Increased cerebral blood flow but no reversal or prevention of vasospasm in response to l-arginine infusion after subarachnoid hemorrhage

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Object. The reduction in the level of nitric oxide (NO) is a purported mechanism of delayed vasospasm after subarachnoid hemorrhage (SAH). Evidence in support of a causative role for NO includes the disappearance of nitric oxide synthase (NOS) from the adventitia of vessels in spasm, the destruction of NO by hemoglobin released from the clot into the subarachnoid space, and reversal of vasospasm by intracarotid NO. The authors sought to establish whether administration of l-arginine, the substrate of the NO-producing enzyme NOS, would reverse and/or prevent vasospasm in a primate model of SAH.

Methods. The study was composed of two sets of experiments: one in which l-arginine was infused over a brief period into the carotid artery of monkeys with vasospasm, and the other in which l-arginine was intravenously infused into monkeys over a longer period of time starting at onset of SAH. In the short-term infusion experiment, the effect of a 3-minute intracarotid infusion of l-arginine (intracarotid concentration 10−6 M) on the degree of vasospasm of the right middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF) was examined in five cynomolgus monkeys. In the long-term infusion experiment, the effect of a 14-day intravenous infusion of saline (control group, five animals) or l-arginine (10−3 M; six animals) on the occurrence and degree of cerebral vasospasm was examined in monkeys. The degree of vasospasm in all experiments was assessed by cerebral arteriography, which was performed preoperatively and on postoperative Days 7 (short and long-term infusion experiments) and 14 (long-term infusion experiment). In the long-term infusion experiment, plasma levels of l-arginine were measured at these times in the monkeys to confirm l-arginine availability.

Vasospasm was not affected by the intracarotid infusion of l-arginine (shown by the reduction in the right MCA area on an anteroposterior arteriogram compared with preoperative values). However, intracarotid l-arginine infusion increased rCBF by 21% (p < 0.015; PCO2 38–42 mm Hg) in all vasospastic monkeys compared with rCBF measured during the saline infusions. In the long-term infusion experiment, vasospasm of the right MCA occurred with similar intensity with or without continuous intravenous administration of l-arginine on Day 7 and had resolved by Day 14. The mean plasma l-arginine level increased during infusion from 12.7 ± 4 µg/ml on Day 0 to 21.9 ± 13.1 µg/ml on Day 7 and was 18.5 ± 3.1 µg/ml on Day 14 (p < 0.05).

Conclusions. Brief intracarotid and continuous intravenous infusion of l-arginine did not influence the incidence or degree of cerebral vasospasm. After SAH, intracarotid infusion of l-arginine markedly increased rCBF in a primate model of SAH. These findings discourage the use of l-arginine as a treatment for vasospasm after SAH.

Article Information

Address reprint requests to: Ryszard M. Pluta, M.D., Ph.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D-37, 9000 Rockville Pike, Bethesda, Maryland 20892. email: rysiek@helix.nih.gov.

© AANS, except where prohibited by US copyright law.

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    Bar graph depicting relative changes in rCBF in response to intracarotid infusion of saline (five animals) or l-arginine (six animals) in a primate model of vasospasm. Infusion was made through a catheter placed in the ICA. Regional CBF increased during intracarotid infusion of l-arginine (* p < 0.015, paired t-test). Regional CBF was measured continuously (one measurement every 4.5 seconds) before, during, and after intracarotid infusion of saline and l-arginine. The values presented are the means ± standard deviation of the CBF ratio during saline or l-arginine infusion in the same animals.

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    Bar graph showing degrees of vasospasm on Days 7 and 14 post-SAH in groups that received continuous infusion of saline (five animals) or l-arginine (six animals). We found no significant difference in the degree of vasospasm between the saline and l-arginine groups on Day 7 or Day 14. Values represent the percent decrease in the proximal 14-mm segment of the right MCA (RMCA) on postoperative AP arteriograms obtained after onset of SAH compared with the values obtained before SAH. The values presented are the means ± standard error of the mean of the decrease measured by three researchers who measured the vessel diameters in a blinded fashion.

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    Graph depicting levels of l-arginine and l-citrulline in plasma (µg/ml) during long-term intravenous infusion of l-arginine in six monkeys. Plasma l-arginine levels increased in response to the continuous intravenous infusion (* p < 0.05 on Day 7, ANOVA; ** p < 0.03 on Day 14, ANOVA); however, there was no change in plasma l-citrulline levels (p = 0.7). Error bars demonstrate the standard deviation of the mean.

References

  • 1.

    Afshar JKBPluta RMBoock RJet al: Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 83:1181221995Afshar JKB Pluta RM Boock RJ et al: Effect of intracarotid nitric oxide on primate cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 83:118–122 1995

  • 2.

    Barna MKomatsu TReiss CS: Activation of type III nitric oxide synthase in astrocytes following a neurotropic viral infection. Virology 223:3313431996Barna M Komatsu T Reiss CS: Activation of type III nitric oxide synthase in astrocytes following a neurotropic viral infection. Virology 223:331–343 1996

  • 3.

    Bevan JABevan RD: Arterial wall changes in chronic cerebrovasospasm: in vitro and in vivo pharmacological evidence. Annu Rev Pharmacol Toxicol 28:3113291988Bevan JA Bevan RD: Arterial wall changes in chronic cerebrovasospasm: in vitro and in vivo pharmacological evidence. Annu Rev Pharmacol Toxicol 28:311–329 1988

  • 4.

    Buchanan JEPhillis JW: The role of nitric oxide in the regulation of cerebral blood flow. Brain Res 610:2482551993Buchanan JE Phillis JW: The role of nitric oxide in the regulation of cerebral blood flow. Brain Res 610:248–255 1993

  • 5.

    Carter LPErspamer RBro WJ: Cerebral blood flow: thermal diffusion vs. isotope clearance. Stroke 12:5135181981Carter LP Erspamer R Bro WJ: Cerebral blood flow: thermal diffusion vs. isotope clearance. Stroke 12:513–518 1981

  • 6.

    Creager MAGallager SJGirerd XJet al: L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 90:124812531992Creager MA Gallager SJ Girerd XJ et al: L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 90:1248–1253 1992

  • 7.

    Drexler HZeiher AMeinzer Ket al: Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 338:154615501991Drexler H Zeiher A Meinzer K et al: Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 338:1546–1550 1991

  • 8.

    Edwards DHByrne JVGriffith TM: The effect of chronic subarachnoid hemorrhage on basal endothelium-derived relaxing factor activity in intrathecal cerebral arteries. J Neurosurg 76:8308371992Edwards DH Byrne JV Griffith TM: The effect of chronic subarachnoid hemorrhage on basal endothelium-derived relaxing factor activity in intrathecal cerebral arteries. J Neurosurg 76:830–837 1992

  • 9.

    Endoh MMaiese KWagner J: Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res 651:921001994Endoh M Maiese K Wagner J: Expression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res 651:92–100 1994

  • 10.

    Espinosa FWeir BOverton Tet al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 1: Clinical and radiological findings. J Neurosurg 60:116711751984Espinosa F Weir B Overton T et al: A randomized placebo-controlled double-blind trial of nimodipine after SAH in monkeys. Part 1: Clinical and radiological findings. J Neurosurg 60:1167–1175 1984

  • 11.

    Gold MEWood KSBuga GMet al: L-arginine causes whereas L-argininosuccinic acid inhibits endothelium-dependent vascular smooth muscle relaxation. Biochem Biophys Res Com 161:5365431989Gold ME Wood KS Buga GM et al: L-arginine causes whereas L-argininosuccinic acid inhibits endothelium-dependent vascular smooth muscle relaxation. Biochem Biophys Res Com 161:536–543 1989

  • 12.

    Goretski JHollocher TC: Trapping of nitric oxide produced during denitrification by extracellular hemoglobin. J Biol Chem 263:231623231988Goretski J Hollocher TC: Trapping of nitric oxide produced during denitrification by extracellular hemoglobin. J Biol Chem 263:2316–2323 1988

  • 13.

    Hirose HIde KSasaki Tet al: The role of endothelin and nitric oxide in modulation of normal and spastic cerebral vascular tone in the dog. Eur J Pharmacol 277:77871995Hirose H Ide K Sasaki T et al: The role of endothelin and nitric oxide in modulation of normal and spastic cerebral vascular tone in the dog. Eur J Pharmacol 277:77–87 1995

  • 14.

    Iadecola CPelligrino DAMoskowitz MAet al: Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab 14:1751921994Iadecola C Pelligrino DA Moskowitz MA et al: Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab 14:175–192 1994

  • 15.

    Iadecola CZhang FXu Set al: Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:3783841995Iadecola C Zhang F Xu S et al: Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:378–384 1995

  • 16.

    Ignarro LJ: Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30:5355601990Ignarro LJ: Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30:535–560 1990

  • 17.

    Ignarro LJ: Endothelial-derived nitric oxide: actions and properties. FASEB J 3:31361989Ignarro LJ: Endothelial-derived nitric oxide: actions and properties. FASEB J 3:31–36 1989

  • 18.

    Ignarro LJ: Signal transduction mechanisms involving nitric oxide. Biochem Pharmacol 41:4854901991Ignarro LJ: Signal transduction mechanisms involving nitric oxide. Biochem Pharmacol 41:485–490 1991

  • 19.

    Ignarro LJAdams JBHorwitz PMet al: Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange. J Biol Chem 261:499750021986Ignarro LJ Adams JB Horwitz PM et al: Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange. J Biol Chem 261:4997–5002 1986

  • 20.

    Irikura KHuang PLMa Jet al: Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression. Proc Natl Acad Sci USA 92:682368271995Irikura K Huang PL Ma J et al: Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression. Proc Natl Acad Sci USA 92:6823–6827 1995

  • 21.

    Irikura KMaynard KIMoskowitz MA: Importance of nitric oxide synthase inhibition to the attenuated vascular responses induced by topical L-nitroarginine during vibrissal stimulation. J Cereb Blood Flow Metab 14:45481994Irikura K Maynard KI Moskowitz MA: Importance of nitric oxide synthase inhibition to the attenuated vascular responses induced by topical L-nitroarginine during vibrissal stimulation. J Cereb Blood Flow Metab 14:45–48 1994

  • 22.

    Kajita YSuzuki YOyama Het al: Combined effect of L-arginine and superoxide dismutase on the spastic basilar artery after subarachnoid hemorrhage in dogs. J Neurosurg 80:4764831994Kajita Y Suzuki Y Oyama H et al: Combined effect of L-arginine and superoxide dismutase on the spastic basilar artery after subarachnoid hemorrhage in dogs. J Neurosurg 80:476–483 1994

  • 23.

    Kasuya HWeir BKANakane Met al: Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage. J Neurosurg 82:2502551995Kasuya H Weir BKA Nakane M et al: Nitric oxide synthase and guanylate cyclase levels in canine basilar artery after subarachnoid hemorrhage. J Neurosurg 82:250–255 1995

  • 24.

    Keilin DHartree E: Reaction of nitric oxide with haemoglobin and methemoglobin. Nature 139:5481937Keilin D Hartree E: Reaction of nitric oxide with haemoglobin and methemoglobin. Nature 139:548 1937

  • 25.

    Kim PJones JDBurnett PCet al: Decrease in high-energy phosphates in the cerebral artery during chronic vasospasm in Sano KTakakura KKassell NFet al (eds): Cerebral Vasospasm. Tokyo: University of Tokyo Press1990 pp 8386Kim P Jones JD Burnett PC et al: Decrease in high-energy phosphates in the cerebral artery during chronic vasospasm in Sano K Takakura K Kassell NF et al (eds): Cerebral Vasospasm. Tokyo: University of Tokyo Press 1990 pp 83–86

  • 26.

    Macdonald RLWeir BKA: A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke 22:9719821991Macdonald RL Weir BKA: A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke 22:971–982 1991

  • 27.

    Mayberg RMOkada TBark DH: The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg 72:6266331990Mayberg RM Okada T Bark DH: The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg 72:626–633 1990

  • 28.

    Mayer BHeinzel BKlatt Pet al: Nitric oxide synthase-catalyzed activation of oxygen and reduction of cytochromes: reaction mechanisms and possible physiological implications. J Cardiovasc Pharmacol 20 (Suppl 12):S54S561992Mayer B Heinzel B Klatt P et al: Nitric oxide synthase-catalyzed activation of oxygen and reduction of cytochromes: reaction mechanisms and possible physiological implications. J Cardiovasc Pharmacol 20 (Suppl 12):S54–S56 1992

  • 29.

    McPherson RWKirsch JRGhaly RFet al: Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates. Stroke 26:6826871995McPherson RW Kirsch JR Ghaly RF et al: Effect of nitric oxide synthase inhibition on the cerebral vascular response to hypercapnia in primates. Stroke 26:682–687 1995

  • 30.

    Moncada S: The L-arginine: nitric oxide pathway. Acta Physiol Scand 145:2012271992Moncada S: The L-arginine: nitric oxide pathway. Acta Physiol Scand 145:201–227 1992

  • 31.

    Moncada SHiggs A: The L-arginine-nitric oxide pathway. N Engl J Med 329:200220121993Moncada S Higgs A: The L-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012 1993

  • 32.

    Moncada SPalmer RMJHiggs EA: Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol 38:170917151989Moncada S Palmer RMJ Higgs EA: Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol 38:1709–1715 1989

  • 33.

    Moncada SPalmer RMJHiggs EA: Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:1091421991Moncada S Palmer RMJ Higgs EA: Nitric oxide: physiology pathophysiology and pharmacology. Pharmacol Rev 43:109–142 1991

  • 34.

    Morikawa EHuang ZRosenblatt Set al: Therapeutic potential of L-arginine, a precursor of nitric oxide, in focal cerebral ischemia in Bevan RDBevan JA (eds): The Human Brain Circulation. Totowa, NJ: Humana Press1994 pp 373387Morikawa E Huang Z Rosenblatt S et al: Therapeutic potential of L-arginine a precursor of nitric oxide in focal cerebral ischemia in Bevan RD Bevan JA (eds): The Human Brain Circulation. Totowa NJ: Humana Press 1994 pp 373–387

  • 35.

    Morikawa ERosenblatt SMoskowitz MA: L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia. Br J Pharmacol 107:9059071992Morikawa E Rosenblatt S Moskowitz MA: L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia. Br J Pharmacol 107:905–907 1992

  • 36.

    Murphy SMinor RL JrWelk Get al: Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide. J Neurochem 55:3493511990Murphy S Minor RL Jr Welk G et al: Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide. J Neurochem 55:349–351 1990

  • 37.

    Nakaki THishikawa KSuzuki Het al: L-arginine-induced hypotension. Lancet 336:6961990 (Letter)Nakaki T Hishikawa K Suzuki H et al: L-arginine-induced hypotension. Lancet 336:696 1990 (Letter)

  • 38.

    Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 6:305130641992Nathan C: Nitric oxide as a secretory product of mammalian cells. FASEB J 6:3051–3064 1992

  • 39.

    Ngai AMeno JWinn H: Effects of nitric oxide synthase inhibition on the pial dilator responses to hypercarbia and somatosensory stimulation. J Cereb Blood Flow Metab 13 (Suppl 1):S1351993 (Abstract)Ngai A Meno J Winn H: Effects of nitric oxide synthase inhibition on the pial dilator responses to hypercarbia and somatosensory stimulation. J Cereb Blood Flow Metab 13 (Suppl 1):S135 1993 (Abstract)

  • 40.

    Nozaki KMoskowitz MAMaynard KIet al: Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 13:70791993Nozaki K Moskowitz MA Maynard KI et al: Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 13:70–79 1993

  • 41.

    Olesen JPaulson OB: The effect of intra-arterial papaverine on the regional cerebral blood flow in patients with stroke or intracranial tumor. Stroke 2:1481591971Olesen J Paulson OB: The effect of intra-arterial papaverine on the regional cerebral blood flow in patients with stroke or intracranial tumor. Stroke 2:148–159 1971

  • 42.

    Palmer RMJAshton DSMoncada S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:6646661988Palmer RMJ Ashton DS Moncada S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664–666 1988

  • 43.

    Pluta RMAfshar JKBBoock RJet al: Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in subarachnoid hemorrhage. J Neurosurg 88:5575611997Pluta RM Afshar JKB Boock RJ et al: Temporal changes in perivascular concentrations of oxyhemoglobin deoxyhemoglobin and methemoglobin in subarachnoid hemorrhage. J Neurosurg 88:557–561 1997

  • 44.

    Pluta RMOldfield EHBoock RJ: Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. J Neurosurg 87:7467511997Pluta RM Oldfield EH Boock RJ: Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage. J Neurosurg 87:746–751 1997

  • 45.

    Pluta RMThompson BGDawson TMet al: Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm. J Neurosurg 84:6486541996Pluta RM Thompson BG Dawson TM et al: Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm. J Neurosurg 84:648–654 1996

  • 46.

    Pluta RMZauner AMorgan JKet al: Is vasospasm related to proliferative arteriopathy? J Neurosurg 77:7407481992Pluta RM Zauner A Morgan JK et al: Is vasospasm related to proliferative arteriopathy? J Neurosurg 77:740–748 1992

  • 47.

    Pollock JSFörstermann UMitchell JAet al: Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci USA 88:10480104841991Pollock JS Förstermann U Mitchell JA et al: Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci USA 88:10480–10484 1991

  • 48.

    Reutens DCMcHugh MDToussaint PJet al: L-arginine infusion increases basal but not activated cerebral blood flow in humans. J Cereb Blood Flow Metab 17:3093151997Reutens DC McHugh MD Toussaint PJ et al: L-arginine infusion increases basal but not activated cerebral blood flow in humans. J Cereb Blood Flow Metab 17:309–315 1997

  • 49.

    Rosenblum WINishimura HNelson GH: Endothelium-dependent L-Arg- and L-NMMA-sensitive mechanisms regulate tone of brain microvessels. Am J Physiol 259:H1396H14011990Rosenblum WI Nishimura H Nelson GH: Endothelium-dependent L-Arg- and L-NMMA-sensitive mechanisms regulate tone of brain microvessels. Am J Physiol 259:H1396–H1401 1990

  • 50.

    Suzuki SKassell NFLee KS: Hemin activation of an inducible isoform of nitric oxide synthase in vascular smooth-muscle cells. J Neurosurg 83:8628661995Suzuki S Kassell NF Lee KS: Hemin activation of an inducible isoform of nitric oxide synthase in vascular smooth-muscle cells. J Neurosurg 83:862–866 1995

  • 51.

    Suzuki YKajita YOyama Het al: Dysfunction of nitric oxide in the spastic basilar arteries after subarachnoid hemorrhage. J Auton Nerv Syst 49 (Suppl):S83S871994Suzuki Y Kajita Y Oyama H et al: Dysfunction of nitric oxide in the spastic basilar arteries after subarachnoid hemorrhage. J Auton Nerv Syst 49 (Suppl):S83–S87 1994

  • 52.

    Tapia R: Glutamine metabolism in brain in Mora JPalacois R (eds): Glutamine: Metabolism Enzymology and Regulation. New York: Academic Press1980 p 285Tapia R: Glutamine metabolism in brain in Mora J Palacois R (eds): Glutamine: Metabolism Enzymology and Regulation. New York: Academic Press 1980 p 285

  • 53.

    Thompson BGPluta RMGirton MEet al: Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates. J Neurosurg 84:71781995Thompson BG Pluta RM Girton ME et al: Nitric oxide mediation of chemoregulation but not autoregulation of cerebral blood flow in primates. J Neurosurg 84:71–78 1995

  • 54.

    Toda NAyajiki KYoshida Ket al: Impairment by damage of the pterygopalatine ganglion of nitroxidergic vasodilator nerve function in canine cerebral and retinal arteries. Circ Res 72:2062131993Toda N Ayajiki K Yoshida K et al: Impairment by damage of the pterygopalatine ganglion of nitroxidergic vasodilator nerve function in canine cerebral and retinal arteries. Circ Res 72:206–213 1993

  • 55.

    Tomimoto HNishimura MSuenaga Tet al: Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissue. J Cereb Blood Flow Metab 14:9309381994Tomimoto H Nishimura M Suenaga T et al: Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissue. J Cereb Blood Flow Metab 14:930–938 1994

  • 56.

    Vane JRÄnggård EEBotting RM: Regulatory functions of the vascular endothelium. N Engl J Med 323:27361990Vane JR Änggård EE Botting RM: Regulatory functions of the vascular endothelium. N Engl J Med 323:27–36 1990

  • 57.

    Wang QPaulson OBLassen NA: Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension. J Cereb Blood Flow Metab 12:9479531992Wang Q Paulson OB Lassen NA: Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension. J Cereb Blood Flow Metab 12:947–953 1992

  • 58.

    Wang QPellegrino DABaughman VLet al: The role of neuronal nitric oxide synthase in regulation of cerebral blood flow in normocapnia and hypercapnia in rats. J Cereb Blood Flow Metab 15:7747781995Wang Q Pellegrino DA Baughman VL et al: The role of neuronal nitric oxide synthase in regulation of cerebral blood flow in normocapnia and hypercapnia in rats. J Cereb Blood Flow Metab 15:774–778 1995

  • 59.

    Weir BGrace MHansen Jet al: Time course of vasospasm in man. J Neurosurg 48:1731811978Weir B Grace M Hansen J et al: Time course of vasospasm in man. J Neurosurg 48:173–181 1978

  • 60.

    Wink DAMitchell JB: Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25:4344561998Wink DA Mitchell JB: Chemical biology of nitric oxide: insights into regulatory cytotoxic and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25:434–456 1998

  • 61.

    Yoshida TWaeber CHuang Zet al: Induction of nitric oxide synthase activity in rodent brain following middle cerebral artery occlusion. Neurosci Lett 194:2142181995Yoshida T Waeber C Huang Z et al: Induction of nitric oxide synthase activity in rodent brain following middle cerebral artery occlusion. Neurosci Lett 194:214–218 1995

  • 62.

    Zhang ZGChopp MMaynard KIet al: Cerebral blood flow changes during cortical spreading depression are not altered by inhibition of nitric oxide synthesis. J Cereb Blood Flow Metab 14:9399431994Zhang ZG Chopp M Maynard KI et al: Cerebral blood flow changes during cortical spreading depression are not altered by inhibition of nitric oxide synthesis. J Cereb Blood Flow Metab 14:939–943 1994

  • 63.

    Ziegler TRBenfell KSmith RJet al: Safety and metabolic effects of L-glutamine administration in humans. J Parenter Enteral Nutr 14 (Suppl 4):137S146S1990Ziegler TR Benfell K Smith RJ et al: Safety and metabolic effects of L-glutamine administration in humans. J Parenter Enteral Nutr 14 (Suppl 4):137S–146S 1990

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