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J Appl Physiol 290: 1364–1368, 2008; doi:10.1152/japplphysiol.90597.2008. Point:Counterpoint Point:Counterpoint: Sympathetic activity does/does not influence cerebral blood flow POINT: SYMPATHETIC ACTIVITY DOES INFLUENCE CEREBRAL BLOOD FLOW 1364 8750-7587/08 $8.00 Copyright © 2008 the American Physiological Society http://www. jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 7, 2017 Cerebral arteries are abundantly innervated by sympathetic fibers, but their influence on cerebral vessels was held unimportant for almost a century (2, 20). Whether there is sympathetic influence on cerebral blood flow (CBF) is important in the management of hypotensive patients. If there is no ␣-adrenergic influence on CBF, a low mean arterial pressure (MAP) can be increased to the cerebral autoregulation (CA) range by ␣-adrenergic receptor agonists and secure CBF and cerebral oxygenation (ScO2). On the other hand, if CBF is influenced by cerebral ␣-adrenergic stimulation, CBF and ScO2 decline while MAP increases in response to administration of the ␣-adrenergic agonist. In this context it is important that in humans, middle cerebral artery (MCA) mean blood velocity (Vmean) decreases in response to trigeminal ganglion stimulation (27) and CBF increases after stellate ganglion blockade (24). Studies performed in erect and exercising healthy subjects as in patients with heart failure provide further direct and indirect support for modulation of cerebral perfusion by sympathetically mediated vasoconstriction consequent to a reduced cardiac output (CO). A relationship between CBF and CO is established when standing up as both MCA Vmean and ScO2 decrease together with CO (25). This reduction in cerebral perfusion manifests although MAP increases, indicating a role for sympathetic activation in cerebrovascular resistance control. Alternatively, the orthostatic reduction in cerebral perfusion is alleged to be caused by the postural decrease in end-tidal carbon dioxide tension (PETCO2) (3). The reduction in arterial CO2 tension (PaCO2) accounts, however, for only one-half of the orthostatic influence on MCA Vmean (13, 23). In support, both MCA Vmean and ScO2 increase when the standing position is supplemented by leg-muscle tensing, attenuating sympathetic activity by enhancing CO (25). This observation might be related to an effect of stroke volume on the arterial baroreceptors where dynamic input from stroke volume is important in the regulation of sympathetic activity in humans (5). During dynamic exercise, MCA Vmean and ScO2 increase (14). However, when exercise with -adrenergic blockade attenuates the increase in CO, e.g., from 19 to 15 l/min (19), the increase in MCA Vmean is also reduced (12). Yet the usual 25% increase in MCA Vmean is reestablished if sympathetic activity to the brain is eliminated by stellate ganglion blockade (10). Similarly, in patients with heart failure the patient’s ability to increase CO during exercise relates to the increase in MCA Vmean (11). When comparing one- with two-legged exercise, heart failure patients demonstrate a normal increase in MCA Vmean that is attenuated, or eliminated, during twolegged exercise (7, 8, 16). An increment in CO with volume expansion increases MCA Vmean as a reduction in CO with application of negative pressure to the lower parts of the body (LBNP) decreases MCA Vmean at a maintained MAP (18). This takes place with no change in PaCO2 and, therefore, cerebral vasoconstriction indicates increased sympathetic drive. The orthostatic decrease in MAP at brain level is within the CA range, but the reduction in CO is by ⬃20%. Lowering MAP using trimethaphan and subsequently restoring it with phenylephrine evaluates sympathetic influence in the control of CBF during moderate LBNP (29). The similarity of reductions in mean, systolic, and pulse arterial pressures in addition to pulsatile change in MCA Vmean and PETCO2 before vs. during ganglionic blockade was taken to suggest that sympathetic vasoconstriction is not the mechanism underlying the reduction in CBF during central hypovolemia. An implicit assumption was that phenylephrine does not affect the cerebral vasculature. However, phenylephrine may lower CBF while increasing MAP (22). Against that background, the study (29) indicates that phenylephrine balances ␣-blockade for the brain. Among the mechanisms by which changes in stroke volume may affect CBF, altered shear stress related to changes in pulsatile flow is proposed through flow-mediated regulatory mechanisms like nitric oxide (NO) (29). NO is involved in the regulation of CBF in both animals and humans. Endothelial dysfunction is proposed to affect cerebral artery myogenic tone and CA, but its role in the regulation of CBF during central hypovolemia is not established. CA may be NO mediated (28), but in healthy subjects an exogenous NO donor does not affect the control of CBF. Similarly, inhibition of NO production does not impair dynamic CA (30) and neither affects MCA Vmean in healthy subjects (9). Thus, in humans, the role of NO in the control of CBF remains elusive. The observation that steady-state CBF, MCA Vmean, and ScO2 decrease on standing seems to be at odds with CA, i.e., that CBF is relatively stable within a wide range of perfusion pressures (21, 25). Comparable to what happens to skeletal muscle blood flow during exercise, regional flow is allowed to increase for as long as it does not affect MAP. However, when CO is restricted and challenges MAP, flow to exercising muscles and to the brain becomes limited (22). Stimulation of sympathetic nerves to the brain may cause a marked reduction in CBF, whereas under conditions where MAP is not challenged by a restricted CO, the influence of sympathetic stimulation on CBF is abolished (1). Or, according to Bill and Linder (1), under certain conditions stimulation of the sympathetic nerves to the brain causes a marked reduction in CBF, whereas under normal conditions the effect of such stimulation is practically nil. An influence of the sympathetic activity on CBF is likely to explain the discrepancy between the lack of influence of MAP on CBF and ScO2 as long as the central blood volume (CBV) is maintained during anesthesia (lowest level 37 mmHg) (17), and the decrease in CBF and Vmean when MAP declines below ⬃80 mmHg in response to deliberate reduction in central blood volume by LBNP, head-up tilt, or hemorrhage (Fig. 1). When considering the stimulus to the arterial baroreceptors against a background of different effects of steady vs. pulsatile pressure on baroreceptor discharge, we accept that the influence of CO on CBF may be through the pulse pressure generated by the stroke volume and detected by the Point:Counterpoint 1365 arterial baroreceptors where data from animal studies support that baroreceptors detect flow as well as pressure (4). Nevertheless, in animals the separate effects of different components of arterial pressure have not been identified (6) and also parasympathetic influence of CBF needs to be established. Taken together, an inability to maintain, or to increase, CO adequately induces peripheral vasoconstriction not only in working skeletal muscle (19) but also in the brain (26). We take it that ␣-adrenergic influence on CBF is important and that administration of ␣-adrenergic agonists affects CBF and ScO2. As long as CBV is adequate, such an effect is masked to become evident with central hypovolemia. The exception to that rule is the patient with significant arteriosclerosis in the arteries serving the brain. For such a patient, CBF is pressure dependent but that distracts from the notion that recording of MAP does not provide information on whether CBF and ScO2 are maintained. The implication of these observations is that for the unconscious patient, routine monitoring of CBF or ScO2 needs to be established because recording of blood pressure can not in itself predict whether CBF is maintained. REFERENCES 1. Bill A, Linder J. Sympathetic control of cerebral blood flow in acute arterial hypertension. Acta Physiol Scand 96: 114 –121, 1976. 2. Busija DW, Heistad DD. Effects of activation of sympathetic nerves on cerebral blood flow during hypercapnia in cats and rabbits. J Physiol 347: 35– 45, 1984. 3. Cencetti S, Bandinelli G, Lagi A. Effect of PCO2 changes induced by head-upright tilt on transcranial Doppler recordings. Stroke 28: 1195– 1197, 1997. 4. Chapleau MW, Abboud FM. Determinants of sensitization of carotid baroreceptors by pulsatile pressure in dogs. Circ Res 65: 566 –577, 1989. 5. Charkoudian N, Joyner MJ, Johnson CP, Eisenach JH, Dietz NM, Wallin BG. Balance between cardiac output and sympathetic nerve activity in resting humans: role in arterial pressure regulation. J Physiol 568: 315–321, 2005. J Appl Physiol • VOL 290 • OCTOBER 2008 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 7, 2017 Fig. 1. Cerebral oxygenation (ScO2) related to mean arterial pressure (MAP) including the data obtained with a maintained central blood volume (CBV) during anesthesia (broken line) and data from subjects for whom the central blood volume was reduced deliberately during head-up tilt [solid line (15)]. Nomogram illustrates distribution of the lowest MAP in anesthetized patients of this study. Reproduced from Ref. 17. 6. Eckberg DL, Sleight P. Human Baroreflexes in Health and Disease. Oxford: Oxford University Press, 1992. 7. Hellstrøm G, Magnusson G, Saltin B, Wahlgren NG. Cerebral haemodynamic effects of physical exercise in patients with chronic heart failure. Cerebrovasc Dis 4: 256 –261, 1994. 8. Hellstrøm G, Magnusson G, Wahlgren NG, Saltin B. Physical exercise may impair cerebral perfusion in patients with chronic heart failure. Cardiol Elderly 4: 191–194, 1996. 9. Hjorth Lassen L, Klingenberg Iversen H, Olesen J. A dose-response study of nitric oxide synthase inhibition in different vascular beds in man. Eur J Clin Pharmacol 59: 499 –505, 2003. 10. Ide K, Boushel R, Sorensen HM, Fernandes A, Cai Y, Pott F, Secher NH. Middle cerebral artery blood velocity during exercise with beta-1 adrenergic and unilateral stellate ganglion blockade in humans. Acta Physiol Scand 170: 33–38, 2000. 11. Ide K, Gulløv AL, Pott F, Van Lieshout JJ, Koefoed BG, Petersen P, Secher NH. Middle cerebral artery blood velocity during exercise in patients with atrial fibrillation. Clin Physiol 19: 284 –289, 1999. 12. Ide K, Pott F, Van Lieshout JJ, Secher NH. Middle cerebral artery blood velocity depends on cardiac output during exercise with a large muscle mass. Acta Physiol Scand 162: 13–20, 1998. 13. Immink RV, Secher NH, Roos CM, Pott F, Madsen PL, Van Lieshout JJ. The postural reduction in middle cerebral artery blood velocity is not explained by PaCO2. Eur J Appl Physiol 96: 609 – 614, 2006. 14. Jørgensen LG, Perko M, Hanel B, Schroeder TV, Secher NH. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans. J Appl Physiol 72: 1123–1132, 1992. 15. Madsen P, Pott F, Olsen SB, Nielsen HB, Burcev I, Secher NH. Near-infrared spectrophotometry determined brain oxygenation during fainting. Acta Physiol Scand 162: 501–507, 1998. 16. Magnusson G, Kaijser L, Isberg B, Saltin B. Cardiovascular responses during one- and two-legged exercise in middle-aged men. Acta Physiol Scand 150: 353–362, 1994. 17. Nissen P, Van Lieshout JJ, Nielsen HB, Secher NH. Frontal lobe oxygenation is maintained during hypotension following propofol-phentanyl anesthesia. AANA J 2008. 18. Ogoh S, Brothers RM, Barnes Q, Eubank WL, Hawkins MN, Purkayastha S, Yurvati A, Raven PB. The effect of changes in cardiac output on middle cerebral artery mean blood velocity at rest and during exercise. J Physiol 569: 697–704, 2005. 19. Pawelczyk JA, Hanel B, Pawelczyk RA, Warberg J, Secher NH. Leg vasoconstriction during dynamic exercise with reduced cardiac output. J Appl Physiol 73: 1838 –1846, 1992. 20. Sándor P. Nervous control of the cerebrovascular system: doubts and facts. Neurochem Int 35: 237–259, 1999. 21. Scheinberg P, Stead EA. The cerebral blood flow in male subjects as measured by the nitrous oxide technique. Normal values for blood flow, oxygen utilization, glucose utilization and peripheral resistance, with observations on the effect of tilting and anxiety. J Clin Invest 28: 1163–1171, 1949. 22. Secher NH, Seifert T, Van Lieshout JJ. Cerebral blood flow and metabolism during exercise, implications for fatigue. J Appl Physiol 104: 306 –314, 2008. 23. Serrador JM, Hughson RL, Kowalchuk JM, Bondar RL, Gelb AW. Cerebral blood flow during orthostasis: role of arterial CO2. Am J Physiol Regul Integr Comp Physiol 290: R1087–R1093, 2006. 24. Umeyama T, Kugimiya T, Ogawa T, Kandori Y, Ishizuka A, Hanaoka K. Changes in cerebral blood flow estimated after stellate ganglion block by single photon emission computed tomography. J Auton Nerv Syst 50: 339 –346, 1995. 25. Van Lieshout JJ, Pott F, Madsen PL, Van Goudoever J, Secher NH. Muscle tensing during standing: effects on cerebral tissue oxygenation and cerebral artery blood velocity. Stroke 32: 1546 –1551, 2001. 26. Van Lieshout JJ, Wieling W, Karemaker JM, Secher NH. Syncope, cerebral perfusion, oxygenation. J Appl Physiol 94: 833– 848, 2003. 27. Visocchi M, Chiappini F, Cioni B, Meglio M. Cerebral blood flow velocities and trigeminal ganglion stimulation. A transcranial Doppler study. Stereotact Funct Neurosurg 66: 184 –192, 1996. 28. White RP, Vallance P, Markus HS. Effect of inhibition of nitric oxide synthase on dynamic cerebral autoregulation in humans. Clin Sci (Lond) 99: 555–560, 2000. 29. Zhang R, Levine BD. Autonomic ganglionic blockade does not prevent reduction in cerebral blood flow velocity during orthostasis in humans. Stroke 38: 1238 –1244, 2007. Point:Counterpoint 1366 30. Zhang R, Wilson TE, Witkowski S, Cui J, Crandall GG, Levine BD. Inhibition of nitric oxide synthase does not alter dynamic cerebral autoregulation in humans. Am J Physiol Heart Circ Physiol 286: H863–H869, 2004. COUNTERPOINT: SYMPATHETIC NERVE ACTIVITY DOES NOT INFLUENCE CEREBRAL BLOOD FLOW It is intuitively clear that the cerebral circulation cannot take part in general cardiovascular regulation. During states of shock, where the sympathetic nervous system is activated, leading to a decrease in the perfusion of kidneys and mesenteric vascular bed, the cerebral circulation is kept functioning as long as possible and experiences only a modulating effect on autoregulation by sympathetic perivascular nerves. The cerebral arteries are innervated like other vascular beds by neurons arising in the peripheral nervous system and also by intrinsic neurons (4, 9). Sympathetic nerves in contact with the cerebral arteries originate from the superior cervical ganglion, but peculiarly under normal conditions seem to have little influence on cerebral blood flow (CBF). Already Fog (3) in his early studies of pial arteries in cats found no effect of acute sympathetic, vagal, or baroreceptor denervation on the autoregulatory responses. Chronic sympathetic denervation in animals does not influence CBF autoregulation (2, 15). Electric stimulation or acute sympathetic denervation in animals likewise has little effect on CBF if blood pressure is kept stable. In humans, bladder distension caused a powerful sympathetic activation with a 35% rise in blood pressure with a rise in heart rate and papillary dilatation, but did not influence CBF (11). A weak modulatory effect of the sympathetic perivascular nerves on CBF autoregulation can only be detected at extremes of blood pressure. During hemorrhagic hypotension, the otherwise inactive nerves constrict the larger cerebral resistance vessels, the “inflow tract” of the brain, thereby counteracting the autoregulatory response of the smaller arteries and arterioles (1, 5). This response is a weak analog of the intense vasoconstriction seen in the peripheral and visceral vascular beds. Likewise, during acutely induced hypertension, sympathetic activation, either endogenously or by electric stimulation, can constrict the inflow tract and hence contribute to autoregulation and exert a protective effect on the cerebral resistance vessels (8, 12). The net effect is a shift of the autoregulation curve toward higher blood pressure. Interestingly, during acutely induced hypertension in the anesthetized rat an interaction between the sympathetic nervous system and the renin-angiotensin system can be demonstrated. Blockade of the renin-angiotensin system with captopril causes a shift of the upper limit of autoregulation toward lower J Appl Physiol • VOL REFERENCES 1. Du Boulay G, Symon L, Shah S, Dorsch N, Ackerman R. Cerebral arterial reactivity and spasm after subarachnoid haemorrhage. Proc R Soc Med 65: 80 – 82, 1972. 2. Eklöf B, Ingvar DH, Kågström E, Olin T. Persistence of cerebral blood flow autoregulation following chronic bilateral cervical sympathectomy in the monkey. Acta Physiol Scand 82: 172–176, 1971. 3. Fog M. Cerebral circulation II: Reaction of pial arteries to increase in blood pressure. Arch Neurol Psychiat 41: 260 –268, 1939. 4. Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 100: 1059 –1064, 2006. 5. Harper AM, Deshmukh VD, Rowan JO, Jennett WB. The influence of sympathetic nervous activity on cerebral blood flow. Arch Neurol 27: 1–7, 1972. 6. Jordan J, Shannon JR, Diedrich A, Black B, Costa F, Robertson D, Biaggioni I. Interaction of carbon dioxide and sympathetic nervous system activity in the regulation of cerebral perfusion in humans. Hypertension 36: 383–388, 2000. 7. LeMarbre G, Stauber S, Khayat RN, Puleo DS, Skatrud JB, Morgan BJ. Baroreflex-induced sympathetic activation does not alter cerebrovascular CO2 responsiveness in humans. J Physiol 551.2: 609 – 616, 2003. 8. MacKenzie ET, McGeorge AP, Graham DI, Fitch W, Edvinsson L, Harper AM. Effect of increasing arterial pressure on cerebral blood flow in the baboon: influence of the sympathetic nervous system. Pflugers Arch 378: 189 –195, 1979. 9. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metabol Rev 2: 161–192, 1999. 10. Przybylowsky T, Bangash MF, Reichmuth K, Morgan BJ, Skatrud JB, Dempsey JA. Mechanisms of the cerebrovascular response to apnoea in humans. J Physiol 548.1: 323–332, 2003. 11. Skinhoj E. The sympathetic nervous system and the regulation of cerebral blood flow in man. Stroke 3: 711–716, 1972. 12. Strandgaard S, Boisvert DJP, MacKenzie ET, Harper AM. Influence of sympathetic stimulation on the pial arteriolar response to severe hypertension. Acta Neurol Scand 60, Suppl 72: 138 –139, 1979. 105 • OCTOBER 2008 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.33.6 on May 7, 2017 Johannes J. van Lieshout1,2 Niels H. Secher3,4 Department of Internal Medicine, Medium Care Unit, Human Cardiovascular Physiology Unit, AMC Center for Heart Failure Research, Academic Medical Center, University of Amsterdam The Netherlands; Department of Anaesthesiology, The Copenhagen Muscle Research Center, Rigshospitalet University of Copenhagen, Copenhagen, Denmark e-mail: [email protected] blood pressure, and this shift is abolished by concomitant electric stimulation of the cervical sympathetic trunk (14). In a study in normal humans, lower body negative pressure was used to create a baroreflex-induced activation of the sympathetic nervous system. Such activation did not alter cerebrovascular reactivity to hypercapnia or hypocapnia, as studied by medial cerebral artery velocity (7). Likewise, the same group found no effect of ganglionic blockade on cerebrovascular CO2 reactivity (10). By contrast, in a related study, where sympathetic activation was achieved by head-up tilt and sympathetic tone was removed by ganglionic blockade, a slight effect of sympathetic activation was found on CO2 reactivity (6). These finding may have been influenced by methodological errors, as discussed in detail by LeMarbre et al. (7). Interestingly, ganglionic blockade with trimetaphan did not appear to influence cerebrovascular CO2 reactivity in normotensive and hypertensive humans (13). Lower body negative pressure induces a decrease in cerebral blood flow velocity even if blood pressure is maintained by infusion of a pressor drug. This cerebral vasoconstrictor response was preserved in healthy individuals under ganglionic blockade with trimetaphan, excluding participation of the sympathetic nervous system (16). Thus it may be concluded that the sympathetic perivascular nerves have little or no effects on CBF and its regulation under normal conditions, but may be activated to constrict the inflow tract cerebral vessels at very high or very low blood pressure. It is gratifying that this point of view was also expressed in a recent review on perivascular nerves and the regulation of cerebrovascular tone (4).