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Brain Stem Catecholamine Mechanisms in Tonic and Reflex Control of Blood Pressure DONALD J. REIS, ANTONIO R. GRANATA, TONG H. JOH, CHRISTOPHER DAVID A. RUGGIERO, AND DONG H. A. Ross, PARK Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 SUMMARY Neurons of the lower brain stem maintain resting levels of arterial pressure (AP), mediate reflex responses from cardiopulmonary receptors, and are an important site of the hypotensive actions of a2-adrenergic agonists. Details of the pathways and transmitters that mediate tonic and reflex control of AP are emerging. Afferent fibers of cardiopulmonary receptors in the ninth and tenth nerves terminate bilaterally in the nucleus of the tractus solitarius (NTS). Although some neurons contain substance P, the primary neurotransmitter appears to be the excitatory amino acid L-glutamate (L-glu). Neurons in rostral ventrolateral medulla, which most probably comprise the Cl group of epinephrine neurons, are also critical in AP control. Cl neurons project to innervate cholinergic preganglionic sympathetic neurons in the spinal cord. Stimulation of the Cl area electrically or with L-glu increases AP, while lesions or local injection of the inhibitory amino acid gamma-aminobutyric acid (GABA) lowers AP to levels comparable to spinal cord transection. Lesions of Cl neurons or their pathways abolish vasodepressor reflexes from baroreceptors and vagal afferents. In contrast, noradrenergic neurons of the caudal ventrolateral medulla, the Al group, project rostrally to innervate, in part, vasopressin neurons of the hypothalamus. Stimulation of Al neurons lowers AP, while lesions or GABA elevates it. We propose that Cl neurons comprise the so-called tonic vasomotor center of the brain stem and also mediate, via a projection from the NTS, the vasodepressor limb of baroreflexes. The NTS-C1 projection may be GABAergic. (Hypertension 6 (Suppl II): II-7-II-15, 1984) KEY WORDS • adrenergic • adrenaline neurons • noradrenergic neurons baroreceptor reflexes • blood pressure * nucleus of the tractus solitarius I T has long been recognized that neurons within the lower brain stem, which comprise the medulla oblongata and pons, are critical for the tonic and reflex regulation of systemic arterial pressure (AP).1"3 Neurons in the lower brain: (1) maintain tonic background drive to sympathetic preganglionic neurons, thereby maintaining normal resting levels of AP2"4; (2) are the site of termination of cardiopulmonary afferents, which includes those from high and low pressure baro- and other cardiopulmonary receptors5"8; and (3) are the major targets of those centrally acting a-adrenergic agonists that act as antihypertensive agents, most notably, clonidine and a-methyldopa.9"12 Indeed that these agents, which act on receptors in the brain normally stimulated by catecholamines, produce cardiovascular actions by stimulation of baroreceptors," n raises questions about the relationship between the central networks responsible for maintaining AP and the central catecholamine neurons. This paper reviews recent research from our laboratory directed toward clarifying the networks in the lower brain stem that are responsible for maintaining normal levels of AP and mediating barorefiex responses. Our findings suggest an important new role for catecholamine cell groups of the lower medulla in such control. We review these studies with the present knowledge of control of the circulation by the brain stem. Nucleus of the Tractus Solitarius and Arterial Pressure The nucleus of the tractus solitarius (NTS) is the major site of termination of afferents of the ninth and tenth cranial nerves. As such, the NTS is the major relay nucleus for information arising from baroreceptors and cardiopulmonary afferents. Interestingly, recognition that the NTS is critical for baroreceptor reflex function is relatively recent and has From the Laboratory of Neurobiology, Department of Neurology, Cornell University Medical College, 1300 York Avenue, New York, New York 10021. Address for reprints: A. R. Granata, Lab. of Neurobiology, 411 E. 69th St., New York, New York 10021. 1-7 11-8 HYPERTENSION SUPPL II VOL 6, No5, SEPTEMBER-OCTOBER 1984 Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 been elaborated on only over the past 20 years. The evidence for its role in control of AP stems from a variety of physiological and anatomical studies.5"8 In brief: (1) The NTS has been demonstrated by retrograde transport techniques to be the site of termination of afferents that arise from cardiopulmonary receptors. (2) Neurons in the NTS can be demonstrated to respond monosynaptically to stimulation of baroreceptor afferents and also to fire in synchrony with the arterial pulse, which indicates that they are locked into the baroreceptor reflex chain. (3) Electrical stimulation of the NTS can, with stimuli of appropriate frequency, simulate the baroreceptors, while (4) lesions of the NTS have been demonstrated to abolish cardiopulmonary reflexes.13 Indeed, lesions of the NTS, produced either by destruction of local neurons or by appropriate drugs, have been shown to result in neurogenic hypertension.14-l5 drugs such as gamma-aminobutyric acid (GABA), pentobarbital, or clonidine,10 36~38 reduce AP, sometimes to a magnitude comparable to that produced by spinal cord transection. In contrast, electrical stimulation or local administration of excitatory amino acids to the region has been observed to elevate AP. 34 Such evidence suggests the RVL may be responsible for maintaining tonic levels of AP. The region also may mediate vasodepressor responses to baroreflex stimulation: baroreflex responses disappear after bilateral lesions of, or application of kainic acid to, the area.39- ^ Anatomical studies have also supported the view that the RVL is important in control of AP; evidence is available that neurons in the RVL project into regions of the spinal cord that contain preganglionic autonomic neurons41^3 and that RVL receives projections from the NTS.44"17 The cardiovascular portions of the NTS are abundantly innervated by inputs from a variety of brain areas as well as from branches of the ninth and tenth nerves. These areas include the area postrema, parabrachial nucleus of the pons, various monoamine brain stem nuclei of pons, paraventricular and lateral hypothalamic nuclei, amygdala, and forebrain.16"18 These areas contain a wide variety of peptide and monoamine transmitters.18 The transmitter of the primary afferent input is uncertain. Studies from this laboratory over the past several years have demonstrated that the baroreceptor response may be mediated by the excitatory amino acid L-glutamate19"23 and not by monoaminergic nor cholinergic inputs,23"27 although these agents may modulate the response (as may the various peptides innervating the area). On the other hand, there is histochemical and immunochemical evidence that substance P also is contained in baroreceptor afferent fibers that innervate the NTS. 28 Whether substance P acts to mediate baroreflex responses or to modulate them is uncertain, and the results of application of this drug locally to the NTS have been variable depending on species and investigators.29"31 Caudal Ventrolateral Medulla Ventrolateral Medulla and Cardiovascular Control Although neurons in the NTS relay all information arising from cardiopulmonary receptors to other centers in the brain, the pathways by which such information is relayed, particularly those that signal an inhibition of vasomotor tone — the hallmark of the baroreceptor vasodepressor response — until recently have been unknown. Attention has focused on the ventrolateral medulla as the area of importance in controlling tonic and reflex control of AP. The ventrolateral medulla can be separated into a rostral zone, the rostral ventrolateral medulla (RVL), and a caudal zone, the caudal ventrolateral medulla (CVL), which, as will be discussed, differ functionally with respect to their activities in regulating the circulation. Rostral Ventrolateral Medulla Studies have documented that bilateral lesions of the RVL,32"34 c o o ling of the area,35 or local application of The CVL differs from the RVL with respect to its actions on AP. Electrical or chemical stimulation of neurons in the region under appropriate conditions lowered AP,48-49 while lesions of the area resulted in elevations of AP.49"5' Neurons in the CVL do not project to the spinal cord (see next section). Thus, in functional terms, the RVL and CVL appear to have opposite actions on AP. What has not been determined are the identity of the neurons and their transmitters within each of these areas that are responsible for the cardiovascular effects. That it is different sets of catecholamine neurons within these regions that account for the functional differentiation has been suggested by some recent studies, largely from this laboratory. Catecholamine Neurons in Rostral Ventrolateral Medulla: Cl Group It has long been known that the areas of the ventrolateral medulla that have functionally been established as controlling AP contain neurons that synthesize and release catecholamines. In their pioneering studies, Dahlstrom and Fuxe52"53 described a group of histofluorescent neurons in the ventrolateral medulla that were presumed on the basis of their histofluorescence to contain norepinephrine. These, the Al neurons, were believed to project to the spinal cord. It should be emphasized that histofluorescence cannot differentiate, with certainty, between dopamine, norepinephrine, or epinephrine. It required the introduction of immunocytochemical techniques for the localization of catecholamine biosynthetic enzymes to provide a tool that could establish which catecholamine a neuron could synthesize. Thus, neurons that contained only tyrosine hydroxylase had only the capacity for synthesizing dopamine. The presence of tyrosine hydroxylase and dopamine-/3-hydroxylase indicated that the neuron could synthesize norepinephrine, while the presence of the enzyme phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine, indicated that such a cell was adrenergic. In 1974 Hokfelt et al., 54 using an antibody to PNMT, discovered that a subpop- BRAIN STEM CATECHOLAMINE MECHANISMS//?m et al. Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 ulation of neurons called the Cl group, which were situated in the most rostral portion of the Al group, contained this enzyme. The ventrolateral Al group therefore was not homogeneous, but consisted of two parts: a rostral adrenergic Cl group and a caudal noradrenergic Al group with admixing in between." Further evidence that the Al and Cl neurons differ has come from examination of their projections. Using tracer techniques, it has been established that the Al neurons do not, as first believed, project to the spinal cord but rather send their axons rostrally, innervating in large measure magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus—56~58 neurons that synthesize vasopressin and project into the posterior pituitary. In contrast, a large population of Cl neurons also send their axons caudally to innervate almost exclusively the intermediolateral column of the spinal cord (Figure I).59"61 Indeed, the major catecholaminergic innervation of the spinal cord originating in the medulla oblongata is adrenergic.59 Possible Function of Cl Adrenergic Neurons in the Tonic Control of AP It has long been known that electrical stimulation of the RVL will elicit elevations of AP and heart rate.3 Whether these effects are mediated by the C1 cells in the RVL, however, remained to be established. A144 Medulla II-9 In a recent series of experiments by combining electrical and chemical stimulation techniques along with careful correlation with the anatomy of neurons staining for PNMT, we 39 - w have demonstrated an extremely tight correlation between the responses elicited from the Cl area and the distribution of neurons and their axonal processes, which contain the enzyme PNMT. In summary, electrical stimulation of the Cl area or within the axonal pathways elicited a powerful elevation of arterial pressure and heart rate (Figure 2A). Such stimulation also elicited a release of adrenal medullary catecholamines and arginine vasopressin (AVP) from the hypofhalamus. The response to electrical stimulation was dependent on the stimulus frequency in so far as the response was elicited with frequencies of more than 2 Hz and reached a maximum at stimulus frequencies greater than 100 Hz. The response was graded with respect to the stimulus intensity. The threshold for the response was less than 15 piAmp at 5 times the threshold that elicited an elevation of AP in excess of 80 mm Hg. The pressor response to electrical stimulation of the Cl area was dependent on stimulation of intrinsic neurons as elevations of AP of comparable magnitude could be elicited by the microinjection of very small amounts of the excitatory amino acid Lglutamate (L-glu) into the area. Because L-glu did not excite fibers of passage, we concluded that it was excitation of intrinsic neurons in the C1 area that caused the sympathetic neurons to discharge. In contrast to the effects of excitation, interference with the activity of neurons in the Cl area resulted in a collapse of AP to levels comparable to those produced by spinal cord transection. Thus, small electrolytic lesions (Table I),62"63 the introduction of tetrodotoxin (Figure 2B),60 or the inhibitory amino acid GABA39 all lowered arterial pressure. The effects of such disturbances were graded: unilateral lesions only produced partial reductions of AP.62 Comparable reductions of AP to those produced by lesions in the Cl cell body area could also be produced by transecting lesions in the brain stem that affect the fiber bundle stained for PNMT (unpublished observations). These experiments therefore suggest that neurons in the RVL are tonically active and that these neurons are tonically inhibited by GABA. These studies are entirely consistent with the view that the Cl neurons of the RVL provide tonic vasomotor tone. Role of the Cl Area in Baroreceptor Reflexes FIGURE I. Autoradiographic demonstration of projections from the Cl region to the intermediolateral column (ILC). 10 = inferior olive; IVN = inferior vestibular nucleus; MVN = medial vestibular nucleus; NTS = nucleus of the tractus solitarius; PP = nucleus prepositus; RPa = raphe pallidus; STN = spinal trigeminal nucleus; STT = spinal trigeminal tract. (From Ross et al.60) That the RVL participates in baroreceptor reflex responses has been suggested by two lines of evidence: (1) Neurons in the RVL have been shown to be innervated by inputs from the NTS44"46; (2) bilateral lesions of the RVL or the application of drugs to neurons subadjacent to it3- *° abolished vasodepressor responses elicited by electrical or natural stimulation of cardiopulmonary afferents (Table 1). Physiological studies, however, have been interpreted with difficulty because lesions or drugs may often drop blood pressure to levels below that reached by maximal stimulation of baroreceptors. 11-10 HYPERTENSION SUPPLII VOL6, No5, SEPTEMBER-OCTOBER 1984 PNMT Label TS -200 -150 lOOmmHg Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 LOSEC triln FIGURE 2a. Cardiovascular responses elicited from the Cl region in chloralose-anesthetized, paralyzed, artificially ventilated rats. a. A single electrode tract is seen passing through the ventrolateral medulla (right side of illustration). At each point, the animal was stimulated for 10 seconds with a square-wave pulse of 20 fxAmp, 100 Hz. Note that the pressor responses are highly localized to regions that correspond with the distribution of cells labeled for phenvlethanolamine N'-methyltransferase (PNMT) at the same level of the brain stem (left side of illustration). TETRODOTOXIN AFTER SPINAL TRANSECTION INJECTION 200 MEAN ARTERIAL PRESSURE (mmHgl ) m 0 200 ARTERIAL PRESSURE 100 (mmHg) 0 600 HEART RATE 400 (beats/mi n) 200 TTX TTX lOmin lOntin lmin FIGURE 2b. Cardiovascular responses to bilateral injections of tet rodo toxin (lOpmolellOO nl saline) into the Cl area. The first injection (TTX), indicated by an arrow on the bottom of chart recording, produced a partial reduction of AP, while injection into the contralateral side (second arrow) resulted in a collapse of AP to le\'els comparable to that produced by subsequent spinal cord transeclion. CST = corticospinal tract; 10 = inferior olive; IVN = inferior vestibular nucleus; MVN = medial vestibular nucleus; NA = nucleus ambiguus; NTSr = nucleus tractus solitarius pars rostralis; PP = nucleus prepositus; RPa = raphe pallidus; STN = spinal trigeminal nucleus; STT = spinal trigeminal tract; TS = tractus solitarius. (From Ross, et al.60) BRAIN STEM CATECHOLAMINE MECHANISMS//?m et al. II-l TABLE I. Effec ts upon Resting and Reflex Changes in Arterial Pressure and Heart Rate ofLe\ion(s) ofCI Area Alone or Combined with a Unilateral Lesion of the NTS* Before lesion After lesion Vagal stimulation Vagal stimulation (mean change) (mean change) Control Control Treatment Bilateral Cl area lesions HR MAP HR MAP HR 380.8 ±30.2 -32.5 ±3.1 -50 5 ±5.0 50.5 ±5.0t 220.5 ±20.6t -1.3 ±1 0* -1.5 ±1.1* -36 2 368.0 96.9 ±15.2 ±6.6 ±2.5 By permission of the American Heart Association -29.8 ±5.4 89.4 ±7 1 399.6 ±26.9 -2.2 ±1.0* -1.8 ±0.8* Contralateral NTS and ipsilateral Cl area lesions N MAP 4 98.5 ±8.2 4 MAP HR *From Granata et al.62 +p < 0 025. %p < 0.01. when compared with controls (before lesion). NOTES: Unilateral vagal stimulation performed with pulse of 2-msec duration. 5 Hz and 10 times threshold current intensity; 10-sec train of stimulus. Values are expressed as means ± SEM, N = number of experiments. MAP = mean arterial pressure (mm Hg), HR = heart rate (beats/min); NTS = nucleus of the tractus solitarius. Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 That the Cl neurons of the RVL may mediate the baroreflex response was suggested to us by our finding that the Cl area was heavily innervated, largely unilaterally, by a projection of the cardiovascular portions of the NTS.64 To test the hypothesis that the NTS-C1 projection mediates the vasodepressor response from baroreceptor afferents, we devised an experimental model. The model has been based on the facts that the projections from cardiopulmonary afferents of the ninth and tenth nerves are distributed bilaterally8; that the projection from NTS appears primarily unilateral64; and that lesions of a single Cl area only partially reduce resting AP (unpublished observations). We therefore used a preparation in which the left vagus nerve is transected and stimulated electrically, and a lesion is placed in the right NTS, thereby isolating the reflex arc from the vagal afferents or carotid sinus afferents on that side to a single loop of the left NTS-left Cl area. A lesion then placed in the left Cl area should totally interfere with the reflex arc, but as the right Cl area remains undamaged, background arterial pressure should be maintained. Conversely, a lesion of the right Cl area would have no effect on reflex responses as the afferent loop of information from the left vagus and carotid sinus nerves innervating the right Cl has been interrupted by the unilateral lesion of the right NTS. We have discovered that (1) lesions of the right NTS resulted in a slight elevation of resting AP and in partial interference with the magnitude of the vasodepressor response to electrical stimulation of the left vagus nerve or stretch of the left carotid sinus region; (2) the addition of a lesion of either the right or left Cl area resulted in a lowering of AP to a level comparable to that in the unoperated anesthetized rat (Table 1); (3) a lesion of the left Cl area totally abolished reflex responses elicited by electrical stimulation of the left vagus nerve (Table 1) or carotid sinus (Table 2); (4) electrolytic lesion of the right NTS combined with a lesion of the right Cl area had no further effect on vasodepressor responses than did the NTS lesion alone; (5) if kainic acid was injected into the left Cl area rather than placement of an electrolytic lesion, a TABLE 2. Effects upon Cardiovascular Responses to Carotid Sinus Stretch of Le.sion(s) ofCI Area Alone or Combined with a Unilateral Lesion of the NTS* After lesion Before lesion Carotid sinus stretch (mean change) Control Treatment N Bilateral Cl area lesions 4 Contralateral NTS and ipsilateral Cl area lesions 5 HR MAP HR 98.9 ±8.5 346 ±20.8 -27.8 ±6.1 -27.2 ±7.1 95.8 ±10.5 355.0 ±10.1 -29.8 ±6.7 -30.5 ±7.5 MAP Carotid sinus stretch (mean change) Control HR HR MAP 51.01±8.1 233.3t ±25.0 -1.5* ±1.3 - 1 8* ± 1.4 89.9 ±7.5 340.5 ±16.0 -1.8 ±1.1* - 1.5 ±1.1* MAP *From Granata et al. 62 tp < 0.025. *p < 0.01 when compared with controls (before lesion). NOTES: The carotid sinus baroreceptors were stimulated naturally (stretched) by pulling the ligature looped around the common carotid artery downward toward the heart for 12 sec. In all cases, ipsilateral and contralateral are referred to the side of the vagal stimulation or carotid sinus stretch. Values are expressed as mean ± SEM; N = number of experiments; MAP = mean arterial pressure (mm Hg); HR = heart rate (beats/min); NTS = nucleus of the tractus solitarius. HYPERTENSION 11-12 SUPPLII V O L 6 , comparable abolition of baroreceptors was obtained, which indicated that the effects of electrolytic lesions are on neurons in the region rather than on fibers of passage.63 Most recently we have obtained evidence that lesions restricted to the axonal bundles of PNMTcontaining fibers that project dorsally and then descend into the spinal cord produce effects comparable to those obtained with electrolytic lesions of the cell bodies (unpublished observations). These observations raise the question as to whether or not Cl neurons may be important in the expression of several forms of hypertension. That a unilateral Cl lesion reduced the significant elevation of arterial pressure produced by NTS lesions, demonstrates that its integrity is necessary for the expression of at least the neurogenic hypertension produced by bilateral lesions of the NTS (NTS hypertension). Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 Contrasting Roles of A l Neurons of the Caudal Ventrolateral Medulla in Cardiovascular Function Electrical stimulation of the A1 area in the rabbit48 or 49 rat resulted in changes of AP that were very different from those elicited from the Cl area. Electrical stimulation of the region with low-frequency stimuli (5-15 Hz) or the microinjection of the excitatory amino acid L-glu resulted in graded reductions of AP. Electrical stimulation with higher frequencies resulted in a pressor response. In the rabbit the vasodepressor response was accompanied by bradycardia; in the rat, by tachycardia. No 5, SEPTEMBER-OCTOBER 1984 Lesions of the Al area produced effects entirely different from that produced by lesions of the Cl area. Thus, electrolytic lesions or the introduction of kainic acid into the Al area of rabbit50"51 or rat49 resulted in elevations of AP, which led inevitably in the rat and often in the rabbit, to fulminating pulmonary edema and death. The microinjection of GAB A into the Al area also resulted in an elevation of arterial pressure.48 Lesions of the Al area, in contrast to those of the Cl area, did not substantially alter the magnitude of the vasodepressor response to maximal stimulation of vagal afferent fibers or to carotid sinus stretch.49 Chronically, lesions of the A1 area, however, may impair the gain of the baroreceptor reflex curve.50 The hypertension produced by Al lesions was substantially, but not totally, the result of an increase in the release of AVP from the pituitary.49"50 Thus, interference with Al function by electrolytic lesions or kainic acid elevated AP, and the response to hypertension was significantly reduced by treatment with an AVP antagonist. The Neuroanatomical Substrate of the Tonic and Baroreceptor Reflex Control From these considerations and previous work from our laboratory, we constructed a working diagram of the neuroanatomy of the baroreceptor reflex arc (Figure 3). In brief, afferent information arising from baroreceptors projects into the NTS. From here it engages neurons that project to the Cl area; Cl neurons project Primary afferents (Glu) FIGURE 3. Medulla Carotid sinus Thoracic cord Preganglionic sympathetic neuron (Ach) Heart Adrenal medulla Postganglionic sympathetic neuron (NE) Diagrammatic representa- tion of proposed pathways and neurotransmitters that mediate baroreceptor reflex activity. Afferent fibers of the ninth (IX) and tenth (X) nerves terminate in the nucleus of the tractus solitarius (NTS) with a proposed neurotransmitter being L-glutamate (Glu). Here they synapse on neurons that relay into the Cl area. The transmitter of these neurons may be gamma-aminobutyric acid (GABA). These neurons, which synthesize epinephrine (E), innervate cholinergic neurons in the intermediolateral (IML) and inter mediomedial levels of the spinal cord, which then relay either into the adrenal medulla or into sympathetic ganglion where they contact noradrenergic postganglionic neurons, which in turn innervate noradrenergic sympathetic neurons (NE), which innervate blood vessels, the heart, or both. Also shown are neurons in the dorsal motor nucleus (DMX) of the \<agus and in the nucleus of Nosaka (N), which provide efferent innervation of the heart and nucleus ambiguus (NA). BRAIN STEM CATECHOLAMINE MECHANISMS//?m et al. Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 into the intermediolateral column of the cord, with neurons of that region projecting directly to the adrenal medulla or to sympathetic ganglia, which make contact with those ganglionic neurons that innervate the blood vessels and the heart. A provisional statement can be made about the neurochemistry of this loop. The neurotransmitter of the primary afferent fibers is still not completely established. As described previously, there is substantial evidence to suggest that these fibers may contain L-glu and that the release of this amino acid transmits information from baroreceptors onto neurons of the NTS. Because, however, afferent fibers contain substance P, they may exert some yet unknown function on the reflex response. The transmitter of the NTS-C1 projection is not yet clearly established; however, the abundant evidence66"67 that (1) GAB A is essential in mediating baroreceptor reflex responses on heart rate and also on blood pressure, (2) the site of action seems to be in the ventrolateral medulla, and (3) neurons in the NTS will release GABA in vitro (Meeley MP, Reis DJ, unpublished observation), makes this a reasonable candidate for this limb of the reflex arc. Excitation of the Cl area was necessary to mediate the tonic vasomotor and reflex vasodepressor responses, and hence the transmitter in this limb could be epinephrine. Whether or not it is epinephrine that is released to act on preganglionic neurons in the spinal cord to lower arterial pressure remains to be established. That the microiontophoresis of epinephrine in the area of preganglionic neurons purportedly reduces their activity rather than elevates it is a perplexing paradox.68"*9 That Cl neurons have been discovered to contain other neuropeptides, however, such as neuropeptide Y,70 raises the possibility that the release of some agent other than epinephrine may produce the effect. The transmitter from the preganglionic sympathetic neuron to the ganglion cells is presumably acetylcholine, although these neurons may contain cotransmitters, and finally, the effective transmitter released from noradrenergic neurons on blood pressure is norepinephrine. We must emphasize that the neurochemical wiring diagram of the baroreceptor reflex arc acting on blood pressure is provisional and a working hypothesis. Sufficient surprises have emerged from studies of neurotransmitter systems over the last decade to make enthusiastic statements premature in identifying transmitters). References 1. Alexander RS. Tonic and reflex functions of medullary sympathetic cardiovascular centers. J Neurophysiol I946;9:2O5-217 2. Reis DJ. Central neural mechanisms governing the circulation with particular reference to the lower brain stem and cerebellum. In: Zanchetti A., ed. Neural and psychological mechanisms in cardiovascular disease. Proceedings of a symposium held in Stresa, Italy, July I9th-21st, 1971. Milano: II ponte, 1972;255-280 11-13 3. Dampney RAL. Functional organization of central cardiovascular pathways. Clin Exp Pharmacol Physiol 1981;8:241 4. Kumada M, Dampney RAL, Reis DJ. Profound hypotension and abolition of the vasomotor component of the cerebral ischemic response produced by restricted lesions of the medulla oblongata: relationship to the so-called tonic vasomotor center. Circ Res 1979;45:63-70 5. Miura M, Reis DJ. Termination and secondary projection of carotid sinus nerve in cat brain stem. Am J Physiol 1969;217:142-153 6. Kalia M, Mesulam MM. Brain stem projections and motor components of the vagus complex in the cat. 1. The cervical vagus and nodose ganglion. II. Laryngeal, tracheobronchial, pulmonary, cardiac and gastrointestinal branches. J Comp Neural 1980; 193:435-^66 7. Spyer KM. Neural organization and control of the baroreceptor reflex. Rev Physiol Biochem Pharmacol 1981;88:24-124 8. Kalia MP. Localization of aortic and carotid baroreceptor and chemoreceptor primary efferents in the brain stem. In: Buckley JP, Ferrario CM, eds. Central nervous system mechanisms in hypertension. New York: Raven Press, 1981:9-24 9. HaeuslerG. 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Acta Physiol Scand 1983;117:315-318 Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 Brain stem catecholamine mechanisms in tonic and reflex control of blood pressure. D J Reis, A R Granata, T H Joh, C A Ross, D A Ruggiero and D H Park Hypertension. 1984;6:II7 doi: 10.1161/01.HYP.6.5_Pt_2.II7 Downloaded from http://hyper.ahajournals.org/ by guest on May 3, 2017 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1984 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. 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