Skip to main content
SpringerLink
Log in

Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man

  • Clinical Articles
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Summary

A possible involvement of perivascular vasodilatory neuropeptides in subarachnoid haemorrhage (SAH) has been evaluated in man by measuring the levels of calcitonin gene related peptide (CGRP)-, substance P (SP)- and vasoactive intestinal peptide (VIP)-like immunoreactivity (LI) in the cranial venous outflow and in CSF in 34 patients admitted to the hospital after an acute SAH.

After operation with aneurysm clipping and nimodipine treatment, blood samples were taken from the external jugular vein (EJV) or cerebrospinal fluid (CSF) and analysed for neuropeptide levels with specific radioimmuno assays (RIA) during the postoperative course. The degree of vasoconstriction in the patients was monitored with Doppler ultrasound recordings bilaterally from the middle cerebral (MCA) and internal carotid arteries (ICA) following the EJV blood sampling every second day.

The mean value of all CGRP-LI measurements in EJV during the entire course of SAH (n=20) revealed a significantly higher level as compared to controls. The highest CGRP-LI levels were found in patients with the highest velocity index values (vasospasm). The relationship Vmean MCA/Vmean ICA was used as an index of vasoconstriction. In patients with MCA aneurysms (n=10), a significant correlation (r=0.65, p<0.05) was found between the vasospasm index and CGRP-LI levels. There were no changes observed in the SP- and VIP-LI levels. Alterations in cerebrovascular tone induced by changing arterial CO2 tension or lowering of blood pressure (ketanserin infusion test) did not alter the levels of the perivascular peptides in the EJV. In addition, CGRP-, SP-, VIP- and neuropeptide Y (NPY)-LI were analysed in CSF in the post-operative course after subarachnoid haemorrhage (SAH) in 14 patients. The CSF VIP-LI was lower in SAH than in control (p<0.05). The CGRP-LI level was measurable in SAH CSF but not in CSF of controls. In individual patients with marked vasoconstriction increased levels of CGRP-LI (up to 14 pmol/L) and NPY-LI (up to 232 pmol/L) were observed.

The results of this study are in support of our hypothesis that there is an involvement of the sensory peptide CGRP in a dynamic reflex aimed at counterbalancing vasoconstriction in SAH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aaslid R, Huber P, Nornes H (1984) Evaluation of cerebrovascular spasm with transcranial Doppler ultrasound. J Neurosurg 60: 37–41

    PubMed  Google Scholar 

  2. Aaslid R, Markwalder TM, Nornes H (1982) Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 57: 769–774

    PubMed  Google Scholar 

  3. Arienta C, Balbi S, Caroli M, Fumagalli G (1991) Depletion of calcitonin gene-related peptide in perivascular nerves during acute phase of posthemorrhagic vasospasm in the rabbit. Brain Res Bull 27: 605–609

    PubMed  Google Scholar 

  4. Brodin E, Lindefors N, Theodorsson-Norheim E, Peterson L-L, Bartfai T, Øgren S-O, Rosell S (1985) Tachykinins in rat central nervous system: distribution, molecular forms, release and effects of chronic treatment with antidepressant drugs. In: Håkanson R, Sundler F (eds) Tachykinin antagonists. Elsevier, Amsterdam, pp 15–27

    Google Scholar 

  5. Edvinsson L, Alafaci C, Delgado T, Ekman R, Jansen I, Svendgaard NA, Uddman R (1991) Neuropeptide Y and vasoactive intestinal peptide in experimental subarachnoid hemorrhage: immunocytochemistry, radioimmunoassay and pharmacology. Acta Neurol Scand 83: 103–109

    PubMed  Google Scholar 

  6. Edvinsson L, Delgado-Zygmunt T, Ekman R, Jansen I, Svendgaard N-A, Uddman R (1990) Involvement of perivascular sensory fibers in the pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. J Cereb Blood Flow Metab 10: 602–607

    PubMed  Google Scholar 

  7. Edvinsson L, Ekman R, Jansen L, McCulloch J, Mortensen AA, Uddman R (1991) Reduced levels of calcitonin gene-related peptide-like immunoreactivity in human brain vessels after subarachnoid haemorrhage. Neurosci Lett 121: 151–154

    PubMed  Google Scholar 

  8. Edvinsson L, Ekman R, Thulin T (1991) Increased plasma levels of neuropeptide Y-like immunoreactivity and catecholamines in severe hypertension remain after treatment to normotension in man. Reg Pept 32: 279–287

    Google Scholar 

  9. Edvinsson L, Erlinge D, Ekman R, Thulin T (1992) Sensory nerve terminal activity in severe hypertension as reflected by circulating calcitonin gene-related peptide (CGRP) and substance P. Blood Pressure 1: 223–229

    PubMed  Google Scholar 

  10. Edvinsson L, Hara H, Uddman R (1989) Retrograde tracing of nerve fibers to the rat middle cerebral artery with true blue: colocalization with different peptides. J Cereb Blood Flow Metab 9: 212–218

    PubMed  Google Scholar 

  11. Edvinsson L, Jansen I, Kingman TA, McCulloch J (1990) Cerebrovascular responses to capsaicin in vitro and in situ. Br J Pharmacol 100: 312–318

    PubMed  Google Scholar 

  12. Edvinsson L, McCulloch J, Kingman TA, Uddman R (1987) Functional significance of the trigemino-cerebrovascular innervation: Involvement in cerebrovascular disorders. Advances in headache research. In: Clifford Rose F (ed) Libbey, UK, pp 87–93

    Google Scholar 

  13. Edvinsson L, Uddman R (eds) (1993) Vascular innervation and receptor mechanisms. Academic Press, San Diego, pp 1–475

    Google Scholar 

  14. Edvinsson L, McCulloch J, Kingman TA, Uddman R (1986) On the functional role of the trigemino-cerebrovascular system in the regulation of cerebral circulation. In: Owman C, Hardebo JE (eds) Neural regulation of brain circulation. Elsevier, Amsterdam, pp 407–418

    Google Scholar 

  15. Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6: 1–9

    PubMed  Google Scholar 

  16. Gibbins IL, Brayden JE, Bevan JA (1984) Distribution and origin of VIP-immunoreactive nerves in the cephalic circulation of the cat. Peptides 5: 209–212

    Google Scholar 

  17. Gjerris A, Gjerris F, Sorensen PS,et al (1988) Do concentrations of neurotransmitters measured in lumbar cerebrospinal fluid reflect the concentrations at brain level? Acta Neurochir (Wien) 91: 55–59

    Google Scholar 

  18. Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33: 48–59

    PubMed  Google Scholar 

  19. Goadsby PJ, Edvinsson L, Ekman R (1988) Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol 23: 193–196

    PubMed  Google Scholar 

  20. Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of human during migraine headache. Ann Neurol 28: 183–187

    PubMed  Google Scholar 

  21. Gray (1989) Veins of the head and neck. In: Williams PL, Warwick R, Dyson M, Bannister LH (eds) Gray's anatomy. pp 739–805

  22. Grolimund P, Seiler RW (1988) Age dependence of the flow velocity in the basal cerebral arteries — a transcranial Doppler ultrasound study. Ultrasound Med Biol 3: 191–198

    Google Scholar 

  23. Grunditz T, Ekman R, Håkanson R (1986) Calcitonin generelated peptide in thyroid nerve fibers and C cells. Effects on thyroid hormone secretion and response to hypercalcemia. Endocrinology 119: 2313–2324

    PubMed  Google Scholar 

  24. Hara H, Edvinsson L (1987) Perivascular innervation of the cerebral circulation: involvement in the pathophysiology of subarachnoid hemorrhage. Rev Neurosurg 10: 171–179

    Google Scholar 

  25. Hara H, Hamill GS, Jacobowitz DM (1985) Origin of cholinergic nerves to the rat major cerebral arteries: Coexistence with vasoactive intestinal polypeptide. Brain Res Bull 14: 179–188

    PubMed  Google Scholar 

  26. Hara H, Nosko M, Weir B (1986) Cerebral perivascular nerves in subarachnoid hemorrhage. A histochemical and immunological study. J Neurosurg 65: 531–539

    PubMed  Google Scholar 

  27. Heistad DD, Marcus ML, Said SI,et al (1980) Effect of acetylcholine and vasoactive intestinal peptide on cerebral blood flow. Am J Physiol 239: H 73-H 80

    Google Scholar 

  28. Helm G, Ekman R, Rydhström H, Sjöberg NO, Walles B (1985) Changes in oviductal VIP contents induced by sex stereoids and inhibitory effect of VIP on spontaneous oviductal contractility. Acta Physiol Scand 125: 219–224

    PubMed  Google Scholar 

  29. Hunt WE, Hess RM (1988) Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28: 14–20

    Google Scholar 

  30. Hunt WE, Kassell N, Pertuiset B, Sano K, Teasdale G, de Villier J, Drake CG (1988) Report of the World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Haemorrhage Grading Scale. J Neurosurg 68: 985–986

    PubMed  Google Scholar 

  31. Jackowski A, Crockard A, Burnstock G, Lincoln J (1989) Alterations in serotonin and neuropeptide Y content of cerebrovascular sympathetic nerves following experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 9: 271–279

    PubMed  Google Scholar 

  32. Jansen I, Uddman R, Ekman R, Olesen J, Ottosson A, Edvinsson L (1992) Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides 13: 527–536

    PubMed  Google Scholar 

  33. Jennet B, Bond M (1975) Assessment of outcome after severe brain damage. A practical scale. Lancet 1: 480–484

    PubMed  Google Scholar 

  34. Juul R, Edvinsson L, Fredriksen TA, Ekman R, Brubakk AO, Gisvold SE (1990) Changes in the levels of Neuropeptide Y-LI in the external jugular vein in connection with vasoconstriction following subarachnoid haemorrhage in man. Involvement of sympathetic neuropeptide Y in cerebral vasospasm. Acta Neurochir (Wien) 107: 75–81

    Google Scholar 

  35. Juul R, Edvinsson L, Gisvold SE,et al (1990) Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigemino-cerebrovascular system? Br J Neurosurg 4: 171–180

    PubMed  Google Scholar 

  36. Kobayashi S, Kyoshima K, Olshowka JA, Jacobowitz DM (1983) Vasoactive intestinal polypeptide immunoreactive and cholinergic nerves in the whole mount preparation of the major cerebral arteries of the rat. Histochemistry 79: 377–381

    PubMed  Google Scholar 

  37. Kontos HA (1989) Validity of cerebral arterial blood flow calculations from velocity measurements. Stroke 20: 1–3

    PubMed  Google Scholar 

  38. Larsen JJ, Boeck V, Ottesen B (1981) Effect of vasoactive intestinal polypeptide on cerebral blood flow in the goat. Acta Physiol Scand 111: 471–474

    PubMed  Google Scholar 

  39. Lindegaard K-F, Grolimund P, Aaslid R, Nornes H (1986) Evaluation of cerebral AVMs using transcranial Doppler ultrasound. J Neurosurg 65: 335–344

    PubMed  Google Scholar 

  40. Lindegaard K-F, Nornes H, Bakke SJ, Sorteberg W, Nakstad P (1988) Vasospasm after subarachnoid haemorrhage investigated by means of transcranial Doppler ultrasound. Acta Neurochir (Wien) [Suppl] 42: 81–84

    Google Scholar 

  41. Linnik MD, Sakas DE, Uhl GR, Moskowitz MA (1989) Sub-arachnoid blood and headache: altered trigeminal tachykinin gene expression. Ann Neurol 25: 179–184

    PubMed  Google Scholar 

  42. Mayberg MR, Zervas NT, Moskowitz MA (1984) Trigeminal projections to supratentorial pial and dura blood vessels in cats demonstrated by horseradish peroxidase histochemistry. J Comp Neurol 223: 46–56

    PubMed  Google Scholar 

  43. McCulloch J, Edvinsson L (1980) Cerebral circulatory and metabolic effects of vasoactive intestinal polypeptide. Am J Physiol 238: H 449-H 456

    Google Scholar 

  44. McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci USA 83: 5731–5735

    PubMed  Google Scholar 

  45. Moskowitz MA, Wei EP, Saito K, Kontos HA (1988) Trigeminalectomy modifies arteriolar responses to hypertension or norepinephrine. Am J Physiol 255: H 1-H 6

    Google Scholar 

  46. Nozaki K, Moskowitz MA, Maynard KI, Koketsu N, Dawson TM, Bredt DS, Snyder SH (1993) Possible origins and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 13: 70–79

    PubMed  Google Scholar 

  47. Nozaki K, Kikuchi H, Mizuno (1989) Changes in calcitonin gene-related peptide-like immunoreactivity in cerebrovascular nerve fibers in the dog after experimentally produced subarachnoid hemorrhage. Neurosci Lett 102: 27–32

    PubMed  Google Scholar 

  48. Olsen KS, Videbaek C, Schmidt JF, Paulson OB (1992) The effect of ketanserin on cerebral blood flow and cerebrovascular CO2 reactivity in healthy volunteers. Acta Neurochir 119: 7–11

    Google Scholar 

  49. Sakas DE, Moskowitz MA, Wei EP, Kontos HA, Kano M, Ogilvy CS (1989) Trigeminovascular fibers increase blood flow in cortical gray matter by axon reflex-like mechanisms during acute severe hypertension or seizure. Proc Natl Acad Sci USA 86: 1401–1405

    PubMed  Google Scholar 

  50. Seylaz J, Hara H, Pinard E, Mraovitch S, MacKenzie ET, Edvinsson L (1988) Effect of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat. J Cereb Blood Flow Metab 8: 875–879

    PubMed  Google Scholar 

  51. Suzuki N, Hardebo JE, Kåhrström J,et al (1990) Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat. J Cereb Blood Flow Metab 10: 383–391

    PubMed  Google Scholar 

  52. Suzuki N, Hardebo JE, Owman C (1988) Origins and pathways of cerebrovascular vasoactive intestinal polypeptide-positive nerves in rat. J Cereb Blood Flow Metab 8: 697–712

    PubMed  Google Scholar 

  53. Suzuki Y, Sato S, Suzuki H, Namba J, Ohtake R, Hashigami Y, Suga S, Ishihara N, Shimoda S-I (1989) Increased neuropeptide Y concentrations in cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage. Stroke 20: 1680–1684

    PubMed  Google Scholar 

  54. Svendgaard NA, Edvinsson L, Owman C, Sahlin C (1977) Increased sensitivity of the basilar artery to norepinephrine and 5-hydroxytryptamine following experimental subarachnoid hemorrhage. Surg Neurol 8: 191–195

    PubMed  Google Scholar 

  55. Teasdale G, Jennet B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2: 81–84

    PubMed  Google Scholar 

  56. Uddman R, Edvinsson L (1989) Neuropeptides in the cerebral circulation. Cerebrovasc Brain Metab Rev 1: 230–252

    PubMed  Google Scholar 

  57. Uddman R, Edvinsson L, Ekman R, McCulloch J, Kingman TA (1985) Innervation of the feline cerebral vasculature by nerve fibres containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 62: 131–136

    PubMed  Google Scholar 

  58. Walters BB, Gillespie SA, Moskowitz MA (1986) Cerebrovascular projections from the sphenopalatine and otic ganglion to the middle cerebral artery of the cat. Stroke 17: 488–494

    PubMed  Google Scholar 

  59. Widelöv E, Lindström LH, Wahlestedt C,et al (1988) Neuropeptide Y (NPY) and peptide Y (PYY) as possible cerebrospinal fluid markers for major depression and schizophrenia, respectively. J Psychiatr Res 22: 69–79

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University Hospital of Trondheim, Norway

    R. Juul & T. A. Fredriksen

  2. Department of Biomedical Engineering, University Hospital of Trondheim, Norway

    A. O. Brubakk

  3. Department of Anesthesia, University Hospital of Trondheim, Norway

    S. E. Gisvold

  4. Department of Neurology, Rigshospitalet, Copenhagen, Denmark

    G. Waldemar & J. F. Schmidt

  5. Department of Internal Medicine, University Hospital of Lund, Sweden

    H. Hara, R. Ekman & L. Edvinsson

Authors
  1. R. Juul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. E. Gisvold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. O. Brubakk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T. A. Fredriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Waldemar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. F. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Ekman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. Edvinsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Juul, R., Hara, H., Gisvold, S.E. et al. Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man. Acta neurochir 132, 32–41 (1995). https://doi.org/10.1007/BF01404845

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01404845

Keywords

Search

Navigation