Restricted accessResearch articleFirst published online 2005-5
The effect of I.V. L-N G Methylarginine Hydrochloride (L-NMMA: 546C88) on Basal and Acetazolamide (Diamox®) induced Changes of Blood Velocity in Cerebral Arteries and Regional Cerebral Blood flow in Man
The aim of this study was to estimate the effect of Nitric Oxide synthase (NOS)-inhibition (L-NMMA) on the diameter of the middle cerebral artery (MCA) and on regional cerebral blood flow (rCBF). Furthermore, to assess the effect of L-NMMA on acetazolamide induced increases in MCA blood velocity (Vmean) and rCBF. In an open crossover design 12 healthy subjects attended the laboratory twice. The first day 6 mg/kg L-LNMMA i.v. over 15 min preceded 1 g acetazolamide iv over 5 min. Eight days later only acetazolamide was given. Vmean in MCA was determined with transcranial Doppler (TCD) and rCBF with Xe-133 inhalation SPECT at baseline, after L-NMMA and 25 and 55 min after acetazolamide infusion. After L-NMMA the decrease in rCBFMCA was 6.8% (± 7.4) (P < 0.019, n = 12), whereas Vmean was not affected (P = 0.83, n = 8). The change in MCA diameter was estimated to -1.3% (P = 0.44, n = 8). L-NMMA did not affect acetazolamide increases in Vmean (P = 0.67, n = 8) nor rCBF (P = 0.29, n = 12). The percentage increase of Vmean was 1.5 times that of rCBF (n = 8). Our data suggest that the basal tone of human cerebral arterioles but not of conduit arteries is NO-dependent. The action of acetazolamide in man is not NO-dependent.
LassenLHAshinaMChristiansenIUlrichVOlesenJ. Nitric oxide synthase inhibition in migraine. Lancet1997; 349: 401–2.
3.
NagayamaMZhangFIadecolaC. Delayed treatment with aminoguanidine decreases focal cerebral ischemic damage and enhanges neurologic recovery in rats. J Cereb Blood Flow Metab1998; 18: 1107–13.
4.
O'NeilMJMurrayTKMcCartyDRHicksCADellCPPatrickKE, ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia. Brain Res2000; 871: 234–44.
5.
AldertonWKCooperCEKnowlesRG. Review article. Nitric oxide synthases: structure, function and inhibition. Biochem J2001; 357: 593–615.
6.
IadecolaCPelligrino DA, MoskowitzMALassenNA. State of the art review. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab1994; 14: 175–92.
7.
KissBDallingerSFindlORainerGEichlerH-GSchmettererL. Acetazolamide-induced cerebral and ocular vasodilatation is independent of nitric oxide. Am J Physiol1999; 276: 1661–7.
8.
WhiteRPDeaneCVallancePMarkusHS. Nitric oxide synthase inhibition in humans reduces cerebral blood flow but not the hyperemic response to hyper capnia. Stroke1998; 29: 467–72.
9.
Van MilAHMSpiltAVan BuchemMABollenELEMTeppemaLWestendorpRGJ, Nitric oxide mediates hypoxia-induced cerebral vasodilatation in humans. J Appl Physiol2002; 92: 962–6.
10.
WhiteRPHindleyCBloomfieldPMCunninghamVJVallancePBrooksDJ, The effects of nitric Oxide synthase inhibitor L-NMMA on basal CBF and vasoneuronal coupling in man: a PET study. J Cereb Blood Flow Metab1999; 19: 673–8.
11.
OlesenJThomsenLLLassenLHOlesenIJ. The nitric oxide hypothesis of migraine and other vascular headaches. Cephalalgia1995; 15: 94–100.
12.
LauritzenM. Review article. Pathophysiology of the migraine aura. The spreading depression theory. Brain1994; 117: 199–210.
13.
OlesenJFribergLOlsenTSIversenHKLassenNAAndersenAR, Timing and tomography of cerebral blood flow, aura and headache during migraine attacks. Ann Neurol1990; 28: 791–8.
14.
CelsisPGoldmanTHenriksenLLassenNA. A method for calculating regional cerebral blood flow from emission computed tomography of inert gas concentrations. J Comput Assist Tomogr1981; 5: 641–5.
15.
HolmS. Radiation doses with Xenon-133, xenon-127 and Tc99m HMPAO. In: OlesenJ, editor. Migraine and Other Headaches: the Vascular Mechanisms. New York: Raven Press, 1991: 43–6.
16.
SortebergW. Cerebral artery blood velocity and cerebral blood flow. In: NewellDWAaslidR, editors. Transcranial Doppler. New York: Raven Press, 1992: 57–67.
17.
DahlARussellDNyberg-HansenRRootweltK. Effect of nitroglycerin on cerebral circulation measured by transcranial doppler and SPECT. Stroke1989; 20: 1733–6.
18.
MarkwalderT-MGrolimundPSeilerRWRothFAaslidR. Dependency of blood flow velocity in the middle cerebral artery on end-tidal carbon dioxide partial pressure – A Transcranial Ultrasound Doppler Study. J Cereb Blood Flow Metab1984; 4: 368–72.
19.
JoshiSYoungWLDuongHOstapkovichNDAagaaardBDHashimotoTPile–SpellmanJ. Intracarotid infusion of the nitric oxide synthase inhibitor, L-NMMA, modestly decreases cerebral blood flow in human subjects. Anesthesiology2000; 93: 699–707.
20.
IrikuraKMaynardKIMoskowitzMA. Importance of nitric oxide synthase inhibition to the attenuated vascular responses induced by topical L-Nitroarginine during vibrissal stimulation. J Cereb Blood Flow Metab1994; 14: 45–8.
MicieliGBosoneBCostaACavalliniAMarcheselliSPompeoF, Opposite effects of 1-arginine and nitroglycerin on cerebral blood velocity: Nitric oxide precursors and cerebral blood velocity. J Neurol Sci1997; 150: 71–5.
23.
LassenNA. Cerebral blood flow and oxygen consumption in man. Physiol Rev1959; 39: 183–238.
24.
LassenLHIversenHKOlesenJO. A dose-respose study of nitric oxide synthase inhibition in different vascular beds in man. Eur J Clin Pharmacol2003; 59: 499–505.
25.
LassenLHChristiansenIIversenHKJansen-OlesenIOlesenJ. The effects of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs. Cephalalgia2003; 23: 877–86.
26.
SchmettererLWolztMGrasilliUFindlOStrennKSimakS, Nitric oxide synthase inhibition in the histamine headache model. Cephalalgia1997; 17: 175–82.
27.
AdamsRJNicholsFTHessDC. Normal values and physiological variables. In: NewellDWAaslidR, editors. Transcranial Doppler. New York: Raven Press, 1992: 41–8.
28.
LiuGTVolpeNJGalettaSL. Pseudotumor cerebri and its treatment. Drugs Today1998; 34: 563–74.
29.
HaanJSluisPFerrariM. Acetazolamide treatment for migraine aura status. Neurology2000; 55: 1588–9.
30.
VahediKTaupinPDjombyREl-AmraniMLutzGFilipettiV, Diamig investigators. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol2002; 249: 206–11.
31.
SeveringhausJWCotevS. Carbonic acidosis and cerebral vasodilation after diamox. Scand J Clin Lab Invest1968; 102: I: E.
32.
BicklerPELittLBanvilleDLSeveringhausJW. Effects of acetazolamide on cerebral acid-base balance. J Appl Physiol1988; 65: 422–7.
33.
VorstrupSJensenKEThomsenCHenriksenOLassenNAPoulsonOB. Neuronal pH regulation: constant normal intracellular pH is maintained in brain during low extra cellular pH induced by acetazolamide 31P NMR study. J Cereb Blood Flow Metab1989; 9: 417–21.
34.
JensenKEThomsenCHenriksenO. In vivo measurement of intracellular pH in human brain during different tensions of carbon dioxide in arterial blood. A 31P-NMR Study. Acta Physiol Scand1988; 134: 295–8.
35.
CseteKBarzóPBodosiMPappJG. Influence of nitrovasodilators and cyclooxygenase inhibitors on cerebral vasoreactivity in conscious rabbits. Eur J Pharmacol2001; 412: 301–9.
36.
WangQPoulsonOBLassenNA. 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 Metab1992; 12: 947–53.
37.
HeinzelBJohnMKlattPBöhmeEMayerB. Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. Biochem J1992; 281: 627–30.
38.
DahlARussellDRootweltKNyberg-HansenRKertyE. Cerebral vasoreactivity assessed with transcranial doppler and regional cerebral blood flow measurements. Dose, serum concentration, and time course of the response to acetazolamide. Stroke1995; 26: 2302–6.
