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23 Chapter 2 The role of the sympathoadrenal system in exercise Exercise calls for an acute increase in oxygen and fuel supply to the contracting muscle, and these needs are met through the sympathoadrenal (SA) activation of cardiorespiratory system and through the release and increased utilization of metabolic fuels. Increased metabolism during exercise can deplete fuel resources and exceed the capacity of homeostatic mechanisms to maintain constancy of interior environment. During the recovery from exercise, the parasympathetic (PS) and enteric divisions of the autonomic nervous system (ANS) coupled with various behavioral responses correct the deviations in the internal environment and mediate trophic and growth-promoting functions. Endocrine messengers control many of the same functions as does ANS in exercise. Although endocrine and autonomic systems are capable of acting in isolation, a fact that has fostered an artificial notion of their functional separation, in reality they work in concert and engage in complex reciprocal interactions. The ANS plays a central role in coordinating the neural and hormonal responses to exercise and recovery from exercise. Although the sympathetic (S) activation usually produces "fear, fight, or flight response" (Cannon, 1929), that is, a global activation of a large number of functions, it can also differentially activate only some actions in response to particular stressors such as hypoglycemia (Young et al 1984). Autonomic, endocrine and behavioral compensatory responses cooperate in regulation of the internal environment. This chapter addresses the functional role of the ANS and its involvement and interactions with the chemical messengers in exercise. Autonomic nervous system controls visceral functions necessary for the maintenance of the internal environment. It consists of three divisions: sympathetic (SNS), parasympathetic (PNS), and enteric (ENS). The functions of the three divisions of the ANS are to increase cardiorespiratory function and metabolism, biosynthetic processes, and nutrient digestion and absorbtion, respectively. The S and PS divisions include receptors, sensory nerves and associated ganglia, central nervous centers subserving integration of autonomic responses, and motor nerves and associated ganglia innervating the smooth muscles and endocrine and exocrine glands (the viscera), although traditionally only the motor component of this complex system has been recognized as ANS and discussed. The viscera are the origin of dual sensory input to the central nervous system via S and PS afferent neurons that travel along with efferent fibers in respective autonomic nerves. S receptors sense pain and PS receptors monitor chemical, endocrine and mechanical changes in the visceral organs. The smooth muscles and endocrine and exocrine glands receive dual motor innervation from both S and PS neurons with the exception of sweat glands which receive only S innervation. 23 24 Another feature of the ANS is that the autonomic efferent nerves consist of two nerve cells, a preganglionic and a postganglionic neuron (Figure 16). The PS preganglionic cells have longer axons than the S pregangionic neurons and synapse with postgangionic neurons in ganglia that lie close to, or within, the walls of smooth muscles and glands. The S preganglionic cells are shorter and form synapses in the ganglia in paired paravertebral sympathetic trunks adjacent to the spinal cord or in prevertebral ganglia (solar plexus) located at the points where celiac, superior, and inferior mesenteric arteries branch from the aorta. Figure 16. Composition and neurotransmitters of autonomic motor nerves. The autonomic efferent nerves consist of a preganglionic and a postganglionic cell. ACH is the neurotransmitter in preganglionic SNS and PNS cells, and it activates nicotinic receptors (NR) on postganglionic cells. Preganglionic PS cells are longer than S preganglionic cells because S ganglia are located some distance from target tissues and PS ganglia are located adjacent or inwalls of target tissues. Postganglionic PS cells use ACH as a messenger and it acts muscarinic receptors (MR). Postganglionic S neurons use NE as neurotransmitter, and adrenal medullary cells (developmentally derived from S postganglionic cells), a mixture of NE and E. Catecholamines (NE and E) activate adrenergic receptors (AR). ____________________________________________________________________ Both types of preganglionic neurons use ACH as a neurotransmitter and activate nicotinic cholinergic receptors on postganglionic neurons (Figure 16). The postganglionic PS neurotransmitter is ACH which activates muscarinic cholinergic receptors on target cells. The S postganglionic neurons release NE and predominantly act on alpha adrenergic receptors on target cells. The exception are fibers to the sweat glands which, like the postganglionic PS neurons, release ACH as a neurotransmitter 24 25 and act on muscarinic receptors. The chromaffin cells of the adrenal medulla differentiate under the influence of cortisol into endocrine cells capable of converting NE into E (Figure3). In addition to NE, other chemical messengers have been found in sympathetic postganglionic neurons. The neuropeptide Y (NPY, Pernow & Lundberg, 1988) and the ATP (Burnstock & Kennedy 1986) are colocalized with NE and are implicated in vasomotor control. The calcitonin gene-related peptide (CGRP) and the vasoactive intestinal polypeptide (VIP) are colocalized with ACH (Landis & Fredieu 1986) and participate in sudomotor control. The sympathetic division of the ANS. The S afferents transmit pain or nociceptive information from the viscera in S nerves to the higher brain centers where it reaches consciousness (Cervero & Foreman, 1990), and their cell bodies are in segmental dorsal root ganglia (Figure 17). In contrast to PNS, S afferent input contributes only 20% of fibers to the splanchnic nerves, and most of these fibers are unmyelinated. The S sensory fibers project to laminae I and V in the the spinal gray matter of the thoracic and upper two lumbar spinal segments. Here they are joined by ten times more numerous sensory fibers from receptors in the muscles and the skin. Because of the quantitatively limited afferent S input and convergence of visceral and the more numerous somatic afferents, visceral pain is generally referred to skin areas. The heart pain in angina pectoris is felt in the superficial areas of arms and upper chest, while the pain in esophagus, gall bladder and duodenum is referred to the overlying superficial areas of the body (Wall & Melzack, 1985). The visceral nociceptive information is transmitted in several centripetal pathways to the higher brain centers (Figure 18) from where the autonomic, emotional, and behavioral responses are organized. The lateral (LSTT) and medial spinothalamic tracts (MSTT) carry, respectively, the information about the location of the pain from neurons in laminae I and V, and about tonic aspects of pain, associated with motivational and emotional responses, from deeper parts of spinal gray matter to the ventroposterolateral and medial thalamus, respectively (Figure 18). The spinoreticular tract to pontine reticular formation, and the spinomesencephalic tract to brachium conjunctivum (BC) and the periaqueductal gray (PAG) in the pons, that end in thalamus and cortical pain areas, are additional relays for pain . Pain afferents also reach the lateral hypothalamic area (LHA) and brainstem nuclei (nucleus of the tractus solitarius, NTS and parabrachial nucleus (PB), that are involved in the central integration of autonomic function (Menetrey & Basbaum, 1987). 25 26 Figure 17. Anatomical arrangement of the S nerves The arrangement of afferent and efferent (right) S nerves form a spinal reflex arc. The bodies of visceral afferent neurons (left) are located in the dorsal root ganglia, and their central dendrites synapse with neurons in laminae I and V of the gray matter in the spinal dorsal horn. Their peripheral dendrite travels through the white ramus (WR) of the spinal nerve, the S ganglion, and splanchnic nerve to peripheral pain receptors. PS afferents can make contact with and influence postganglionic S neurons in prevertebral ganglia. S neurons that innervate blood vessels of the skin and muscle (A) terminate in the paravertebral ganglia. Their postganglionic cell leaves the S trunk in gray communicating rami (GR) and reach the skin in segmental somatic nerves. Preganglionic S neurons that innervate the gastrointestinal tract (B) traverse the paravertebral ganglia to form synapses with postganglionic cells in prevertebral gangia. Spinal internuncial neurons connect afferent and preganglionic neurons and are the anatomical basis of the simplest autonomic reflexes. ____________________________________________________________________ 26 27 Figure 18. Projections of the afferent S fibers S fibers carry information about visecral pain from laminae I and V of the spinal gray matter to the thalamus (A) in the lateral and medial spinothalamic tracts, to the brainstem reticular formation (B) in the spinoreticular tract, and to the BC and periaqueductal gray (C) in the spinomesencephalic tract. BC=brachium conjunctivum, IC=inferior colliculus, ML=medial lemniscus, NC= central nucleus of the thalamus, PT=pyramidal tract, PAG=periaqueductal gray, SC= superior colliculus, TG= tegmental gray in the brainstem reticular formation, VPL= ventroposetrolateral nucleus of the thalamus. _____________________________________________________________________ The outcome of S activation is increased cardiorespiratory function, constriction of all or selected vascular beds and mobilization and increased utilization of metabolic fuels. While definitive identification of circuits selectively responsible for these effects is not complete, a limitied number of forebrain and brain stem areas have been implicated 27 28 in the integration of autonomic sensory input and direct facilitation of S outflow. They are (Figure 19), insular cerebral cortex, paraventricular hypothalamic nucleus (PVN), A5 Figure 19. Brain controls of S outflow The excitatory brain areas with connections to preganglionic cells in the IML area of the spinal cord are insular cerebral cortex, paraventricular nucleus of the hypothalamus (PVN, plane A), the noradrenergic cell groups in the pons (A5, plane B) and medulla (A1, plane C), and RVLM and caudal raphe nuclei in the medulla (plane C).. IML=intermediolateral column of the spinal gray matter, PVN=paraventricular hypothalamic nucleus, raphe obscurus and pallidus =caudal raphe nuclei, RVLM= rostral ventrolateral medulla. ___________________________________________________________________ 28 29 noradrenergic cell group and reticular formation in the pons, and in the medulla, noradrenergic A1 cell group,caudal raphe nuclei (obscurus and pallidus) and reticular rostral ventrolateral medullary nucleus (RVLM). The insular cerebral cortex is involved in emotions of startle, fear and rage that influence cardiorespiratory function because of the connections with the hypothalamic and brainstem sympathoexcitatory circuit (Cechetto & Saper, 1990). The PVN is thought to be the key coordinator of the entire autonomic outflow (Brown & Fisher, 198 , Luiten et al., 1987, Strack et al. 1989) and through its chemically-coded neurons to play a key role in the regulation of body fluids and energy and immune responses (see later). Another hypothalamic area, the dorsomedial nucleus (DMN) has been implicated in patterning of respiratory and locomotor rhythm during exercise (Eldridge 1985, Marshall & Timms, 1980). The catecholamine A1 and A5 cell groups provide noradrenergic input, and A5 noradrenergic cells may control regional redistribution of blood from the viscera to themuscle (Stanek et al, 1984) that occurs during exercise. The caudal raphe nuclei provide serotonergic activating influence to S outflow. Raphe nuclei also contain TRH and substance-P releasing neurons (Guyenet 1990). A characteristic of these S centers is that they are tonically active, and the RVLM neurons in the medullary reticular formation that include NE fibers also impose a rhythmic discharge pattern to cardiac and respiratory neurons. The RVLM neurons are also responsible for the vasoconstrictor tone (Gebber 1990, Guyenet 1990, Loewy, 1990). The are caudal to the Botzinger complex that initiates and times respiratory movements (Richter & Spyer, 1990), and this provides a neural basis for the respiratory control over cardiovascular function. The brain areas that generate a S response are integrative centers that receive both S and PS input, project to both S and PS preganglionic neurons, and have complex reciprocal connections. The paraventricular hypothalamic nucleus (PVN) deserves special notice because of its central role in coordination of S responses, regulation of energy and fluid balance, and activation of immune response. The PVN has three functionally differentiated parts that can have discrete actions or act together. The lateral part of PVN (and the supraoptic nucleus, SO) are magnocellular (Figure 20), and their large cells synthetize hormones AVP or ADH and oxytocin (OXY), transport them in axons along with neurophysins I and II that are byproducts of prohormone processing, through the hypothalamohypophyseal stalk, and store them in posterior pituitary (Harris & Loewy, 1990). The AVP and OXY are released into capillaries of the inferior hypophyseal artery and reach systemic circulation through efferent veins. The magnocellular SO and PVN neurons discharge in a characteristic bursting pattern, and their coordinated discharge is facilitated by cell coupling through tight junctions . The two AVP secreting nuclei receive projections from brain areas involved in body fluid regulation and from autonomic centers that regulate cardiovascular function. Two of the eight circumventricular organs (CVOs) and MPON are structures involved in regulation of body fluids that have neural connections with PVN. The CVOs are brain areas without the blood-brain barrier with 29 30 receptors that allow them to monitor and, in chemical changes in systemic circulation Figure 20. Role of PVN in antidiuresis and cardiovascular control. The lateral, magnocellular part of the PVN along with the SO nucleus participates in release of AVP (and OXY). Sensory information from angiotensin II receptors in SFO, from osmoreceptors and sodium receptors in SFO and OVLT and from atrial receptors and arterial baroreceptors reaches the PVN and leads to release of AVP and antidiuretic action on the kidney. At higher stimulus intensities, greater amounts of AVP are released to also influences the cadiovascular system by enhancing baroreflex, increasing neurotransmission in S ganglia, and by causing 30 31 peripheral vasoconstriction. The circumventricular organs (ME, OVLT, PB, PP, OVLT, SCO, and SFO) are shown in the upper left . AVP= arginine vasopressin, ME=median eminence, OC=optic chiasm, OVLT= organum vasculosum of lamina terminalis, P=pineal gland, PP=posterior pituitary gland, PVN=paraventricular hypothalamic nucleus, SCO= subcommissural organ,SO= supraoptic hypothalamic nucleus. _____________________________________________________________________ some of them, in cerebrovascular space. Among the CVOs, AP is involved in the control of both food and fluid homeostasis and receives input from carotid baroreceptors, vagus, and dorsomedial and PVN hypothalamic nuclei. It sends projections to the commissural NTS and PB nucleus (Johnson & Loewy, 1990). The OVLT acts as central osmoreceptor and sodium receptor, and SFO has receptors for angiotensin II as well as osmoreceptors and sodium receptors. The cardiovascular involvement of the magnocellular PVN includes a tonic inhibition by atrial receptors and the baroreceptors, input from A1 noradrenergic cells secreting NE and NPY, C1 adrenergic cells acting on alpha1 receptors, and pontine and tegmental projections (Harris & Loewy, 1990). The AVP is secreted in response to hypovolemia signalled by atrial receptors, to fall in blood pressure detected by arterial baroreceptors, and to increased osmolarity detected by osmoreceptors. The AVP has two effects, an antidiuretic effect on the V2 receptors on distal convoluted tubules in the kidney (hence the term ADH), and at higher concentrations associated with massive fluid losses, a vasoconstrictor action. The vasoconstrictor effect is the outcome of threefold AVP action, on the brain (probably on the CVO AP) where it potentiates baroreflexes (Cowley et al., 1984), on the sympathetic ganglia where it enhances neurotransmission (Peters & Kreulen, 1985), and on the on V1 receptors on smooth muscle of blood vessels where it causes contraction (Altura & Altura, 1984). The AVP can also be released in response to activation of pain receptors (group III, myelinated and IV, unmyelinated) in muscles and their arteries, or by injection of bradykinin (Yamashita et al, 1984). This is the probable mechanism of reflex AVP release during intense isometric exercise . Reduction in muscle blood flow raises metabolite concentration and triggers a reflex increase blood pressure (metaboreflex) through muscle arteriole vasoconstriction caused by both by increased S discharge (Rowell & O'Leary, 1990) and increased AVP release. 31 32 Figure 21. Role of PVN in CRF release and in S elicitation of E secretion. The medial parvocellular part of the PVN (horizontal hatching) secretes CRF into hypophyseal portal vessels in the external layer of the ME. CRF stimulates release of ACTH from the anterior pituitary, and the ACTH, in turn, stimulates cortisol secretion from the adrenal cortex. The dorsal and ventral portions of the PVN (vertical hatching) are involved in activation of S outflow and adrenomedullary E secretion. Cortisol also stimulates biosynthesis of E in the adrenal cortex, and E stimulates ACTH secretion from the pituitary. __________________________________________________________________ The medial PVN contains small cells ("parvocellular") that synthesize CRF and secrete this hormone into the hypophyseal portal vessels in the external layer of the median eminence (ME, Figure 21). The CRF stimulates the anterior pituitary corticotrophs to secrete ACTH from the POMC precursor (Figure 12). The ACTH, in turn, stimulates cortisol secretion from the fascicular zone of the adrenal cortex (Figure 6). 32 33 Figure 22. Role of PVN in activation of immune response. The PVN controls S outflow to lymphoid organs, spleen, thymus, bone marrow and lymph nodes and release of activated immune cells from lymphoid organs. Monocytes and microphages release IL-I which stimulates CRF release from the parvocellular PVN. IL-1 may reach the PVN through circulation, by paracrine action from monocytes that migrate out of blood vessels into brain tissue, or from neural hypothalamic circuits that use IL-1 as a neurotransmitter. Besides its action on CRF neurons, IL-1 may directly stimulate ACTH production from pituitary corticotrophs. The cortisol that is released as a result of ACTH stimulation of adrenal cortex, inhibits IL-1 production probably through negative feedback at the PVN. ACTH=adrenocorticotropic hormone, CRF=corticotropin releasing factor, IL1=interleukin-1. __________________________________________________________________ 33 34 The parvocellular part of PVN is sensitive to corticosteroid feedback, and almost all of PVN stimulatory actions on food intake and ingestion of carbohydrates to NE stimulation of alpha2 receptors and to NPY administration (Tempel & Leibowitz, 1993) require glucocorticoid presence and feedback. Although the remaining dorsal and ventral portions of the PVN are involved in the activation of sympathetic outflow and adrenomedullary E secretion, their elicitation of E release (Figure 22) also depends on presence and action of CRF (Fisher et al. 1982). In effect, PVN appears to be one of the few brain centers that regulates the entire S outflow (Strack et al, 1989). In addition to the facilitatory role of CRF in S outflow from the PVN, cortisol also stimulates biosynthesis of E in the adrenal medulla and E stimulates ACTH secretion from the pituitary thus illustrating multiple reciprocal interactions between PVN endocrine and autonomic actions. The parvocellular PVN also plays two key roles in the control of immune responses (Figure 22). As the center controlling the S outflow, PVN is involved in the stimulation of lymphoid organs, spleen, thymus, bone marrow and lymph nodes which receive direct S innervation (Friedman & Irwin, 1997). An important outcome of such stimulation (Hori et al., 1995) during stress and exercise (Mackinnon 1992) is release of activated immune cells from lymphoid organs. The interleukin-1, a chemical mesenger released from activated macrophages and monocytes, triggers CRF release from parvocellular PVN (Berkenbosch et al. 1987). The IL-1 may reach PVN through circulation, by paracrine action from monocytes and microphages that migrate out of blood vessels into brain tissue, or from neural hypothalamic circuits that use IL-1 as a neurotransmitter. Thus in stress, the SNS activates the immune response, and the immune-system chemical messengers stimulate in turn the pituitary stress response. Besides its action on CRF neurons, the IL-1 may directly stimulate ACTH production from pituitary corticotrophs (Ruzicka & Akil, 1995). The cortisol that results from the ACTH stimulation of adrenal cortex, inhibits IL-1 production probably through a negative feedback at the PVN (Uehara et al. 1989). The cell bodies of S preganglionic neurons are located in the intermediolateral column (IML) of the spinal gray matter (Figure 17). Although there are about 25 pairs of segmental paravertebral ganglia extending from the cranial through the sacral end of the spinal cord, the preganglionic S nerves leave the spinal cord only through the 12 thoracic and the first two lumbar segments and thus form the thoracico-lumbar S outflow (Figure 23). From the IML column, their myelinated axons leave the spinal cord in white communicating rami to synapse on S ganglia. Some preganglionic fibers terminate on neurons in S trunk ganglia. The neurons destined to sweat glands, blood vessels and piloerector muscles of the skin, leave paravertebral ganglia through the gray communicating rami and travel in segmental somatic nerves (Figure 17). 34 35 Figure 23. General plan of autonomic ganglia and nerves. The superior cervical, middle cervical, stellate and about 22 pairs of segmental ganglia form the paired paravertebral S trunks adjacent to the spinal cord. The celiac, superior mesenteric, and inferior mesenteric ganglia are called prevertebral S ganglia (or solar plexus), and they lie some distance from the spinal cord at branching points of the celiac, superior mesenteric and inferior mesenteric arteries from the aorta. Preganglionic S outflow is through the thoracic and the first two lumbar segments. These neurons either form a synapse in the paravertebral ganglia or pass through these ganglia in greater thoracic (gtsn), lesser thoracic (letsn), lowest thoracic (ltsn), and lumbar splanchnic nerves (lsn) to form synapses in prevertebral S ganglia. Postganglionic S fibers then make contact with smooth muscles and glands throughout the body. The PS nerves leave the spinal cord in four cranial nerves, oculomotor (III), facial (VII), glossopharyngeal (IX) and vagus (X), and in pelvic splanchnic nerves arising in sacral spinal cord . The postganglionic PS neurons in the first three cranial nerves 35 36 innervate head and neck glands and smooth muscles, pelvic splanchnic nerves innervate genital organs and glands and the hind gut, and the vagus nerve all other visceral organs throughout the body. The geniculate, petrosal and nodose ganglia contain afferent cell bodies of facial, glossopharyngeal and vagus afferent fibers, respectively. __________________________________________________ The first three pairs of paravertebral ganglia, the superior cervical, the middle cervical and the stellate, are located in the neck, from where the postganglionic fibers from the first one innervate the eye, the glands and the smooth muscles of the head. When the SNS is activated during exercise or in stress, dilator muscles to the pupil contract causing pupilary dilatation (Loewy, 1990a). The fibers from the other two ganglia, along with the postganglionic neurons from the first five thoracic ganglia, project to the heart, lungs, bronchi and trachea as the thoracic S cardiac nerves (Figure 23). Some preganglionic S neurons do not form synapses in the paravertebral ganglia but instead travel (Figure 17) in splanchnic S nerves to prevertebral ganglia. The neurons from fifth through twelfth thoracic segments travel in the greater, lesser and lowest thoracic splanchnic nerves to synapse with postganglionic neurons in the celiac ganglion and in the adrenal medulla (Figure 23). Their postganglionic neurons then reach the foregut and its associated organs and the kidney. The preganglionic neurons from the third and fourth lumbar segments of the spinal cord travel in lumbar splanchnic nerves to the superior and inferior mesenteric ganglia. Their postganglionic neurons innervate, respectively, the mid-gut, and the hind-gut and the pelvic organs. The parasympathetic division of the ANS. The PS afferents principally convey sensory information from the viscera, the tongue, and the smooth muscle and participate in reflexes controlling lung inflation, heart rate, blood pressure, plasma volume, digestion, and energy regulation. Most of this sensory information does not reach cerebral cortex and is not consciously perceived. An exception is taste information that is consciously perceived and associated with affective states, and the role glucose and sodium receptors play in specific cravings, respectievly for sweet or salty substances in situations of energy deficit and sodium deficiency. The PS afferent fibers are about four times more numerous than the efferent fibers in the PS nerves (Prechtl & Powley, 1990). The cell bodies of PS afferent neurons are in the ganglia of cranial nerves (for instance, geniculate ganglion of the VII nerve, petrosal ganglion of the IX nerve, and nodose ganglion of the vagus nerve) and in the sacral dorsal root ganglia. The receptors innervated by PS afferent fibers include mechanoreceptors, chemoreceptors, special ion (sodium) receptors and hormone receptors. Four sets of mechanoreceptors monitor blood pressure in peripheral circulation 36 37 (Spyer, 1990). The high-pressure arterial baroreceptors in the carotid sinuses and the aortic arch, and the renal baroreceptors in the juxtaglomerular apparatus (JGA) sense changes in systemic blood pressure. The low-pressure atrial receptors at the confluence of great veins with the atria monitor changes in plasma volume and venous return to the heart. The stretch receptors in the lungs and the airways react to alveolar stretching. The arterial baroreceptors relay blood pressure information to the central nervous system (CNS) through the sinus nerve, a branch of glossopharyngeal nerve, and the other mechanoreceptors through the vagus nerve. Different receptors project both to discrete regions of the NTS and to a common integrative area (commissural NTS). The osmoreceptors, sodium receptors and angiotensin II and atrial natriuretic factor (ANF) receptors for hormones involved in body fluid homeostasis are located in CVOs (Johnson & Loewy,1990). The chemoreceptors monitoring changes in arterial pCO2 and pO2 are located in the carotid body, aortic sinus and the ventral surface of medulla oblongata. Additional chemoreceptors are located in the muscles where they monitor changes in the metabolic state (Kniffki et al. 1981) and promote cardiorespiratory responses to exercise (Kaufman et al 1983). Chemo- and mechanoreceptors that monitor stimuli associated with ingestion and digestion of nutrients include stretch receptors in the stomach, chemoreceptors in liver, stomach, duodenum, and brain that detect changes in concentration and availability of nutrients and hormones, and taste receptors. As all but taste are located within the gastrointestinal tract and associated organs or the brain areas receiving their afferents, they will be discussed in the section on the ENS. The taste receptors are chemoreceptors located on the tongue, epiglottis and soft palate (Figure 24). Taste receptors in the fungiform papillae on the anterior two thirds of the tongue relay sensory information in the chorda tympani nerve, a branch of the facial nerve. Taste information from the circumvallate and foliate papillae at the back of the tongue travels in lingual, a branch of the IX th nerve . Additional taste afferents from the epiglottis and soft palate travel, respectively in the vagus and a branch of the facial nerve. The taste afferents project to the most rostral part of the NTS, from where some projections go to the motor nuclei of cranial nerves that control chewing and swallowing, and the others ascend to PB nucleus (pontine taste area), hypothalamus (LH and PVN), limbic forebrain (CNA, BNST, and substantia innominata,SI), and taste area of the insular cortex (Loewy, 1990). 37 38 Figure 24. Taste afferents and their CNS projections Taste receptors in the anterior tywo thirds of the tongue, the posterior part of the tongue and the epiglottis and soft palate send afferent fibers, respectively, in branches of VIIth, IXth , and Xth nerves to the rostral NTS. From there taste information ascends to the pontine taste area (BC), hypothalamic nuclei controlling energy balance (LH and PVN), limbic forebrain (CNA, BNST, and SI) and cortical taste area (insular cortex). AC= anterior commissure, BC=brachium conjunctivum, BNST= bed nucleus of the stria terminalis, CNA= central nucleus of the amygdala, CT= chorda tympani, branch of VII nerve, DVN=dorsal vagal nucleus, GG=geniculate ganglion, GP=greater petrosal nerve, branch of VII nerve, LH= lateral hypothalamus, NA= nucleus accumbens, NG=nodose ganglion, NTS= nucleus of the solitary tract, PG=petrosal ganglion, PVN= 38 39 paraventricular nucleus of the hypothalamus, SI= substantia innominata. Figure 25. Projections of the afferent PS neurons The PS chemoreceptor and mechanoreceptor afferents project to discrete areas of the NTS as well as to a common integrative commissural area of this nucleus. The ascending connections of the NTS are with nuclei in medullary reticular formation (raphe, RVLM, and VMM nuclei); pons (BC, A5); mesencephalic central gray (see 39 40 Figure 19 C); hypothalamus (PVN, DM, and LH); limbic forebrain (CNA and BNST); and insular and prefrontal cerebral cortex. The PS preganglionic neurons in the DVN and NA receive projections from the cerebral cortex, hypothalamus, midbrain central gray, pontine nuclei and medullary reticular formation. AP= area postrema, APR=anterior periventricular region, BNST=bed nucleus of stria terminalis, CNA=central nucleus of amygdala, DM=dorsomedial hypothalamic nucleus, DVN=dorsal vagal nucleus, IML=intermediolateral cell column, LC= locus coeruleus, LH=lateral hypothalamic area, MCG=mesencephalic central gray, MPON=medial preoptic nucleus, NA=nucleus accumbens, NTS=nucleus of the solitary tract, PB=parabrachial nucleus, PVN=paraventricular hypothalamic nucleus, RVLM=rostral ventrolateral medulla, VMM=ventromedial medulla. Planes represent, respectively, A= forebrain septum, B= hypothalamus (diencephalon), C=pons, D=rostral medulla, E=caudal medulla, F=thoracic spinal cord. ___________________________________________________________________ The mechano- and chemoreceptors involved in the regulation of cardiorespiratory function, the gastrointestinal receptors, receptors in CVOs associated with fluid regulation, and taste receptors, all have projections to the NTS and its immediate vicinity. From the NTS, ascending nerve fibers make connections with the pontine and forebrain areas (Figure 25.) The cardiorespiratory afferents terminate in adjacent parts of the NTS as well as in a common commissural part of this nucleus. Afferents from the gastrointestinal organs converge in the same area. The area postrema (AP), one of the CVO that receives information from the hormone, sodium, osmo- and glucoreceptors in plasma and in cerebrospinal fluid, relays this information, as does the commissural NTS to the ascending central autonomic network (Loewy, 1990). The main parts of the integrative central autonomic network are, rostral ventrolateral (RVLM) nucleus in the medullary reticular formation; lateral parabrachial nucleus (PB) and noradrenergic A5 cell group in the pons; mesencephalic central gray (see Figure 18 C); paraventricular (PVN), dorsomedial (DM) nuclei and lateral area (LH) of the hypothalamus; central nucleus of the amygdala (CNA) and bed nucleus of stria terminalis (BNST) in the limbic forebrain; and prefrontal cerebral cortex. The PVN, LH, ventromedial hypothalamic nucleus (VMH), CNA and BNST are considered to be part of a central integrative autonomic circuit. The CNA connects with the medial prefrontal cortex that was shown to inhibit cardiorespiratory function (Cechetto & Saper, 1990). The descending projections from the central integrative autonomic circuit include mesencephalic central gray matter, locus coeruleus (LC), PB, NTS, dorsal vagal nucleus (DVN), nucleus ambiguus (NA), and IML (Luiten et al, 1985). The preganglionic cells of the efferent vagus nerve to the gastrointestinal organs and muscles of the upper alimentary canal and trachea are in DVN, while vagal cells supplying the heart and the respiratory muscles originate in the NA (Figure 25). 40 41 The enteric nervous system (ENS) and gastrointestinal hormones. The ENS is a diffuse network of sensory, internuncial, and motor nerve cells that that are located in several layers within the walls of the gut and associated hollow organs (Furness & Costa,1980). Although the heart and blood vessels are excluded from this definition, they also have neural plexuses with features similar to the ENS. The gastrointestinal hormones (Desbuquois, 1990) and their receptors represent the second chemical messenger system in the GI organs that parallels and communicates with another similar system in the brain (Pearse, 1969). Figure 26. Enteric autonomic nerve plexuses Enteric plexuses in the intestinal wall, moving from the mucosal to the serosal end are the periglandular, the submucous or Meissner's, the circular intramuscular, the myenteric or Auerbach;'s, the longitudinal intramuscular, and the subserous plexuses. ____________________________________________________________________ The gastrointestinal organs are supplied with receptors that monitor mechanical and chemical changes associated with ingestion and digestion of food. After the initial chemical stimulation of taste receptors, gastric distension is sensed by the stretch 41 42 receptors in the stomach wall ( Berthoud & Powley, 1992), and glucoreceptors (Nagase et al., 1993), amino acid receptors (Niijima & Meguid, 1995), osmoreceptors (Niijima, 1969) and sodium receptors (Contreras & Kosten, 1981) have been described in the liver (Lautt, 1980). The duodenum also has gluco- and sodium receptors (Walls et al., 1995), and receptors for several hormones appear to be located on the on vagal terminals or cell bodies of vagal efferents, among them cholecystokinin (CCK, Ritter et al., 1989), angiotensin II (Speth et al., 1987 ) , galanin (Calingasan & Ritter, 1992b) and others. The enteric plexuses in the intestinal wall, moving from the mucosal to the serosal end are the periglandular, the submucous or Meissner's, the circular intramuscular, the myenteric or Auerbach;'s, the longitudinal intramuscular, and the subserous plexuses (Figure 26). In the heart, there are cardiac and coronary plexuses. The intrinsic neurons in the autonomic plexuses use several peptidergic messengers (Pearse 1969, Costa et al. 1986). Most common in the submucous and myenteric plexuses are neurons using VIP and enkephalin as messengers, and CCK is the least common. Other neuropeptides in the ENS are somatostatin or somatotropin-releaseinhibiting factor (SRIF), dynorphin, NPY, substance-P and serotonin, and frequently more than one peptide is colocalized in the same neuron. There is differential chemical coding of neurons located in different GI plexuses (Costa et al. 1986). As is the case with other targets of ANS, ENS receives dual afferent and efferent innervation from SNS and PNS. The S afferents and efferents reach the GI organs through several sympathetic splanchnic nerves (Figure 23). The NE fibers inhibit GI motility and ganglia embedded in the plexuses and increase contraction of sphincters. The SNS fibers colocalizing with NPY vasoconstrict splanchnic circulation, and the fibers containing NE and somatostatin inhibit GI secretion (Costa et al. 1986). The PS afferents and efferents innervate the foregut and midgut through the vagus, and the hindgut and reproductive organs through the pelvic splanchnic nerves. The PS ganglia and postganglionic cells are embedded within the ENT plexuses (Willems et al. 1985). The cholinergic fibers stimulate myenteric (Holst et al. 1997) and submucous ganglia (Berthoud et al., 1991), gastric motility, and GI secretory activity. The mucosa of the stomach and intestine contains endocrine cells that produce a number of different hormones (Desbuquois, 1990). Serotonin and somatostatinsecreting cells are found throughout the entire extent of GI tract. The cells producing secretin, cholecystokinin (CCK), gastrin colocalized with CCK, beta-endorphin, neurotensin, and gastric inhibitory peptide (GIP) are mostly found in duodenum and jejunum, and glucagon-secreting cells are more prevalent in jejunum, ileum, and colon. Most of the GI cells producing hormones communicate by endocrine route, and secretin was the very first hormone discovered by Bayliss and Starling in 1902. Some GI hormones are distributed by endocrine as well as paracrine route (SRIF), and a few of them are also released into the GI lumen (gastrin, SRIF, secretin). 42 43 The function of GI hormones is to control digestion of food and GI growth. The digestion is achieved through the control of gut motility, splanchnic circulation, modulation of the pH of the chyme (mixture of food and gastric secretions), and secretion of enzymes and hormones. The hormones that increase GI motility are motilin, SP, CCK, and enkephalins, while secretin, glucagon, VIP, GIP, NPY, and neurotensin inhibit it. Almost all of the GI hormones stimulate GI blood flow, particularly SP and neurotensin, except NPY which is a potent vasoconstrictor. Figure 27. GI endocrine reflexes in control of digestion Serial elicitation of GI hormone release by the passage of food through the GI tract. Food elicits gastrin release, and fat and protein the release of CCK. Both hormones stimulate gastric motility and CCK causes contraction of gall bladder and release of bile acids necessary for the emulsification of fats. Gastrin action is to release hydrochloric acid as the preliminary step in digestion of proteins. The acidity of chyme is the stimulus for secretin release from duodenum, and its action is to trigger secretion of bicarbonate and digestive enzymes from the pancreas. Many GI hormones facilitate the release of insulin with the exception of SRIF which inhibits it. The GI hormones released early in the digestive process stimulate release of other GI hormones. Those released late in the digestive process inhibit the secretion of GI hormones. __________________________________________________________________ Food digestion is facilitated by a series of GI endocrine reflexes (Figure 27). The 43 44 ingested food constitutents are the principal stimulus for the release of gastrin, CCK, motilin, GIP, SRIF, and neurotensin, and in the case of CCK, fats and amino acids. These hormones are released serially according to their regional distribution throughout the GI tract. The initial release of gastrin results in secretion of hydrochloric acid which lowers the pH of the chyme to 2 and aids in the initial digestion of proteins. Increased acidity of chyme is the stimulus for the subsequent release of secretin, the effect of which is secretion of bicarbonate (and of digestive enzymes) from the pancreas and the restoration of neutral pH of the chyme. The dietary fats trigger the release of CCK, and the main CCK action is to release bile acids from the gall bladder and assist in emulsification and digestion of fats. The food also triggers secretion of SRIF throughout the GI tract and of enteroglucagon from the colon. These two hormones as well as serotonin, inhibit secretion of gastrin and of gastric acid secretion. SRIF also inhibits secretion of all other GI and pancreatic hormones. The presence of SRIF is necessary for the GIF, VIP, and GIP to inhibit gastrin release. All GI hormones stimulate secretion of pancreatic insulin, pancreatic polypeptide (PPP), glucagon, and SRI, known also as the incretin effect. Thus GI hormones that are released early in the digestive process facilitate the release of GI and pancreatic hormones released subsequently, and the action of hormones released later in digestive process is to terminate the early steps of this endocrine cascade (Figure 27). Autonomic reflexes. The simplest form of autonomic action is a reflex. A number of reflexes controlled by the ANS operate autonomously or as part of complex neuroendocrine and behavioral responses to disturbance in the internal environment. Some of the more common cardiorespiratory and endocrine reflexes are listed below . Atrial mechanoreceptor reflex is a response to change in plasma volume detected by the low-pressure baroreceptors at the junction of venae cavae with the atria. The Increases in venous return produce bradycardia and reduced vasomotor tone, particularly to the kidney, and diuresis. The latter is in part a result of increased glomerular filtration rate and in part a response to the reflex release of atrial natriuretic peptide (ANP). Baroreflex normalizes systemic blood pressure when it has deviated outside the normal range (Spyer, 1990). The discharge rate of the carotid and sinus nerve afferent fibers innervating arterial high-pressure baroreceptors is directly proportional to arterial blood pressure and triggers reflex reduction in peripheral vasoconstriction, particularly in the muscle and less so in the skin, and in heart rate (bradycardia) and heart contractility (Figure 28). The reflex arc entails a baroreceptor afferent projection to NTS and an efferent vagal output from NA. At the same time baroreceptors exert an inhibitory influence over the S cardioaccelerator nerves by way of internuncial neurons in the medial prefrontal cortex and CNA that suppress the rhythmic cardiac and vasomotor drive from the medullary reticular formation (RVLM and raphe nuclei). 44 45 Figure 28. The baroreflex The discharge rate of carotid sinus and aortic arch baroreceptors is proportional to arterial blood pressure, while in the S cardiac nerves it is inversely proportional. The cell bodies of the afferent neurons innervating the two baroreceptors are, respectively, in petrosal and nodose ganglia and their dendrites project to NTS in sinus and aortic nerves. The inhibition of the heart rate and contractility, and reduction in vasoconstriction of blood vessels, is carried out by vagus with preganglionic neurons in NA. Baroreceptors also activate internuncial neurons that inhibit the RVLM nucleus, the origin of cardiovascular S drive. NA= nucleus accumbens , NG=nodose ganglion of the X nerve , NTS=nucleus of the tractus solitarius, PG=petrosal ganglion of the IX nerve, RVLM=rostral ventrolateral 45 46 medulla, S=sympathetic Chemoreceptor reflex is a response to reduced arterial oxygen partial pressure (pO2) detected by aortic sinus and carotid body chemoreceptors and to increased carbon dioxide partial pressure (pCO2 ) monitored by cells on the ventral surface of the medulla. It corrects these deviations through increases in minute ventilation (VE) and cardiac output (Q), and to a lesser extent through changes in vasoconstriction. The internuncial integrative circuits involve (Richter & Spyer, 1990) cardiovascular and respiratory nuclei in the medulla (Figure 25, planes D and E) that act in coordinated and cooperative fashion, and the inhibitory vagal influence from the NA . Neurons in Botzinger complex that are responsible for initiation and timing of respiratory rhythmsare adjacent and rostral to the RVLM nucleus that initiates and times cardiovascular function so that functional interactions, and subordination of cardiovascular function to respiratory control, as is the case in diving reflex, has an anatomical basis. The patterning of cardiovascular and respiratory responses during exercise is also linked and apparently controlled by posterior hypothalamus or dorsomedial hypothalamus (Eldridge et al., 1985, Saper et al., 1976, Wardrop et al., 1988). Diving reflex entails vagal suppression of the Q and of respiratory drive and bronchoconstriction, mediated by the vagus nerve (Kawakami et al. 1967, Kobayashi & Ogawa, 1973). The PS afferent discharge in the facial (VII) nerve to cooling of the face initates the reflex that subordinates the chemoreceptor signals of reduced pO2 and increased pCO2 to respiratory breath-holding. Reflex is well expressed in diving mammals and less so in humans. Metaboreflex entails vasoconstriction in response to build-up of metabolic products in the muscle during ischemia that is associated with isometric muscle contractions. It was described in the preceeding section. Orthostatic or postural reflex entails redistribution of blood to the head and upper regions of the body after a change in body position from recumbent to upright. It utilizes afferent input from baro- atrial mechano- and chemoreceptors. Postural hypotension is the condition where the orthostatic reflex operates sluggishly causing transient cerebral ischemia and dizziness. Sudomotor reflex also is a component of thermoregulatory response. It involves reflex activation of eccrine sweat glands by the cholinergic sympathetic neurons. Temperature change is detected by somatic temperature-sensitive neurons in the skin or in the central nervous system. A greater change in internal or external temperature is required to elicit this reflex than the vasomotor reflex (Stolwijk & Hardy, 1977). Vasomotor reflex is a component of thermoregulatory response. It involves reflex changes in the degree of vascular constriction in response to changes in blood or ambient temperature and in selective constriction of peripheral or deep limb veins in response to cold or hot stimulus, respectively. Changes in vascular tone are achieved 46 47 through variation in the degree of vasoconstrictive S action. Temperature change is detected by somatic temperature-sensitive neurons in the skin or in the central nervous system. Selective activation of S motoneurons to skin blood vessels and not to muscle vascular beds is controlled by the A5 noradrenergic cell group (Stanek et al., 1984, Figure 25, plane C) and by the RVLM nucleus (Dampney & McAllen, 1988, Figure 25, plane D) in response to thermoregulatory challenge. The central control of thermoregulatory reflexes involves integration of afferent input from central and peripheral thermoreceptors. Hypothalamic nuclei that also control body fluid balance and hypothalamic areas responsible for S activation and heat production are involved in the interaction, but the anatomical and functional details are poorly understood (Strand et al 1986). Autonomic control of endocrine reflexes. There are numerous and complex reciprocal interactions between the ANS and the endocrine systems. Only a few of these interactions will be mentioned here to show their relationship to the ANS function. Additional details and more extensive discussion of these reflexes can be found in the chapters dealing with receptor mechanisms (3), exercise as an emergency (4), regulation of fuel use during exercise (5), and temperature and fluid balance during exercise (8). Adrenomedullary catecholamine release. The adrenomedullary catecholamine release is triggered by the action potentials in preganglionic neurons originating in the last three thoracic and first lumbar spinal segments (Figures 21, 23) that reach the adrenal medulla through the lesser and lowest splanchnic sympathetic nerves. They communicate through transmission of ACH and act on nicotinic receptors. Some preganglionic neurons form synapses in the celiac ganglion and send postganglionic fibers to blood vessels supplying the adrenal gland. They release NE and act on alpha adrenergic receptors. Adrenal medulla also receives PS innervation through the two celiac branches of the vagus nerve (Berthoud & Powley, 1993). The central control of adrenomedullary hormone release (Edwards, 1990) is mediated by hypothalamic (PVN, Figure 19, plane A) and medullary nuclei (caudal raphe, RVLM, VMM, and A5, Figure 19, planes B and C). This reflex is elicited by glucoprivation with concurrent supression of the S activity (Egawa et al. 1989, Ritter et al. 1995) , a response that is mediated by the PVN (Katafuchi et al. 1988). This reflex is elicited during exercise together with activation of the SNS (Young & Landsberg, 1983). The adrenomedullary catecholamines have cardiorespiratory and metabolic actions. Both E and NE can activate either of two principal types of adrenergic receptors, alpha and beta, but NE has higher affinity for alpha receptors while E has higher affinity for beta receptors (Parkinson, 1990). Receptor distribution varies by tissue types, which together with differential receptor affinities for the two hormones allows for diverse biological effects. The two principal receptor types can be subdivided 47 48 into several variants. Table 6 lists the principal adrenergic receptor types, their biological effects, and some commonly used receptor agonists and antagonists.. Figure 29. Renin-angiotensin-aldosterone reflex When blood pressure declines, renal S nerve triggers and potentiates renal release of renin to hypovolemic stimulus. Renin converts circulating angiotensinogen into angiotensin I. The endothelial converting enzyme transforms the angiotensin I into angiotensin II. The angiotensin helps expand plasma volume through three actions. It 48 49 stimulates release of aldosterone from the adrenal cortex with the consequent increased renal sodium reabsorbtion. It binds to the SFO, one of the circumventricular organs and stimulates the magnocellular hypothalamic nuclei (SO,PVN) to release ADH. Finally it enhances neurotransmission in the S celiac ganglion which causes renal vasoconstriction and reduced glomerular filtration rate. ___________________________________________________________________ The adrenomedullary and adrenocortical hormones have reciprocal interactions. While cortisol permits E synthesis, E stimulates pituitary ACTH release which in turn triggers cortisol release (Figure 21). This positive feed-back loop may operate under stressful conditions, including extreme exercise, when actions of both hormones are complementary and beneficial. Antidiuretic endocrine reflex of the posterior pituitarywas described in the context of magnocellular PVN functions Reflex release of plasma renin to hypovolemia. The loss of sodium from the extracellular compartment with the consequent reduction in plasma volume is sensed by the baroreceptors in the JGA, the specialized contact area between the ascending limb of the kidney tubule (macula densa) and the afferent arteriole to the glomerulus. The renal S nerve activity triggers renin secretion and potentiates its release to hypovolemic stimuli (Kopp & DiBona, 1993, Saxena et al., 1992). The granular cells of the afferent arteriole secrete renin, the principal action of which is to catalyze conversion of plasma angiotensinogen into angiotensin I (Figure 29). The converting enzyme in the vascular endothelia converts angiotensin I to the biologically active angiotensin II. Angiotensin II stimulates secretion of aldosterone from the external glomerular zone of the adrenal cortex and thereby increases reabsorbtion of sodium from tubular lumen into plasma. It also potentiates the neurotransmission in the celiac ganglion causing renal vasoconstriction and reduced glomerular filtration rate. The angiotensin II binds to the SFO and stimulates PVN and SO nuclei to release ADH. By increasing sodium and water reabsorbtion and reducing glomerular filtration, this reflex leads to expansion of plasma volume. Finally, this messenger elicits both thirst and sodium hunger by acting on the CVO angiotensin II receptors. Autonomic control of pancreatic hormone release. The endocrine pancreas is innervated by the preganglionic vagal fibers originating in DVN, preganglionic S fibers from fifth through ninth thoracic segments and postganglionic S fibers originating in the celiac ganglion. During exercise or other circumstances that elicit increased S outflow, NE from S nerve terminals inhibits insulin secretion by acting on alpha2 receptors on beta cells of pancreatic islets and stimulates glucagon and SRIF release by acting on alpha1 and beta receptors located on alpha and delta cells, respectively (Edwards, 1990). The stimulation of beta adrenergic receptors has a stimulatory effect on insulin release. The integrative centers needed for the reflex increases in hepatic 49 50 glycogenolysis and in E and glucagon release during glucoprivation are NTS, lateral PB, LC, AP, PVN, and DVN ( Ritter & Dinh, 1994) with the NTS and AP playing the more critical role (Calingasan & Ritter, 1992 a). The PVN also is the site of receptors where NE, NPY and cortisol increase (Tempel & Leibowitz, 1993), and serotonin (Leibowitz et al. 1993) and CRF decrease carbohydrate intake (Bray 1993) after glycogen depletion. Reduced oxidative utilization of lipids is monitored by different set of peripheral receptors, peptide mediators (Akabayashi et al. 1994) and brain nuclei governing selection of dietary fat (Ritter & Dinh, 1994). During ingestion of food, cephalic-phase insulin secretion occurs before the arrival of absorbed food into the blood. It is triggered by hepatic and intestinal glucoreceptors and the respective branches of vagus (Berthoud & Powley, 1990). Upon absorbtion, increased plasma concentrations of nutrients directly stimulate insulin, glucagon, and pancreatic polypeptide secretion and inhibit SRIF release .In addition, intestinal and hepatic glucoreceptors elicit reflex vagal stimulation of insulin and glucagon secretion by acting on cholinergic muscarinic receptors while the activity of hepatic splanchnic nerve is decreased . Concurrently the hepatic branch of the vagus is also activated and stimulates glycogen synthesis (Niijima, 1989). The role of autonomic nervous system in exercise. From the preceding discussion of the functional properties of the ANS it is now possible to highlight its several important roles in exercise. In evaluating the evidence for the role of ANS in exercise it is useful to be reminded of limitations of different methods used to assess ANS activity. Direct measurements of catecholamines in circulation do not identify the relative contributions of the SNS and the adrenal medulla, as the medulla secretes both catecholamines, and at high exercise intensities, NE (Leuenberger et al., 1993) and NPY (Kaijser et al., 1994) spill over from the nerve endings into plasma. Without additional information about NE appearance and clearance rates, circulating concentrations give limited information. Measurements of arteriovenous NE differences circumvent this limitation. Daily urinary catecholamine output is another valid way to quantify sympathoadrenal activity but is of limited use in studies examining S control in exercise. Pharmacological blockade and stimulation can yield useful information when direct effects of such manipulations on physical performance are assessed and controlled. An indirect method of estimating PS and S activity in exercise is spectral analysis of heart rate variability (Yamamoto & Hughson, 1991). It entails separating total spectral power (Pt) of HR variability into harmonic and nonharmonic components, and harmonic component into high (Ph) and low frequencies. (Pl). The ratios of Ph/Pt and Pl/Pt then represent respective measures of PS and S effects on the heart, and by implication on the rest of the body. Direct measurements of S nerve activity have also been done on the limbs (Saito, 1995). 50 51 The three most important roles of the ANS in exercise are, its coordination of several different physiological functions during exercise, its capacity to increase physiological responses in anticipation of actual needs, and its capacity to maintain constancy of the internal environment by compensating for the perturbations caused by exercise. The integrative role of catecholamines is inherent in their ability to directly affect a number of different processes. The SNS and the adrenal medullary hormones control the chronotropic (HR) and inotropic (heart contractility) functions of the heart, contraction of vascular beds and as a consequence, blood pressure and redistribution of blood from the splanchnic beds to muscle during exercise. The SNS and the adrenal medullary hormones also control mobilization and utilization of metabolic fuels, and reflecting the evolutionary function of physical activity in fight or flight situations, controls over defense reactions such as aggregation of platelets ( Larsson et al., 1994) that is important in blood clotting, and activation of cells mediating immune responses. The ANS contributes also to general arousal, increased pupillary diameter, piloerection, and release of endogenous opiates that have analgesic functions. Finally, the sympathoadrenal system engages other endocrine systems in support of its cardiorespiratory, circulatory and metabolic functions in exercise, and these will be explored in greater detail in later chapters. The anticipatory function of the ANS is seen in increased cardiorespiratory function prior to the onset of physical activity (Mason et al., 1973) and in the dosedependent release of catecholamines in proportion to the intensity or stressfulness of exercise. While both the S nerve activity and adrenal catecholamines increase with exercise intensity (Figure 30) , E requires greater stimulus intensities for its release than is the case for S activation. The PS tone declines at low exercise intensities (Nakamura et al. 1993) and increases during the recoveryphase when it can lead to post-exercise fall in blood pressure (Halliwill et al.,1996) or increase in anabolic and biosynthetic functions. The systematic relationship with exercise intensity is also seen in a number of hormones that are released during exercise and are influenced by S nerve activity such as dose-dependent decreases in plasma insulin and increases in secretion of glucagon (Saltin & Gollnick, 1988 ), cortisol , ACTH , aldosterone (Luger et al., 1988 ), AVP among others. The third important role of the ANS in exercise is its regulation of the internal environment during exercise and recovery from exercise. During exercise, homeostatic control mechanisms often undergo readjustment to meet increased functional demands of exercise. For instance baroreflex is reset to a higher pressure level to operate at increased blood pressure ranges encountered during exercise ( Rowell & O'Leary, 1990). As exercise creates disturbances in the internal environment, the ANS generates corrective reflexes or more complex responses. The priorities for maintenance of different aspects of the internal environment shift during exercise. Increased heat generated by muscle activity leads to excessive heat gain which is counteracted by vasomotor and sudomotor reflexes and appropriate thermoregulatory behaviors. As a 51 52 consequence of increased sweating, an imbalance develops in body fluid volume. Conservation of plasma volume through AVP or renin-angiotensin-aldosterone reflexes now assumes higher priority than the regulation of body temperature. Figure 30. Time course and dose-dependence of the sympathoadrenal exercise responses to A conceptual illustration of changes in the relative activities of S and PS nerves and in secretion of adrenomedullary E as a function of intensity or duration of exercise and during recovery from exercise. At the start of exercise, PS tone declines and is transiently increased during recovery when it participates in restorative biosynthetic actions. At the start of exercise, S tone increases in proportion to intensity or stressfulness of exercise. Higher exercise intensities are required to elicit E secretion which also is secreted in dose-dependent fashion. The decay of S nerve activity is faster than the disappearance of E from circulation. ______________________________________________________________________ The control by the sympathoadrenal system of fuel mobilization and use during exercise changes as a function of exercise intensity and duration (Young & Landsberg, 1983). These changes reflects variable contributions of alpha and beta receptor stimulation as the relative activities of S nerves and adrenal E change under different conditions of exercise. During the early stage of exercise or at low exercise intensities, increased S nerve activity and NE release from the nerve terminals (Figure 30) results 52 53 in predominant stimulation of alpha adrenergic receptors in the liver and the adipose tissue (Table 6). These conditions facilitate hepatic glucose production via the gluconeogenic Cori cycle, increased muscle glucose uptake and glycolysis and low level of lipid utilization due to inhibitory alpha adrenergic effects on lipolysis and lack of transport of FFAs from vasoconstricted splanchnic vasculature. As the intensity or duration of exercise increase (middle part of Figure 30), fuel metabolism is controlled by both increased S nerve activity and adrenal E secretion. Catecholamines now stimulate glycogenolysis in the liver and in the muscle. In addition to glycolysis, beta receptor activation stimulates carbohydrate oxidation. The alpha adrenergic ation on the Cori gluconeogenic cycle is at its peak, so that this phase of metabolism is characterized by carbohydrate dependence. At this stage, increased beta adrenergic stimulation accelerates lipolysis in the adipose tissue and removes the peripheral circulatory restraints over FFA release. This permits greater access of albumin-bound FFAs to plasma and exercising muscle. Table 6 Principal types of adrenergic receptors ALPHA 1 ALPHA 2 BETA 1 BETA 2 vasoconstriction vasoconstriction ∧ heart rate broncholdilatation vasodilatation ∧ heart contractility ∨ NE release ∧ heart contactibility glycogenolysis (L,M) gluconeogenesis ∨ lipolysis ∧ lipolysis glycolysis glycogenolysis (L) ∧ platelet aggregation renin release oxidative metabolism ∧ nutrient uptake ∨ insulin release ∧ insulin release glycolysis amylase secretion sweating piloerection AGONISTS 53 54 salivation salbutamol AGONISTS AGONISTS AGONISTS# rimiterol methoxamine clonidine* prenaterol albuterol phenylephrine alpha-methyl-NE tolbutamine terbutaline tramazoline tazolol hexoprenaline xylazine dobutamine soterenol zinterol clenbuterol ANTAGONISTS ANTAGONISTS ANTAGONISTS salmotamol prazosin yohimbine ICI 89, 407 procaterol BE 2254 idazoxan paraoxyprenolol epinephrine corynanthine rauwolscine betaxolol phetolamine phentolamine atenolol ANTAGONISTS practolol ICI 118,551 metoprolol IPS 338 propranolol butoxamine propranolol #Beta 3 receptor has high affinity for the lipolytic action of NE (Yamashita et al., 1993) When exercise intensity is not above the anaerobic threshold, the next stage of exercise favors oxidative utilization of lipids. The shift from carbohydrate to lipid oxidation in the muscle is facilitated by the glucose-fatty acid cycle (Newsholme, 1977) , low insulin concentration, and by reduced muscle sensitivity to alpha adrenergic stimulation as a consequence on increased FFA delivery to the muscle (Burns et al. 54 55 1978). The pattern of sympathoadrenal theses conditions of exercise. activation favors lipid utilization under During recovery from short-term exercise, there is a rapid rise in plasma insulin (Wahren et al. 1973), probably reflecting a decline in S activity and an increase in PS tone. This contributes to the fall in hepatic glucose output and increased glucose uptake by the muscle. During recovery from long -term exercise that has resulted in glycogen depletion and in a fall in plasma glucose, plasma insulin remains low and adrenomedullary release of E and secretion of glucagon are sustained. 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