems that this is a ‘pure’ autonomic reflex but the child ‘learns’ how to control the external anal sphincter and defecation becomes a complex behavior, involving contractions of the voluntary muscles (diaphragm and muscles of the abdominal wall) terminating in relaxation of the external anal sphincter. The same type of reasoning can be applied to other such as vomiting, micturicomplex behaviors, tion. copulation etc. Another interesting example is related to J receptors. These receptors are located in the lungs, in the interstitium between the epithelium and the endothelium (34). Stimulation of these receptors by an increase in pulmonary flow or by drugs (e.g. phenyldiguanide) evoke autonomic responses (bradycardia and hypotension) but, also, respiratory changes mediated by skeletal muscles. Injection of veratridine directly into the left ventricle or into a coronary artery evokes an autonomic reflex (Bezold-Jarisch reflex) characand hypotension; terized by bradycardia moreover, respiratory responses are also observed (apnea or tachypnea). Bilateral vagotomy prevents the autonomic and respiratory responses, indicating that both are reflex by nature (12, 23). The stimulation of baroreceptors by an acute increase of arterial pressure evokes bradycardia (due to an increase in vagal activity) and hypotension (due to both a decrease in sympathetic activity and in increase of cardiac vagal activity) but also a change in the respiratory system, such as an apnea (4). The Bainbridge reflex, caused by an increase in pressure in the atria, is expressed as tachycardia (25). The afferent fibers are in the vagus and the efferent fibers in the cardiac sympathetic nerves. An increase in the atria1 pressure also causes a diuretic effect which is not due to stimulation of efferent fibers of the Autonomic Nervous System. The afferent fibers are also located in the vagus but the diuresis is due, at least in part, to a decrease in the release of the antidiuretic hormone by the neurohypophysis ( 18). All these data clearly show that visceral reflexes evoke, also, complex physiological responses. In other words, the autonomic refiexes are not ‘pure’ in the sense that only autonomic fibers are stimulated. Another interesting question is whether a non-
96 visceral stimulus could evoke an autonomic response. There is no doubt about this and one of the best examples is the defense reaction (1, 3, 5, 19). Thus, visual or auditory stimulation can evoke complex autonomic and somatic responses (changes in blood pressure and heart rate; muscle vasodilatation, midriasis, hyperventilation, limb movements etc). Therefore, a visceral stimulus can evoke a somatic response, and a non-visceral stimulus can also elicit an autonomic effect. These facts would be explained by the absence of ‘pure centers’ for the control of autonomic and somatic systems. Actually, this association is desirable inasmuch the autonomic changes have to support the behavioral patterns. Central integration of ANS
Even the authors who consider the ANS as a pure efferent outflow system, accept that there is an important central control on it (10, 14, 20). For this reason, there is no point of discussion on this subject and we will only cite examples of central integration of the ANS: 1. Spinal cord: defecation and micturition in the newborn baby; 2. Medulla: ‘vasomotor center’, vomiting center, cardiac center, salivary center: hypoten3. Hypothalamus: Hypertension, muscle sron, cholinergic vasodilation, tachycardia, bradycardia, micturition, defecation etc; changes ac4. Limbic system: autonomic companying emotional behaviour (tachycardia, midriasis etc) 5. Reticular formation: an important example of integration in this area is the defense reaction, including behavioral cardiovascular and changes; 6. Cerebral cortex: cardiovascular changes (arterial pressure and heart rate), midriasis , gastric secretion etc. Some authors (20) state that the ANS is a pure efferent outflow system, which operates under the direction of higher centers. We think that these higher centers and the afferent visceral fibers are also parts of the ANS.
MEDICAL
HYPOTHESES
Another interesting question is whether higher centers always operate as a consequence of stimulus from afferent impulses, or are able to generate impulses by themselves. Is there autonomic discharge originated in the Central Nervous System?
The cardiac-related rhythm in sympathetic nerve discharge (2) had been considered by many investigators as a consequence of baroreceptor reflexes. But, other authors have shown that this rhythm is not generated in the spinal cord but rather in brainstem networks (6, 30). These data indicate that central networks are able to control the discharge. of preganglionic sympathetic neurones. But, what would be the action of the baroreceptors? Experiments indicate that the rhythm originated in the brainstem is entrained in 1: 1 relation to the cardiac cycle by the baroreceptor reflexes, which is highly suggestive that a cardiac nerve discharge is originated in the brainstem but is modulated by baroreceptor reflexes. This is another example of integration of the Autonomic Nervous System, with afferent fibers (baroreceptors), centers (brainstem) and efferent fibers (sympathetic discharge).
Concepts of the Autonomic Nervous System The Autonomic Nervous System (ANS) could be defined at least in four different ways (Table). 1. One group of investigators think of the ANS as a purely efferent system, being divided into 2 subsystems: sympathetic and parasympathetic. The visceral afferent fibers and the central control of the efferent fibers are not considered as parts of the ANS (10, 14, 20, 33). We think that this concept is not correct because it does not consider the afferent fibers as a part of the ANS. Recent data show that afferent fibers are very important to modulate release of hormones, such as insulin and glucagon, to regulate cardiovascular functions, such as heart rate, cardiac output and arterial pressure, to modify the renal function etc. 2. The ANS could be divided into 2 parts, the sympathetic and the parasympathetic, both of which composed of afferent and efferent fibers, besides the central integration for both systems (8, 28). This concept could be considered correct at a first glance but it is very difficult to change the mind of the majority of the investigators all
97
THE AUTONOMIC NERVOUS SYSTEM IS NOT A PURELY EFFERENT SYSTEM
Table Four different ways to define the Autonomic Nervous System Sympatheticsystem
1. AutonomicNervous System(efferent)
Parasympatheticsystem Afferent fibers
Sympathetic 2.
AutonomicNervousSystem
Efferent fibers Afferent fibers
Parasympathetic
Efferent
of Integration
3.
Visceral of Integration
4.
of Intergration
Autonomic or Neurovegetative
as purely as efferents,
at the of integration
as parts of the it seems to write or ‘parasympathetic to afferent
to say or
of the of Weiner
is a little different
in the
as it
to write or ‘parasympathetic 3. Another to define a mixture 1 and 2.
be to consider
of historical as only of sympathetic a more complex entity would arise, that is, the Visceral Nervous System, composed of of integration We it created a new concept of is different Autonomic 4. To us,
of As in
the the the
it as parts of a peripheral we should
nervous it viscerar In short be considered of the a central part, composed of of integration peripheral, composed of
of To us, a unique entity. to define
parts
of
be named in accordthe
or ‘efferent’. be splanchnic
is of integration
a
is a mixed nerve it should be described
98 by the names that identify each of the fiber groups included in the nerve. For example, the oculomotor nerve: 1 - somatic afferent or efferent fibers of the oculomotor nerve (eye movements); 2 parasympathetic fibers of the oculomotor nerve (pupillary constriction). In a mixed nerve such as the sciatic nerve, which also includes somatic and visceral fibers, the latter should be called sympathetic fibers of the sciatic nerve and visceral afferent fibers of the sciatic nerve. And last but not least, instead of “sympathetic afferent fibers” of the heart we should say afferent fibers of the cardiac nerves or even cardiac nerves afferents. Conclusions
We have shown in this article that the concept of the autonomic nervous system (ANS) as purely efferent does not seem to describe satisfactorily the patterns of its actions and mobilizing mechanisms. We suggest that the ANS should be rather considered as composed of functional modules comprising the visceral afferent components, the integrating centers and the visceral efferent components (sympathetic and parasympathetic). To avoid incorrect and confusing names such as the widely used terms “sympathetic afferents” and “parasympathetic afferents” the visceral fibers should be identified by adding @@rent or effrent to the particular nerves involved. Accordingly, afferents running in the splanchnic nerves, for example, should be termed splanchnic afferents, those conveying efferent impulses should be called splanchnic efferents and the corresponding fibers in the vagus nerves should be termed vagal afferents and vagal efferents, respectively. By the same token, the so called “sympathetic afferent fibers” of the heart should be better called cardiac nerves afferents. When more than one type of efferents run in a certain nerve, the adjectives sympathetic and parasympathetic should be added, such as in oculomotor nerve parasympathetic fibers and sciatic nerve sympathetic fibers. Acknowledgements The authors thank Prof. Cesar Timo-Iaria (USP, SHo Paulo), Prof. Ramon Cosenza (UFMG, Belo Horizonte) and Prof. Henriaue A. Futuro-Neto (UFES. Vit6ria) for their comments on a preliminary version of this manuscript and Mrs. Maria Celia da Silva Costa for typing the manuscript.
MEDICAL HYPOTHESES Research supported by FINEP (No. 43. 85. 0281.00) and CAFES (No. 047 UFMG) Brazil. The authors were recipients of CNPG fellowships.
References 1. Abrahams V C, Hilton S M, Zbrozyna A W. The role of active muscle vasodilatation in the alerting stage of the defence reaction. Journal of Phvsiolozv 171: 189-202. 1964. 2. Adrian E D, Bronk D W, Phillips G. Discharges in mammalian sympathetic nerves. Journal of Physiology 74: 115-133,1932. 3. Azevedo A D. The defence reaction in the rabbit. Ph.D. Thesis, University of Birmingham, England, 1981. 4. Azevedo A D, Cunha-Melo J R, Freire-Maia L. Arterial hypertension and pulmonary edema induced by catecholamines in unanesthetized rats. Pharmacological Research Communications 11: 157-167, 1979. 5. Azevedo A D. Hilton S M. Timms R J. The defence reaction elicited by midbrain and hypothalamic stimulation in the rabbit. Journal of Physiology 301: 56-57P, 1980. 6. Barman S M, Gebber G L. Sympathetic herve rhythm of brain stem origin. American Journal of Physiology 239 (Regulatory and Integrative Comparative Physiology 8): R 42-47, 1980. 7. Berger A J. The distribution of cat’s carotid sinus nerve afferent and efferent cell bodies using the horseradish peroxidase technique. Brain Research 190: 309-320, 1980. 8. Brobeck J R. Control of smooth muscle and exocrine glands. pg. 9.54-9.65 in Best and Taylor’s Physiological Basis of Medical Practice, 10th ed. (J R Brobeck, ed) Williams & Wilkins, Baltimore, 1979. 9. Bronk D W, Stella G. Afferent impulses in the carotid sinus nerve. Journal of Cellular and Comparative Physiology 1: 113-130, 1932. 10. Brooks C M. The autonomic nervous system, molder and integrator of function. Review of a concept. Brazilian Journal of Medical and Biological Research 14: 151-160, 1981. 11. Caverson M M, Ciriello J, Calaresu F R. Chemoreceptor and baroreceptor inputs to ventrolateral medullary neurons. American Journal of Physiology 247 (Regulatory and Integrative Comparative Physiology 16): R 872-R 879, 1984. 12. Chianca Jr.D, Cunha-Melo J R, Freire-Maia L. The Bezold-Jarisch-like effect induced by veratridine and its potentiation by scorpion toxin in the rat. Brazilian Journal of Medical and Biological Research 18: 237-248, 1982. 13. Coleridge H H, Coleridge J C G. Cardiovascular afferents involved in regulation of peripheral vessels. Annual Review of Physiology 42: 413-427, 1980. 14. Covian M R. Sistema nervoso autbnomo. pp 694-700 in Fisiologia Humana B A Houssay (V G Foglia, Coord. Geral), 5” ed. Tradu@o Brasileira (M R Covian), Rio de Janeiro, 1984. 15. De Groat W C, Nadelhaft I, Morgan C, Schauble T. The central origin of efferent pathways in the carotid sinus nerve of the cat. Science 205: 1017-1018, 1979. 16. Fulton J F. Levels of autonomic function in the, central nervous system. Livro de homenagem aos Prof. Alvaro e I.
THE AUTONOMIC
17.
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27. 28. 29.
NERVOUS
SYSTEM IS NOT A PURELY
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