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On the regulation of the blood supply to the brain: old age concepts and new age ideas

2010; American Physiological Society; Volume: 108; Issue: 6 Linguagem: Inglês

10.1152/japplphysiol.00257.2010

8750-7587

Philip N. Ainslie, Yu‐Chieh Tzeng,

Cardiovascular Health and Disease Prevention

INVITED EDITORIALOn the regulation of the blood supply to the brain: old age concepts and new age ideasP. N. Ainslie, and Y. C. TzengP. N. AinslieDepartment of Human Kinetics, Faculty of Health and Social Development, University of British Columbia Okanagan, Kelowna, British Columbia, Canada; and , and Y. C. TzengPhysiological Rhythms Unit, Department of Surgery and Anesthesia, University of Otago, Wellington, New ZealandPublished Online:01 Jun 2010https://doi.org/10.1152/japplphysiol.00257.2010This is the final version - click for previous versionMoreSectionsPDF (369 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat the critical importance of cerebral blood flow (CBF) control was reported in 1890 in a landmark publication by Roy and Sherrington (15). Although the concept was not fully accepted until confirmed by more sophisticated methods of CBF assessment, these authors postulated that local changes in cerebral functional activity and perfusion are coupled. In this issue of the Journal of Applied Physiology, Brassard and colleagues (3) add valuable new insight into the fundamental mechanisms that regulate blood supply to the brain. At rest and during progressive elevations in exercise intensity, they examined the influence of acute phenylephrine-induced changes in blood pressure on transcranial Doppler (TCD)-determined middle cerebral artery (MCA) mean blood flow velocity (Vmean) and near-infrared spectroscopy (NIRS)-derived frontal lobe oxygenation (ScO2). At rest, consistent with another recent report on this topic (7), mean arterial blood pressure (MAP) was increased by 20% and MCA Vmean was increased by 10% at the highest doses of phenylephrine; at these time points, ScO2 was reduced by 7%. However, with progressive increases in exercise intensity, the phenylephrine-induced changes in MCA Vmean and ScO2 were abolished. The authors concluded that phenylephrine leads to a differential influence on CBF and cortical oxygenation and that this effect is abolished by exercise-induced elevations in cerebral metabolic rate.These new findings are important. Clinically, while a 7% reduction in cerebral oxygenation may seem small, a drop of 13% is associated with cerebral ischemia (1). Interestingly, a recent report showed a 14% decrease in ScO2 with the utilization of phenylephrine in hypotensive patients undergoing elective surgery (13). Therefore, the clinical use of phenylephrine to correct for hypotension may actually have a negative impact on brain oxygenation. At a fundamental level, the findings of Brassard et al. (3) challenge us to reappraise basic assumptions related to human CBF control (Fig. 1) and invite new questions to be raised.Fig. 1.Schematic illustrating major mechanistic pathways involved with human cerebral blood flow (CBF) control. The prime driving force for cerebral perfusion is cerebral perfusion pressure (1; CPP), which is determined by the difference between mean arterial blood pressure and intra-cranial pressure (2; ICP) under conditions where central venous pressure (3; CVP) is lower than ICP. Under steady-state conditions, mean arterial blood pressure is determined by total peripheral resistance (TPR) and cardiac output (CO). Conduit vessels in humans are believed to play no role in CBF control. Resistance vessels (e.g., pial vascular bed) are actively engaged in the regulation of CBF via cerebral autoregulation. Neurogenic control of cerebrovascular tone is controversial, but sympathetic (4) and parasympathetic (5) inputs have been implicated. Cerebral autoregulation is also under the influence of multiple modulating factors such as CO2 and brain metabolism (6). Some controversial evidence suggests that CO influences CBF independently of CPP (7). The mechanism for CO-mediated effects on CBF remains obscure, given that neither stroke volume nor CO is a determinant of blood flow as defined by Poiseuille's law. It is also important to note that, under conditions with elevated CVP and/or ICP, cerebral venous outflow (and, therefore, CBF) may also be "regulated" by a Starling resistor because of the enclosed nature of the cranium (8).Download figureDownload PowerPointIs the Cerebrovascular System Under Adrenergic Control?Both TCD and NIRS provide sufficient temporal resolution to assess the dynamic relationship between blood pressure and CBF. However, despite the widespread application of TCD and NIRS in human physiological research, the results of Brassard et al. (3) suggest that the information derived from these methods is not fully understood and, indeed, that common experimental interventions might alter their interpretation. For example, a bolus dose of the α1-adrenergic receptor agonist phenylephrine elicited reciprocal, rather than parallel, changes in MCA Vmean and ScO2, a finding consistent with recently reported data (7). Brassard et al. speculate that the reduction in ScO2 and increase in MCA Vmean may have been due to direct vasoconstrictive effects of phenylephrine on cerebral conduit and resistance vessels. Although this hypothesis is plausible, several aspects should be carefully considered.Vasoconstriction of the MCA as a mechanism to explain a reduction in ScO2 is possible, given that reductions in MCA caliber would lead to decreased CBF; however, this contrasts with human and animal studies that have reported negligible changes in CBF with intra-arterial injections of adrenergic agonists. Notably, rare conscious human recordings of internal carotid artery blood flow, using an electronic flowmeter, showed no flow changes for ≥20 s after injection of norepinephrine (5), a finding indicative of absent adrenergic modulation of cerebral conduit vessel tone. If the MCA were also devoid of any significant adrenergic modulation, the rise in MCA Vmean following phenylephrine injection observed by Brassard et al. (3) might be consistent with an increase in CBF, rather than a drug-induced decrease in vessel caliber. However, if we consider that MCA diameter remained unchanged and, therefore, that CBF was increased, what then accounts for the reduction in ScO2 following phenylephrine injection?Thus the findings of Brassard et al. (3) lead us to a controversial body of research suggesting that cerebral sympathetic activity is actively engaged in CBF control (16), but important knowledge deficits remain. For example, although changes in adrenergic activity may explain the reduction in ScO2 following phenylephrine injection, whether these effects were due to the direct action of phenylephrine per se or, rather, changes that occurred secondary to the transient hypertension remains unknown. A direct effect of the drug cannot be excluded; however, evidence indicates that the intact blood-brain barrier prevents intravascular catecholamine release from binding to α1-adrenoreceptors of cerebral arterioles (6, 10, 12) and should, therefore, not be confused with vessel constriction due to perivascular release of endogenous catecholamines. Moreover, although the integrity of the blood-brain barrier can be compromised by raised intravascular pressure, which can lead to "leak through" of intravascular catecholamines, this mechanism is likely relevant only following sustained periods (hours) of extreme hypertension (i.e., MAP >190 mmHg) (9). As recognized by Brassard et al. (3), an indirect effect could also account for their observations; whereas peripheral sympathetic nerve activity falls during acute hypertension (due to baroreflex-mediated inhibition), direct recordings in superior cervical ganglion of sheep indicate that the opposite occurs in the brain: cerebral sympathetic nerves are activated during acute hypertension, not hypotension (4). Thus, cerebral vessels may constrict due to an increase in perivascular sympathetic activity secondary to the phenylephrine-induced transient hypertension. This hypothesis is supported by recent studies showing that norepinephrine plasma kinetic measurements made with internal jugular venous sampling reflect extrinsic cerebrovascular sympathetic activity (11). However, in contrast, Bevan et al. (2) found that, compared with the middle meningeal and superficial temporal arteries, fresh human pial arteries received sparse adrenergic/sympathetic innervations and showed only marginal responsiveness to transmural nerve stimulation and topical norepinephrine. Therefore, the findings of Brassard et al. call for new research to determine if there is differential regulation of peripheral vs. cerebral sympathetic nerve activity in humans but, importantly, to explain how cerebral sympathetic activity contributes to CBF control, given the apparently low innervation density of human cerebral resistance vessels.Is Cerebral Metabolism the Predominant Regulator of CBF?The clear findings from Brassard et al. (3) show that exercise-induced elevations in cerebral metabolic rate abolished phenylephrine's differential influence on CBF and oxygenation at rest. Indeed, during functional activity or exercise, elevations in cerebral metabolism (i.e., neuronal demand) require increased CBF to deliver the oxygen required for aerobic metabolism of the brain. As summarized recently (14), these findings confirm that the vasodilatory effects of the exercise-induced increase in brain metabolism can override the effects of drug-induced changes in blood pressure/sympathetic nerve activity, as well as other factors such as hypocapnia. Thus, collective evidence supports cerebral metabolism as the predominant regulator of CBF.In conclusion, the elegant findings of Brassard et al. (3) have allowed us to summarize the current knowledge and controversial areas about our understanding of CBF regulation. Future directions of research, ideally combining additional functional imaging with invasive procedures, have been proposed. Without improvement to our rudimentary understanding of the basic processes governing cerebrovascular physiology, the task of bettering our comprehension of cerebrovascular pathology and then developing novel therapeutic targets for future stroke treatment will be very difficult.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.ACKNOWLEDGMENTSWe are grateful to Professor Mark Haykowsky (University of Alberta) and Chris Willie (University of British Columbia Okanagan) for informal feedback for many of the concepts outlined in this editorial.REFERENCES1. Al-Rawi PG , Kirkpatrick PJ. Tissue oxygen index: thresholds for cerebral ischemia using near-infrared spectroscopy. Stroke 37: 2720–2725, 2006.Crossref | ISI | Google Scholar2. Bevan RD , Dodge J , Nichols P , Penar PL , Walters CL , Wellman T , Bevan JA. Weakness of sympathetic neural control of human pial compared with superficial temporal arteries reflects low innervation density and poor sympathetic responsiveness. Stroke 29: 212–221, 1998.Crossref | PubMed | ISI | Google Scholar3. Brassard P , Siefert T , Wissenberg M , Jensen PM , Hansen CK , Secher NH. Phenylephrine decreases frontal lobe oxygenation at rest but not during moderately intense exercise. J Appl Physiol. 11, 2010; doi:10.1152/japplphysiol.01206.2009.Link | ISI | Google Scholar4. Cassaglia PA , Griffiths RI , Walker AM. Cerebral sympathetic nerve activity has a major regulatory role in the cerebral circulation in REM sleep. J Appl Physiol 106: 1050–1056, 2009.Link | ISI | Google Scholar5. Greenfield JC , Tindall GT. Effect of norepinephrine, epinephrine, and angiotensin on blood flow in the internal carotid artery of man. J Clin Invest 47: 1672–1684, 1968.Crossref | ISI | Google Scholar6. Hardebo JE , Owman C. Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface. Ann Neurol 8: 1–31, 1980.Crossref | PubMed | ISI | Google Scholar7. Lucas SJ , Tzeng YC , Galvin SD , Thomas KN , Ogoh S , Ainslie PN. Influence of changes in blood pressure on cerebral perfusion and oxygenation. Hypertension 55: 698–705, 2010.Crossref | PubMed | ISI | Google Scholar8. Luce JM , Huseby JS , Kirk W , Butler J. A Starling resistor regulates cerebral venous outflow in dogs. J Appl Physiol 53: 1496–1503, 1982.Link | ISI | Google Scholar9. MacKenzie ET , Strandgaard S , Graham DI , Jones JV , Harper AM , Farrar JK. Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res 39: 33–41, 1976.Crossref | PubMed | ISI | Google Scholar10. McCalden TA , Eidelman BH , Mendelow AD. Barrier and uptake mechanisms in the cerebrovascular response to noradrenaline. Am J Physiol Heart Circ Physiol 233: H458–H465, 1977.Link | ISI | Google Scholar11. Mitchell DA , Lambert G , Secher NH , Raven PB , van Lieshout J , Esler MD. Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans. J Physiol 587: 2589–2597, 2009.Crossref | PubMed | ISI | Google Scholar12. Moppett IK , Wild MJ , Sherman RW , Latter JA , Miller K , Mahajan RP. Effects of ephedrine, dobutamine and dopexamine on cerebral haemodynamics: transcranial Doppler studies in healthy volunteers. Br J Anaesth 92: 39–44, 2004.Crossref | ISI | Google Scholar13. Nissen P , Brassard P , Jorgensen TB , Secher NH. Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension. Neurocrit Care 12: 17–23, 2010.Crossref | ISI | Google Scholar14. Ogoh S , Ainslie PN. Cerebral blood flow during exercise: mechanisms of regulation. J Appl Physiol 107: 1370–1380, 2009. Link | ISI | Google Scholar15. Roy CS , Sherrington CS. On the regulation of the blood-supply of the brain. J Physiol 11: 85–158 117, 1890.Crossref | PubMed | Google Scholar16. van Lieshout JJ , Secher NH. Point:Counterpoint: Sympathetic activity does/does not influence cerebral blood flow. Point: Sympathetic activity does influence cerebral blood flow. J Appl Physiol 105: 1364–1366, 2008. Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. N. Ainslie, Dept. of Human Kinetics, Univ. of British Columbia Okanagan, Kelowna, BC, Canada V1V 1V7 (e-mail: Philip.[email protected]ca). 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