Mechanismen der zerebralen Autoregulation, Untersuchungsverfahren und Beurteilung mittels transkranieller Doppler-Sonographie

Zusammenfassung:

Die zerebrovaskuläre Autoregulation sichert in einem Bereich mittlerer Blutdruckwerte von 50 - 170 mmHg auch bei Blutdruckschwankungen die Konstanz der Hirndurchblutung. Statische und dynamische myogene Mechanismen dämpfen plötzliche Blutdruckschwankungen. Neurogene Einflüsse sympathischer, noradrenerger Fasern regulieren besonders die größeren, proximalen Hirngefäße, aber auch Gefäße mit nur 15 - 20 μm Durchmesser. Parasympathische, gefäßerweiternde Impulse sind von geringerem Einfluss. Monoaminerge Hirnstammkerne wie der dorsale Raphekern, der Locus coeruleus oder der Nucleus reticularis pontis oralis nehmen zusätzlich Einfluss auf die Gefäßmodulation. Metabolische, lokale, parenchymale und endotheliale Substanzen spielen für die Anpassung des Hirngefäßtonus ebenfalls eine entscheidende Rolle. Besonders zu nennen sind Stickoxid, Calcitonin gene related peptide, Substanz P, Endothelin, Kaliumkanäle sowie Entzündungsmediatoren wie Histamin, Bradykinin, Arachidonsäure, Prostaglandine, Leukotriene, freie Radikale oder Serotonin. Die klinische Überprüfung der Autoregulation kann durch kurzfristige Veränderungen des Blutdrucks erfolgen. Hierzu eignen sich Substanzen wie Angiotensin, Phenylephrin oder Natrium-Nitroprussid. Blutdruckänderungen können auch durch eine passive Kipptischbelastung, die „leg-cuff”-Methode nach Aaslid oder das Valsalva-Manöver induziert werden. Die Autoregulation lässt sich auch durch Berechnung der Kohärenz und Phasenbeziehung zwischen Modulationen von Blutdruck und Hirndurchblutung in Ruhe oder während metronomischer Atmung bestimmen. Die Messung der Hirndurchblutung erfolgt mittels transkranieller Doppler-Sonographie der proximalen Arteria cerebri media. Teilweise umstritten ist, ob eine Abnahme der hier gemessenen Strömungsgeschwindigkeit im Sinne einer Vasodilatation am beschallten Gefäßsegment zu werten ist oder eine Blutflussreduktion infolge einer Minderung der Perfusion nachgeschalteter Gefäßabschnitte darstellt. Ausführlich werden zahlreiche klinische und tierexperimentelle Studien erörtert, die deutliche Hinweise auf eine Konstanz des beschallten Gefäßdurchmessers und damit eine Abnahme der nachgeschalteten Perfusion geben. Direkte, intraoperative Messungen des Gefäßdurchmessers bestärken die Schlussfolgerung, dass dopplersonographisch gemessene Änderungen der Strömungsgeschwindigkeit in der proximalen Arteria cerebri media auf Perfusionsänderungen in nachgeschalteten Gefäßbereichen hinweisen. Somit eignet sich die transkranielle Doppler-Sonographie zur Beurteilung der zerebralen Autoregulation.

Mechanisms of Cerebral Autoregulation, Assessment and Interpretation by Means of Transcranial Doppler Sonography:

Cerebrovascular autoregulation assures constancy of cerebral perfusion despite blood pressure changes, as long as mean blood pressure remains in a range between 50 - 170 mmHg. Static and dynamic myogenic mechanisms dampen sudden blood pressure changes. Neurogenic influences of sympathetic, noradrenergic fibers modulate primarily proximal, large diameter segments of cerebral arteries, but also small 15 - 20 μm diameter vessels. Parasympathetic, vasodilating impulses are of less influence. Monoaminergic brainstem centers such as the dorsal raphe nucleus, locus coeruleus or nucleus reticularis pontis oralis also influence vessel tone. Metabolic, local parenchymal and endothelial substances have major impact on cerebral vessel tone. Particularly important are nitric oxide, calcitonin gene related peptide, substance P, endothelin, potassium channels and autocoids such as histamine, bradykinin, arachidonic acid, prostanoids, leucotrienes, free radicals or serotonin. The clinical examination of autoregulation is mostly based on brief blood pressure changes induced by drugs such as angiotensin, phenylephrine or sodium nitroprusside, or by challenge maneuvers. Frequently, blood pressure is challenged by a tilt-table maneuver, the “leg-cuff”-method according to Aaslid, or a Valsalva maneuver. The analysis of coherence and phase relation between spontaneous or metronomic breathing modulation of blood pressure and brain perfusion also assesses autoregulatory function. Cerebral blood flow is determined by means of transcranial Doppler sonography, mostly of the proximal segment of the mid-cerebral artery. There is some controversy whether a decrease of cerebral blood flow velocity measured at this segment indicates vasodilatation at the insonated segment or reflects blood flow reduction due to decreased perfusion of down-stream vessel segments. Various clinical and animal studies are presented demonstrating diameter constancy of the insonated mid-cerebral artery segment and thus indicating that slowing of mid cerebral artery blood flow velocity as assessed by transcranial Doppler sonography is due to a decrease of down-stream perfusion. Direct, intraoperative measurements of vessel diameter confirm this conclusion.

Literatur

• 1 Bondar R L, Dunphy P T, Moradshahi P, Kassam M S, Blaber A P, Stein F, Freeman R. Cerebrovascular and cardiovascular responses to graded tilt in patients with autonomic failure.  Stroke. 1997;  28 1677-1685
• 2 Aaslid R, Newell D W, Stooss R, Sorteberg W, Lindegaard K F. Assessment of cerebral autoregulation dynamics from simultaneous arterial and venous transcranial Doppler recordings in humans.  Stroke. 1991;  22 1148-1154
• 3 Diehl R R, Berlit P. Funktionelle Dopplersonographie in der Neurologie. Berlin Heidelberg New York: Springer 1996
• 4 Sorteberg W. Cerebral artery blood flow velocity and cerebral blood flow. In: Newell DW, Aaslid R (Hrsg) Transcranial Doppler New York: Raven Press Ltd. 1992: 57-66
• 5 Low P A, Novak V, Spies J M, Novak P, Petty G W. Cerebrovascular regulation in the postural orthostatic tachycardia syndrome (POTS).  Am J Med Sci. 1999;  317 124-133
• 6 Petty G W, Wiebers D O, Meissner I. Transcranial Doppler ultrasonography: clinical applications in cerebrovascular disease.  Majo Clin Proc. 1990;  65 1350-1364
• 7 Aaslid R. The Doppler principle applied to measurement of blood flow velocity in cerebral arteries. In: Aaslid R (Hrsg) Transcranial Doppler sonography Wien: Springer-Verlag 1986: 22-38
• 8 Widder B. Doppler- und Duplexsonographie der hirnversorgenden Arterien. Berlin Heidelberg: Springer-Verlag 1995
• 9 Santalucia P, Feldmann E. The basic transcranial Doppler examination: technique and anatomy. In: Babikian VL, Wechsler LR (Hrsg) Transcranial Doppler ultrasonography Boston: Butterworth-Heinemann 1999: 13-31
• 10 Giller C A, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy.  Neurosurgery. 1993;  32 737-741 discussion 741-742
• 11 Giller C A, Iacopino D G. Use of middle cerebral velocity and blood pressure for the analysis of cerebral autoregulation at various frequencies: the coherence index.  Neurol Res. 1997;  19 634-640
• 12 Aaslid R, Lindegaard K F, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans.  Stroke. 1989;  20 45-52
• 13 Novak P, Novak V, Low P A, Petty G W. Transcranial Doppler evaluation in disorders of reduced orthostatic tolerance. In: Low PA (Hrsg). Clinical autonomic disorders Philadelphia: Lippincott-Raven 1997: 349-368
• 14 Diehl R R, Linden D, Lucke D, Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation.  Stroke. 1995;  26 1801-1804
• 15 Diehl B, Diehl R R, Stodieck S R, Ringelstein E B. Spontaneous oscillations in cerebral blood flow velocities in middle cerebral arteries in control subjects and patients with epilepsy.  Stroke. 1997;  28 2457-2459
• 16 Symon L. Pathological regulation in cerebral ischemia. In: Wood JH (Hrsg). Cerebral blood flow. Physiologic and clinical aspects New York: McGraw Hill 1987: 423-424
• 17 Paulson O B, Waldemar G. Role of the local renin-angiotensin system in the autoregulation of the cerebral circulation.  Blood Vessels. 1991;  28 231-235
• 18 Wahl M, Schilling L. Regulation of cerebral blood flow - a brief review.  Acta Neurochir Suppl. 1993;  59 3-10
• 19 Ursino M. Mechanisms of cerebral blood flow regulation.  Crit Rev Biomed Eng. 1991;  18 255-288
• 20 McManis P G, Schmelzer J D, Zollman P J, Low P A. Blood flow and autoregulation in somatic and autonomic ganglia. Comparison with sciatic nerve.  Brain. 1997;  120 445-449
• 21 Low P A, Tuck R R. Effects of changes of blood pressure, respiratory acidosis and hypoxia on blood flow in the sciatic nerve of the rat.  J Physiol (Lond). 1984;  347 513-524
• 22 Takeuchi M, Low P A. Dynamic peripehral nerve metabolic and vascular responses to exsanguination.  Am J Physiol. 1987;  253 E349-353
• 23 Brian Jr J E, Faraci F M, Heistad D D. Recent insights into the regulation of cerebral circulation.  Clin Exp Pharmacol Physiol. 1996;  23 449-457
• 24 Bayliss M M. On the local reaction of the arterial wall to changes in intraluminal pressure.  J Physiol. 1902;  28 220-231
• 25 Johnson P C. The myogenic response. In: Bohr DF, Somlyo AP, Sparks HV (Hrsg). Handbook of Physiology. The Cardiovascular System: Vascular Smooth Muscle Bethesda, MD: American Physiological Society 1980
• 26 Wallis S J, Firth J, Dunn W R. Pressure-induced myogenic responses in human isolated cerebral resistance arteries.  Stroke. 1996;  27 2287-2290; discussion 2291
• 27 Purdy P E, Bevan J A. Adrenergic innervation of large cerebral blood vessels of the rabbit studied by fluorescence microscopy. Absence of features that might contribute to non-uniform change in cerebral blood flow.  Stroke. 1977;  8 82-87
• 28 Owman D, Edvinsson L, Nielsen K C. Autonomic neuroreceptor mechanisms in brain vessels.  Blood Vessels. 1974;  11 2-31
• 29 Edvinsson L. Neurogenic mechanisms in the cerebrovascular bed. Autonomic nerves, amine receptors and their effects on cerebral blood flow.  Acta Physiol Scand Suppl. 1975;  427 1-35
• 30 Morita Y, Hardebo J E, Bouskela E. Influence of cerebrovascular sympathetic, parasympathetic, and sensory nerves on autoregulation and spontaneous vasomotion.  Acta Physiol Scand. 1995;  154 121-130
• 31 Chorobsky J, Penfield W. Cerebral vasodilator nerves and their pathway from the medulla oblongata.  Arch Neurol Psychiatr. 1932;  28 1257
• 32 Cobb S, Finesinger J E. The vagal pathway of the vasodilator impulses.  Arch Neurol Psychiatr. 1932;  28 1243
• 33 Pinard E, Purves M J, Seylaz J, Vasquez J V. The cholinergic pathway to cerebral blood vessels. II. Physiological studies.  Pflugers Arch. 1979;  379 165-172
• 34 Edvinsson L, Hara H, Uddman R. Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides.  J Cereb Blood Flow Metab. 1990;  9 212-218
• 35 Hara H, Weir B. Pathway of acetylcholinesterase containing nerves to the major cerebral arteries in rats.  J Comp Neurol. 1986;  250 245-252
• 36 Hara H, Hamill G S, Jacobowitz D M. Origin of cholinergic nerves to the rat major cerebral arteries: coexistence with vasoactive intestinal polypeptide.  Brain Res Bull. 1985;  14 179-188
• 37 Moskalenko Y E, Weinstein G. About the neurogenic mechanism of the total cerebral blood flow regulation during changes of systemic blood pressure. In: Mchedlishvili GI, Purves MJ, Kovach AGB (Hrsg). Regulation of cerebral circulation Budapest: Akademiai Kiado 1979: 39
• 38 Moskalenko Y E, Weinstein G B, Demchenko I T, Kislyakov Y Y, Krivchenko A I. Biophysical aspects of cerebral circulation. Oxford: Pergamon Press 1980
• 39 McHedlishvili G I. Arterial behavior and blood circulation in the brain. New York: Plenum Press 1986
• 40 McHedlishvili G. Physiological mechanisms controlling cerebral blood flow.  Stroke. 1980;  11 240-248
• 41 Pereira J MMS. Histological, histochemical and microsurgical research on anatomo-physiological basis of neurogenic control of cerebral blood flow. In: Gotoh F, Nagai H, Tazaki Y (Hrsg). Cerebral blood flow and metabolism 1979
• 42 Hoff J T, MacKenzie E T, Harper A M. Responses of the cerebral circulation to hypercapnia and hypoxia after 7th cranial nerve transection in baboons.  Circ Res. 1977;  40 258-262
• 43 Heistad D D, Marcus M L. Total and regional cerebral blood flow during stimulation of carotid baroreceptors.  Stroke. 1976;  7 239-243
• 44 Bonvento G, MacKenzie E T, Edvinsson L. Serotonergic innervation of the cerebral vasculature: relevance to migraine and ischaemia.  Brain Res Rev. 1991;  16 257-263
• 45 MacKenzie E T, Scatton B. Cerebral circulatory and metabolic effects of perivascular neurotransmitters.  CRC Crit Rev Clin Neurobiol. 1987;  2 357-419
• 46 Raichle M E, Hartman B K, Eichling J O, Sharpe L G. Central noradrenergic regulation of cerebral blood flow and vascular permeability.  Proc Natl Acad Sci U S A. 1975;  72 3726-3730
• 47 Ohta K, Gotoh F, Shimazu K, Amano T, Komatsumoto S, Hamada J, Takahashi S. Locus coeruleus stimulation exerts different influences on the dynamic changes of cerebral pial and intraparenchymal vessels.  Neurol Res. 1991;  13 164-167
• 48 Kalaria R N, Stockmeier C A, Harik S I. Brain microvessels are innervated by locus coeruleus noradrenergic neurons.  Neuroscience Letters. 1989;  97 203-208
• 49 Bonvento G, Lacombe P, Seylaz J. Effects of electrical stimulation of the dorsal raphe nucleus on local cerebral blood flow in the rat.  J Cereb Blood Flow Metab. 1989;  9 251-255
• 50 Saito A, Lee T L. Serotonin as an alternative transmitter in sympathetic nerves of large cerebral arteries of the rabbit.  Circ Res. 1987;  60 220-228
• 51 Chang J Y, Hardebo J E, Owman C. Kinetic studies on uptake of serotonin and noradrenaline into pial arteries of rats.  J Cereb Blood Flow Metab. 1990;  10 22-31
• 52 Maeda M, Takahashi K, Miyazaki M, Ishii S. The role of the central monoamine system and the cholinoceptive pontine area on the oscillation of ICP ‘pressure waves’. In: Miller JD, Teasdale GM, Rowan JO (Hrsg). Intracranial pressure Berlin: Springer Verlag 1986
• 53 Sakas D E, Moskowitz M A, Wei E P, Kontos H A, Kano M, Ogilvy C S. Trigeminovascular fibers increase blood flow in cortical gray matter by axon reflex-like mechanisms during acute severe hypertension or seizures.  Proc Natl Acad Sci U S A. 1989;  86 1401-1405
• 54 Furchgott R F, Zawadzki J V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.  Nature. 1980;  288 373-376
• 55 Ignarro L J, Buga G M, Woods K S, Byrns R E, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.  Proc Natl Acad Sci USA. 1987;  84 9265-9269
• 56 Karaki H. Ca²⁺ localization and sensitivity in vascular smooth muscle.  Trends Pharmacol Sci. 1989;  10 320-325
• 57 Toda N, Okamura T. Role of nitric oxide in neurally induced cerebroarterial relaxation.  J Pharmacol Exp Ther. 1991;  258 1027-1034
• 58 Murphy S, Minor R J, Welk G, Harrison D. Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide.  J Neurochem. 1990;  55 349-351
• 59 Lee T, Sarwinski S. Nitric oxidergic neurogenic vasodilation in the porcine basilar artery.  Blood Vessels. 1991;  28 407-412
• 60 Garthwaite J, Garthwaite G, Palmer R, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices.  Eur J Pharmacol. 1989;  172 413-416
• 61 Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system.  Trends Neurosci. 1991;  14 60-67
• 62 Busse R, Mulsch A. Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells.  FEBS Lett. 1990;  275 87-90
• 63 Bredt D, Hwang P, Snyder S. Localization of nitric oxide synthase indicating a neural role for nitric oxide.  Nature. 1990;  347 768-769
• 64 Bredt D, Snyder S. Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum.  Proc Natl Acad Sci USA. 1989;  86 9030-9033
• 65 Foerstermann U, Schmidt H HHW, Pollock J S, Heller M, Murad F. Enzymes synthetizing guanylate cyclase-activating factors in endothelial cells, neuroblastoma cells, and rat brain.  J Cardiovasc Pharmacol. 1991;  17 57-64
• 66 Nozaki K, Moskowitz M A, Maynard K I, Koketsu N, Dawson T M, Bredt D S, Snyder S H. Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries.  J Cereb Blood Flow Metab. 1993;  13 70-79
• 67 Yoshida K, Okamura T, Kimura H, Bredt D S, Snyder S H, Toda N. Nitric oxide synthase-immunoreactive nerve fibers in dog cerebral and peripheral arteries.  Brain Res. 1993;  629 67-72
• 68 Murphy S, Simmons M L, Agullo L, Garcia A, Feinstein D L, Galea E, Reis D J, Minc-Golomb D, Schwartz J P. Synthesis of nitric oxide in CNS glial cells.  Trends Neurosci. 1993;  16 323-328
• 69 Brain Jr J E, Kennedy R H. Modulation of cerebral arterial tone by endothelium-derived relaxing factor.  Am J Physiol. 1993;  264 H1245-1250
• 70 Kovach A G, Szabo C, Benyo Z, Csaki C, Greenberg J H, Reivich M. Effects of NG-nitro-L-arginine and L-arginine on regional cerebral blood flow in the cat.  J Physiol (Lond). 1992;  449 183-196
• 71 Thomsen L L, Iversen H K, Brinck T A, Olesen J. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers.  Cephalalgia. 1993;  19 395-399
• 72 Bellantonio P, Micieli G, Buzzi M G, Marcheseli S, Castellano A E, Rossi F, Nappi G. Haemodynamic correlates of early and delayed responses to sublingual administration of isosorbide dinitrate in migraine patients: a transcranial Doppler study.  Cephalalgia. 1997;  17 183-187
• 73 Wahl M, Schilling L, Parsons A A, Kaumann A. Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression.  Brain Res. 1994;  637 204-210
• 74 Lauritzen M, Hansen A J. The effect of glutamate receptor blockade on anoxic depolarization and cortical spreading depression.  J Cereb Blood Flow Metab. 1992;  12 223-229
• 75 Faraci F M. Role of nitric oxide in regulation of basilar artery tone in vivo.  Am J Physiol. 1990;  259 H1216-1221
• 76 Faraci F M. Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs. microcirculation.  Am J Physiol. 1991;  261 H1038-1042
• 77 Faraci F M, Heistad D D. Endothelium-derived relaxing factor inhibits constrictor responses of large cerebral arteries to serotonin.  J Cereb Blood Flow Metab. 1992;  12 500-506
• 78 Kozniewska E, Oseka M, Stys T. Effects of endothelium-derived nitric oxide on cerebral circulation during normoxia and hypoxia in the rat.  J Cereb Blood Flow Metab. 1992;  12 311-317
• 79 Northington F J, Matherne G P, Berne R M. Competitive inhibition of nitric oxide synthase prevents the cortical hyperemia associated with peripheral nerve stimulation.  Proc Natl Acad Sci USA. 1992;  89 6649-6652
• 80 Tanaka K, Gotoh F, Gomi S, Takashima S, Mihara B, Nogawa S, Nagata E. Inhibition of nitric oxide synthesis induces a significant reduction in local cerebral blood flow in the rat.  Neurosci Lett. 1991;  127 129-132
• 81 Wang Q, Paulson O B, Lassen N A. Is autoregulation of cerebral blood flow in rats influenced by nitro-L-arginine, a blocker of the synthesis of nitric oxide.  Acta Physiol Scand. 1992;  145 297-298
• 82 Wahl M, Parsons A A, Schilling L, Kaumann A J. Reduction of pial arterial dilatation during cortical spreading depression by application of an inhibition of nitric oxide synthesis.  Cereb Blood Flow Metabol. 1993;  13 177
• 83 Jaiswal N, Jaiswal R K, Malik K U. Muscarinic receptor-mediated prostacyclin and cGMP synthesis in cultured vascular cells.  Mol Pharmacol. 1991;  40 101-106
• 84 Campbell W B, Halushka P V. Lipid-derived autacoids. Eicosanoids and platelet-activating factors. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (Hrsg). Goodman & Gilman's The pharmacological basis of therapeutics New York: McGraw-Hill 1996; : 601-616
• 85 Durieu-Trautmann O, Federici C, Creminon C, Foignant-Chaverot N, Roux F, Claire M, Strosberg A D, Couraud P O. Nitric oxide and endothelin secretion by brain microvessel endothelial cells: regulation by cyclic nucleotides.  J Cell Physiol. 1993;  155 104-111
• 86 Minc-Golomb D, Tsarfaty I, Schwartz J P. Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.  Br J Pharmacol. 1994;  112 720-722
• 87 Hongo K, Tsukahara T, Kassell N, Ogawa H. Effect of subarachnoid hemorrhage on calcitonin gene-related peptide-induced relaxation in rabbit basilar artery.  Stroke. 1989;  20 100-104
• 88 McCulloch J, Uddman R, Kingman T, Edvinsson L. Calcitonin gene-related peptide: functional role in cerebrovascular regulation.  Proc Natl Acad Sci USA. 1986;  83 5731-5735
• 89 Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects.  J Cereb Blood Flow Metab. 1987;  7 720-728
• 90 Edwards R M, Stack E J, Trizna W. Calcitonin gene-related peptide stimulates adenylate cyclase and relaxes intracerebral arterioles.  J Pharmacol Exp Ther. 1991;  257 1020-1024
• 91 Hong K W, Pyo K M, Lee W S, Yu S S, Rhim B Y. Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation.  Am J Physiol. 1994;  266 H11-16
• 92 Kitazono T, Heistad D D, Faraci F M. Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo.  Am J Physiol. 1993;  265 H581-585
• 93 Wei E P, Moskowitz M A, Boccalini P, Kontos H A. Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilatation in feline cerebral arterioles.  Circ Res. 1992;  70 1313-1319
• 94 Moskowitz M A, Wei E P, Saito K, Kontos H A. Trigeminalectomy modifies pial arteriolar responses to hypertension or norepinephrine.  Am J Physiol. 1988;  255 H1-6
• 95 Jansen I, Alafaci C, McCulloch J, Uddman R, Edvinsson L. Tachykinins (substance P, Neurokinin A, neuropeptide K, and neurokin B) in the cerebral circulation: Vasomotor responses in vitro and in situ.  J Cereb Blood Flow Metab. 1991;  11 567-575
• 96 Rosenblum W I, Shimizu T, Nelson G H. Endothelium-dependent effects of substance P and calcitonin gene-related peptide on mouse pial arterioles.  Stroke. 1993;  24 1043-1047 discussion 1047-1048
• 97 Moskowitz M A, Brody M, Liu-Chen L Y. In vitro release of immunoreactive substance P from putative afferent nerve endings in bovine pia arachnoid.  Neuroscience. 1983;  9 809-814
• 98 O'Shaughnessy C T, Waldron G J, Connor H E. Lack of effect of sumatriptan and UK-14, 304 on capsaicin-induced relaxation of guinea-pig isolated basilar artery.  Br J Pharmacol. 1993;  108 191-195
• 99 Pfister H W, Kumpfel T, Koedel U. Involvement of substance P in pial arteriolar vasodilatation during pneumococcal meningitis in the rat.  Neuroreport. 1995;  6 1301-1305
• 100 Markowitz S, Saito K, Moskowitz M A. Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain.  J Neurosci. 1987;  7 4129-4136
• 101 Faraci F M, Kadel K A, Heistad D C. Vascular responses of dura mater.  Am J Physiol. 1989;  257 H157-161
• 102 Edvinsson L, Brodin E, Jansen I, Uddman R. Neurokinin A in cerebral vessels: Characterization, localization and effect in vitro.  Regul Pept. 1988;  20 181-197
• 103 Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S. Cloning and expression of a cDNA encoding an endothelin receptor.  Nature. 1990;  348 730-732
• 104 Sakurai T, Yanigisawa M, Takuwa Y, Miyazaki H, Kimura S, Goto K, Masaki T. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.  Nature. 1990;  348 732-735
• 105 Davenport A P, Morton A J. 125 I ET-1, ET-2, and ET-3 and vasoactive intestinal contractor are present in adult rat brain and neurone-enriched primary cultures of embryonic brain cells.  Brain Res. 1991;  554 278-285
• 106 Murray M A, Faraci F M, Heistad D D. Effect of protein kinase C inhibitors on endothelin- and vasopressin-induced constriction of the rat basilar artery.  Am J Physiol. 1992;  263 H1643-1649
• 107 Kitazono T, Faraci F M, Heistad D D. Effect of norepinephrine on rat basilar artery in vivo.  Am J Physiol. 1993;  264 H178-182
• 108 Wahl M. Local chemical, neural, and humoral regulation of cerebrovascular resistance vessels.  J Cardiovasc Pharmacol. 1985;  7 S36-46
• 109 Wahl M, Unterberg A, Baethmann A, Schilling L. Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema.  J Cereb Blood Flow Metabol. 1988;  8 621-634
• 110 Schilling L, Wahl M. Histaminergic effects on cerebral hemodynamics. In: Phyllis JW (Hrsg). The regulation of cerebral blood flow Boca Raton: CRC Press 1993: 113-128
• 111 Wahl M, Schilling L. Effects of bradykinin in the cerebral microcirculation. In: Phyllis JW (Hrsg). The regulation of cerebral blood flow Boca Raton: CRC Press 1993: 315-328
• 112 Unterberg A, Schmidt W, Wajl M, Ellis E F, Marmarou A, Baethmann A. Evidence against leukotrienes as mediators of brain edema.  J Neurosurg. 1991;  74 773-780
• 113 Jones S C, Bose B, Furlan A J, Friel H T, Easley K A, Meredith M P, Little J R. CO₂ reactivity and heterogeneity of cerebral blood flow in ischemic, border zone, and normal cortex.  Am J Physiol. 1989;  257 H473-H482
• 114 Borgstrom L, Johannsson H, Siesjo B K. The relationship between arterial po2 and cerebral blood flow in hypoxic hypoxia.  Acta Physiol Scand. 1975;  93 423-432
• 115 Kety S S, Schmidt C F. The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men.  J Clin Invest. 1948;  27 484-492
• 116 Kontos H A, Wei E P, Raper A J, Rosenblum W I, Navari R M, Patterson J LJ. Role of tissue hypoxia in local regulation of cerebral microcirculation.  Am J Physiol. 1978;  234 H582-H591
• 117 Ekstrom-Jodal B, Haggendal E, Linder L E, Nilsson N J. Cerebral blood flow autoregulation at high arterial pressures and different levels of carbon dioxide tension in dogs.  Eur Neurol. 1971;  6 6-10
• 118 Kontos H A. Validity of cerebral arterial blood flow calculations from velocity measurements.  Stroke. 1989;  20 1-3
• 119 Phillis J W. Cerebral vascular responses to hypoxia, hyper- and hypocapnia, and hypotension. In: Phillis JW (Hrsg). The regulation of cerebral blood flow Boca Raton: CRC Press 1993: 249-265
• 120 Novak V, Novak P, Spies J M, Low P A. Autoregulation of cerebral blood flow in orthostatic hypotension.  Stroke. 1998;  29 104-111
• 121 Brooks D J, Redmond S, Mathias C J, Bannister R, Symon L. The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure, with observations on the action of ephedrine.  J Neurol Neurosurg Psychiatry. 1989;  52 962-966
• 122 Gambhir S, Inao S, Tadokoro M, Nishino M, Ito K, Ishigaki T, Kuchiwaki H, Yoshida J. Comparison of vasodilatory effect of carbon dioxide inhalation and intravenous acetazolamide on brain vasculature using positron emission tomography.  Neurol Res. 1997;  19 139-144
• 123 Kuwabara Y, Ichiya Y, Sasaki M, Akashi Y, Yoshida T, Fukumura T, Masuda K. (A comparison of the cerebrovascular responses to CO₂ and Diamox in patients with unilateral occlusive cerebral arteries: a H2(15)O PET study).  Kaku Igaku. 1995;  32 569-577
• 124 Ringelstein E B, Van Eyck S, Mertens I. Evaluation of cerebral vasomotor reactivity by various vasodilating stimuli: comparison of CO₂ to acetazolamide.  J Cereb Blood Flow Metab. 1992;  12 162-168
• 125 Steinling M. The measurement of cerebral perfusion and hemodynamic reserve using SPECT: use in cerebral vascular pathology.  Ann Radiol. 1990;  33 156-169
• 126 Ulrich P T, Becker T, Kempski O S. Correlation of cerebral blood flow and MCA flow velocity measured in healthy volunteers during acetazolamide and CO₂-stimulation.  J Neurol Sci. 1995;  129 120-130
• 127 Werner C, Kochs E. Cerebral blood flow and cerebral blood flow velocity during angiotensin-induced arterial hypertension in dogs.  Can J Anesth. 1993;  40 755-760
• 128 Larsen F S, Olsen K S, Ejlersen E, Hansen B A, Paulson O B, Knudsen G M. Cerebral blood flow autoregulation and transcranial Doppler sonography in patients with cirrhosis.  Hepatology. 1995;  22 730-736
• 129 Smielewski P, Czosnyka M, Kirkpatrick P, McEroy H, Rutkowska H, Pickard J D. Assessment of cerebral autoregulation using carotid artery compression.  Stroke. 1996;  27 2197-2203
• 130 Heckmann J G, Hilz M J, Haagler H, Mück-Weymann M, Neundorfer B. Transcranial Doppler sonography during acute 80 degrees head-down tilt (HDT) for the assessment of cerebral autoregulation in humans.  Neurol Res. 1999;  21 457-462
• 131 Heckmann J G, Mück-Weymann M, Hilz M J, Katalinic A. Autoregulative response of cerebral vessels to elevation in arterial blood pressure, a study using stress TCD.  Clin Auton Res. 1997;  7 47-48
• 132 Heckmann J G, Mück-Weymann M, Katalinic A, Hilz M J, Claus D, Neundorfer B. TCD-Ergometer-Test bei Patienten mit chronischem Kopfschmerz vom Spannungstyp (CKST).  Nervenarzt. 1998;  69 131-136
• 133 Heckmann J G, Hilz M J, Katalinic A, Marthol H, Mück-Weymann M, Neundörfer B. Myogenic cerebrovascular autoregulation in migraine measured by stress transcranial Doppler sonography.  Cephalalgia. 1998;  18 133-137
• 134 Tiecks F P, Planck J, Haberl R L, Brandt T. Reduction in posterior cerebral artery blood flow velocity during caloric vestibular stimulation.  J Cereb Blood Flow Metab. 1996;  16 1379-1382
• 135 Heckmann J G, Leis S, Mück-Weymann M, Hilz M J, Neundörfer B. Vestibular evoked blood flow response in the basilar artery.  Acta Neurol Scand. 1999;  100 12-17
• 136 Tiecks F P, Douville C, Byrd S, Lam A M, Newell D W. Evaluation of impaired cerebral autoregulation by the Valsalva maneuver.  Stroke. 1996;  27 1177-1182
• 137 Bennaroch E E, Sandroni P, Low P A. The Valsalva maneuver. In: Low PA (Hrsg) Clinical autonomic disorders Minnesota: Little, Brown & Co 1993: 209-215
• 138 Tiecks F P, Lam A M, Matta B F, Strebel S, Douville C, Newell D W. Effects of the Valsalva maneuver on cerebral circulation in healthy adults.  Stroke. 1995;  26 1386-1392
• 139 Hilz M J, Steingrueber M, Hagler A, Axelrod F B. Valsalva Maneuvre demonstrates impaired cerebrovascular autoregulation in familial dysautonomia patients.  Clin Auton Res. 1999;  9 37
• 140 Greenfield Jr J C, Rembert J C, Tindall G T. Transient changes in cerebral vascular resistance during the Valsalva maneuver in man.  Stroke. 1984;  15 76-79
• 141 Nichols J S, Beel J A, Munro L G. Detection of impaired cerebral autoregulation using spectral analysis of intracranial pressure waves.  J Neurotrauma. 1996;  13 439-456
• 142 Birch A A, Dirnhuber M J, Hartley-Davies R, Iannotti F, Neil-Dwyer G. Assessment of autoregulation by means of periodic changes in blood pressure.  Stroke. 1995;  26 834-837
• 143 Diehl R R, Linden D, Luecke D, Berlit P. Spontaneous blood pressure oscillations and cerebral autoregulation.  Clin Auton Res. 1998;  8 7-12
• 144 Müller H, Casty M, Moll R, Zehnder R. Response of middle cerebral artery volume flow to orthostatis.  Cerebrovasc Dis. 1991;  1 82-89
• 145 Thomsen L L, Klingenberg-Iversen H, Boesen F, Olesen J. Transcranial Doppler and cardiovascular responses during cardiovascular autonomic tests in migraineurs during and outside attacks.  Brain. 1995;  118 1319-1327
• 146 Huber P, Handa J. Effect of contrast material, hypercapnia, hyperventilation, hypertonic glucose and papaverine on the diameter of the cerebral arteries. Angiographic determination in man.  Invest Radiol. 1967;  2 17-32
• 147 Levine B D, Giller C A, Lane L D, Buckey J C, Blomqvist C G. Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.  Circulation. 1994;  90 298-306
• 148 Mueller S M, Heistad D D, Marcus M L. Total and regional cerebral blood flow during hypotension, hypertension, and hypocapnia. Effect of sympathetic denervation in dogs.  Circ Res. 1977;  41 350-356
• 149 Lindegaard K F, Lundar T, Wiberg J, Sjoberg D, Aaslid R, Nornes H. Variations in middle cerebral artery blood flow investigated with noninvasive transcranial blood velocity measurements.  Stroke. 1987;  18 1025-1030
• 150 Harper A M, Deshmukh V D, Rowan J O, Jennett W B. The influence of sympathetic nervous activity on cerebral blood flow.  Arch Neurol. 1972;  27 1-6
• 151 DuBoulay G H, Symon L. The anesthesist effect upon the cerebral artery.  Pro R Soc Med. 1971;  64 77-80
• 152 Newell D W, Aaslid R, Lam A, Mayberg T S, Winn H R. Comparison of flow and velocity during dynamic autoregulation testing in humans.  Stroke. 1994;  25 793-797
• 153 Nornes H, Sorteberg W, Nakstad P, Bakke S J, Aaslid R, Lindegaard K F. Haemodynamic aspects of clinical cerebral angiography. Concurrent two vessel monitoring using transcranial Doppler ultrasound.  Acta Neurochir. 1990;  105 89-97
• 154 Aaslid R. Visually evoked dynamic blood flow response of the human cerebral circulation.  Stroke. 1987;  18 771-775
• 155 Arts M G, Roevros J M. On the instantaneous measurement of bloodflow by ultrasonic means.  Med Biol Eng. 1972;  10 23-34
• 156 Heistad D D, Marcus M L, Abboud F M. Role of large arteries in regulation of cerebral blood flow in dogs.  J Clin Invest. 1978;  62 761-768
• 157 Levy L L, Wallace J D, Stolwijk J A, Poindexter E R. Cerebral blood flow regulation: vascular resistance adjustments in the circle of Willis.  Stroke. 1976;  7 147-150
• 158 Levy L L, Wallace J D. Cerebral blood flow regulation. II. Vasodilator mechanisms.  Stroke. 1977;  8 189-193
• 159 Tuor U I, Farrar J K. Contribution of the inflow arteries to alterations in total cerebrovascular resistance in the rabbit.  Pflugers Arch. 1985;  403 283-288
• 160 Kontos H A, Wei E P, Navari R M, Levasseur J E, Rosenblum W I, Patterson J L. Responses of cerebral arteries and arterioles to acute hypotension and hypertension.  Am J Physiol. 1978;  234 H371-H383
• 161 Baumbach G, Heistad D. Effects of sympathetic stimulation and changes in arterial pressure on segmental resistance of cerebral vessels in rabbits and cats.  Circ Res. 1983;  52 527-533
• 162 Stromberg D, Fox J. Pressures in the pial arterial microcirculation of the cat during changes in systemic arterial blood pressure.  Circ Res. 1972;  31 229-239
• 163 Berne R M, Winn H R, Rubio R. The local regulation of cerebral blood flow.  Prog Cardiovasc Dis. 1981;  24 243-260