Subarachnoid hemorrhage—induced upregulation of the 5-HT1B receptor in cerebral arteries in rats

Jacob Hansen-Schwartz M.D., Ph.D.1, Natalie Løvland Hoel B.S.1, Cang-Bao Xu M.D., Ph.D.1, Niels-Aage Svendgaard M.D., Ph.D.1, and Lars Edvinsson M.D., Ph.D.1
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  • 1 Department of Clinical Experimental Research, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark; and Department of Internal Medicine, Lund University Hospital, Lund, Sweden
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Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced blood flow in the brain. Inspired by organ culture—induced changes in the receptor phenotype of cerebral arteries, the authors investigated possible changes in the 5-hydroxytryptamine (HT) receptor phenotype after experimental SAH.

Methods. Experimental SAH was induced in rats by using an autologous prechiasmatic injection of arterial blood. Two days later, the middle cerebral artery (MCA), posterior communicating artery (PCoA), and basilar artery (BA) were harvested and examined functionally with the aid of a sensitive in vitro pharmacological method and molecularly by performing quantitative real-time reverse transcription—polymerase chain reaction (PCR).

In the MCA and BA the 5-HT1B receptor was upregulated, as determined through both functional and molecular analysis. In response to selective 5-HT1 receptor agonists both the negative logarithm of the 50% effective concentration was increased (one log unit in the MCA and one half unit in the BA), as was the agonist's potency (increased by 50% in the MCA and doubled in the BA). In addition, the authors found an approximately fourfold increase in the number of copies of messenger RNA coding for the 5-HT1B receptor as determined by quantitative real-time PCR. In the PCoA no upregulation of the 5-HT1B receptor was observed.

Conclusions. Changes in the receptor phenotype in favor of contractile receptors may well represent the end stage in a sequence of events leading from SAH to the actual development of cerebral vasospasm. Insight into the mechanism of upregulation may provide new targets for developing specific treatment against cerebral vasospasm.

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  • 1.

    Allen GS: Cerebral arterial spasm. Clin Neurosurg 32:7078, 1985 Allen GS: Cerebral arterial spasm. Clin Neurosurg 32:70–78, 1985

  • 2.

    Allen GS, , Gold LH, & Chou SN, et al: Cerebral arterial spasm. 3. In vivo intracisternal production of spasm by serotonin and blood and its reversal by phenoxybenzamine. J Neurosurg 40:451458, 1974 Allen GS, Gold LH, Chou SN, et al: Cerebral arterial spasm. 3. In vivo intracisternal production of spasm by serotonin and blood and its reversal by phenoxybenzamine. J Neurosurg 40:451–458, 1974

    • Search Google Scholar
    • Export Citation
  • 3.

    Allen GS, , Henderson LM, & Chou SN, et al: Cerebral arterial spasm. 2. In vitro contractile activity of serotonin in human serum and CSF on the canine basilar artery, and its blockage by methylsergide and phenoxybenzamine. J Neurosurg 40:442450, 1974 Allen GS, Henderson LM, Chou SN, et al: Cerebral arterial spasm. 2. In vitro contractile activity of serotonin in human serum and CSF on the canine basilar artery, and its blockage by methylsergide and phenoxybenzamine. J Neurosurg 40:442–450, 1974

    • Search Google Scholar
    • Export Citation
  • 4.

    Boisvert DP, , Weir BK, & Overton TR, et al: Cerebrovascular responses to subarachnoid blood and serotonin in the monkey. J Neurosurg 50:441448, 1979 Boisvert DP, Weir BK, Overton TR, et al: Cerebrovascular responses to subarachnoid blood and serotonin in the monkey. J Neurosurg 50:441–448, 1979

    • Search Google Scholar
    • Export Citation
  • 5.

    Boullin DJ, , Du Boulay GH, & Rogers AT: Aetiology of cerebral arterial spasm following subarachnoid haemorrhage: evidence against a major involvement of 5-hydroxy-tryptamine in the production of acute spasm. Br J Clin Pharmacol 6:203215, 1978 Boullin DJ, Du Boulay GH, Rogers AT: Aetiology of cerebral arterial spasm following subarachnoid haemorrhage: evidence against a major involvement of 5-hydroxy-tryptamine in the production of acute spasm. Br J Clin Pharmacol 6:203–215, 1978

    • Search Google Scholar
    • Export Citation
  • 6.

    Bradley SR, , Pieribone VA, & Wang W, et al: Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nat Neurosci 5:401402, 2002 Bradley SR, Pieribone VA, Wang W, et al: Chemosensitive serotonergic neurons are closely associated with large medullary arteries. Nat Neurosci 5:401–402, 2002

    • Search Google Scholar
    • Export Citation
  • 7.

    Connor HE, & Beattie DT: 5-hydroxytryptamine receptor subtypes and migraine, in Sandler M, , Ferrari M, & Harnett S (eds): Migraine: Pharmacology and Genetics. London: Chapman and Hall, 1996, pp 1827 Connor HE, Beattie DT: 5-hydroxytryptamine receptor subtypes and migraine, in Sandler M, Ferrari M, Harnett S (eds): Migraine: Pharmacology and Genetics. London: Chapman and Hall, 1996, pp 18–27

    • Search Google Scholar
    • Export Citation
  • 8.

    Ecker A, & Riemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries. With special reference to saccular arterial aneurysms. J Neurosurg 8:660667, 1951 Ecker A, Riemenschneider PA: Arteriographic demonstration of spasm of the intracranial arteries. With special reference to saccular arterial aneurysms. J Neurosurg 8:660–667, 1951

    • Search Google Scholar
    • Export Citation
  • 9.

    Edvinsson L, & Krause DN: Neuropeptide Y, in Edvinsson L, & Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 212221 Edvinsson L, Krause DN: Neuropeptide Y, in Edvinsson L, Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 212–221

    • Search Google Scholar
    • Export Citation
  • 10.

    Forster C, , Whalley ET, & Mohan J, et al: Vascular smooth muscle response to fibrinogen degradation products and 5-hydroxytryptamine: possible role in cerebral vasospasm in man. Br J Clin Pharmacol 10:231236, 1980 Forster C, Whalley ET, Mohan J, et al: Vascular smooth muscle response to fibrinogen degradation products and 5-hydroxytryptamine: possible role in cerebral vasospasm in man. Br J Clin Pharmacol 10:231–236, 1980

    • Search Google Scholar
    • Export Citation
  • 11.

    Gaw AJ, , Wadsworth RM, & Humphrey PP: Neurotransmission in the sheep middle cerebral artery: modulation of responses by 5-HT and haemolysate. J Cereb Blood Flow Metab 10:409416, 1990 Gaw AJ, Wadsworth RM, Humphrey PP: Neurotransmission in the sheep middle cerebral artery: modulation of responses by 5-HT and haemolysate. J Cereb Blood Flow Metab 10:409–416, 1990

    • Search Google Scholar
    • Export Citation
  • 12.

    Gutteridge JM, & Halliwell B: The measurement and mechanism of lipid peroxidation in biological systems. Trends Biochem Sci 15:129135, 1990 Gutteridge JM, Halliwell B: The measurement and mechanism of lipid peroxidation in biological systems. Trends Biochem Sci 15:129–135, 1990

    • Search Google Scholar
    • Export Citation
  • 13.

    Hansen-Schwartz J, , Hoel NL, & Zhou M, et al: Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 52:11881195, 2003 Hansen-Schwartz J, Hoel NL, Zhou M, et al: Subarachnoid hemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 52:1188–1195, 2003

    • Search Google Scholar
    • Export Citation
  • 14.

    Hansen-Schwartz J, , Svensson CL, & Xu CB, et al: Protein kinase mediated upregulation of endothelin A, endothelin B and 5-hydroxytryptamine 1B/1D receptors during organ culture in rat basilar artery. Br J Pharmacol 137:118126, 2002 Hansen-Schwartz J, Svensson CL, Xu CB, et al: Protein kinase mediated upregulation of endothelin A, endothelin B and 5-hydroxytryptamine 1B/1D receptors during organ culture in rat basilar artery. Br J Pharmacol 137:118–126, 2002

    • Search Google Scholar
    • Export Citation
  • 15.

    Hansen-Schwartz JAS, , Adner M, & White L, et al: Modulation of the ETB-receptor in the cerebral circulation of rat. J Cereb Blood Flow Metab 19 (Suppl 1):S752, 1999 (Abstract) Hansen-Schwartz JAS, Adner M, White L, et al: Modulation of the ETB-receptor in the cerebral circulation of rat. J Cereb Blood Flow Metab 19 (Suppl 1):S752, 1999 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 16.

    Hansen-Schwartz JAS, & Edvinsson L: Subarachnoid hemorrhage: extravasation of blood in the subarachnoid space, in Edvinsson L, & Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 466479 Hansen-Schwartz JAS, Edvinsson L: Subarachnoid hemorrhage: extravasation of blood in the subarachnoid space, in Edvinsson L, Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 466–479

    • Search Google Scholar
    • Export Citation
  • 17.

    Hargreaves R, & Beer M: 5-hydroxytryptamine and its receptors, in Edvinsson L, & Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 283294 Hargreaves R, Beer M: 5-hydroxytryptamine and its receptors, in Edvinsson L, Krause DN (eds): Cerebral Blood Flow and Metabolism, ed 2. Philadelphia: Lippincott Williams & Wilkins, 2002, pp 283–294

    • Search Google Scholar
    • Export Citation
  • 18.

    Hoel NL, , Hansen-Schwartz J, & Edvinsson L: Selective up-regulation of 5-HT1B/1D receptors during organ culture of cerebral arteries. Neuroreport 12:16051608, 2001 Hoel NL, Hansen-Schwartz J, Edvinsson L: Selective up-regulation of 5-HT1B/1D receptors during organ culture of cerebral arteries. Neuroreport 12:1605–1608, 2001

    • Search Google Scholar
    • Export Citation
  • 19.

    Hoyer D, , Clarke DE, & Fozard JR, et al: International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157203, 1994 Hoyer D, Clarke DE, Fozard JR, et al: International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203, 1994

    • Search Google Scholar
    • Export Citation
  • 20.

    Hughes JT, & Schianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:515525, 1978 Hughes JT, Schianchi PM: Cerebral artery spasm. A histological study at necropsy of the blood vessels in cases of subarachnoid hemorrhage. J Neurosurg 48:515–525, 1978

    • Search Google Scholar
    • Export Citation
  • 21.

    Leseth KH, , Adner M, & Berg HK, et al: Cytokines increase endothelin ETB receptor contractile activity in rat cerebral artery. Neuroreport 10:23552359, 1999 Leseth KH, Adner M, Berg HK, et al: Cytokines increase endothelin ETB receptor contractile activity in rat cerebral artery. Neuroreport 10:2355–2359, 1999

    • Search Google Scholar
    • Export Citation
  • 22.

    Lobato RD, , Marin J, & Salaices M, et al: Cerebrovascular reactivity to noradrenaline and serotonin following experimental subarachnoid hemorrhage. J Neurosurg 53:480485, 1980 Lobato RD, Marin J, Salaices M, et al: Cerebrovascular reactivity to noradrenaline and serotonin following experimental subarachnoid hemorrhage. J Neurosurg 53:480–485, 1980

    • Search Google Scholar
    • Export Citation
  • 23.

    Martins AN, , Doyle TF, & Wright S: Effect of topically applied serotonin on local cerebral blood flow. Stroke 9:2528, 1978 Martins AN, Doyle TF, Wright S: Effect of topically applied serotonin on local cerebral blood flow. Stroke 9:25–28, 1978

    • Search Google Scholar
    • Export Citation
  • 24.

    Minami N, , Tani E, & Yokota M, et al: Immunohistochemistry of leukotriene C4 in experimental cerebral vasospasm. Acta Neuropathol 81:401407, 1991 Minami N, Tani E, Yokota M, et al: Immunohistochemistry of leukotriene C4 in experimental cerebral vasospasm. Acta Neuropathol 81:401–407, 1991

    • Search Google Scholar
    • Export Citation
  • 25.

    Misra HP, & Fridovich I: The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 247:69606962, 1972 Misra HP, Fridovich I: The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 247:6960–6962, 1972

    • Search Google Scholar
    • Export Citation
  • 26.

    Nilsson T, , Longmore J, & Shaw D, et al: Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol 128:11331140, 1999 Nilsson T, Longmore J, Shaw D, et al: Contractile 5-HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry. Br J Pharmacol 128:1133–1140, 1999

    • Search Google Scholar
    • Export Citation
  • 27.

    Ohkuma H, , Itoh K, & Shibata S, et al: Morphological changes of intraparenchymal arterioles after experimental subarachnoid hemorrhage in dogs. Neurosurgery 41:230236, 1997 Ohkuma H, Itoh K, Shibata S, et al: Morphological changes of intraparenchymal arterioles after experimental subarachnoid hemorrhage in dogs. Neurosurgery 41:230–236, 1997

    • Search Google Scholar
    • Export Citation
  • 28.

    Prunell GF, , Mathiesen T, & Diemer NH, et al: Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery 52:165176, 2003 Prunell GF, Mathiesen T, Diemer NH, et al: Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery 52:165–176, 2003

    • Search Google Scholar
    • Export Citation
  • 29.

    Prunell GF, , Mathiesen T, & Svendgaard NA: A new experimental model in rats for study of the pathophysiology of subarachnoid hemorrhage. Neuroreport 13:25532556, 2002 Prunell GF, Mathiesen T, Svendgaard NA: A new experimental model in rats for study of the pathophysiology of subarachnoid hemorrhage. Neuroreport 13:2553–2556, 2002

    • Search Google Scholar
    • Export Citation
  • 30.

    Qing X, , Svaren J, & Keith IM: mRNA expression of novel CGRP1 receptors and their activity-modifying proteins in hypoxic rat lung. Am J Physiol Lung Cell Mol Physiol 280:L547L554, 2001 Qing X, Svaren J, Keith IM: mRNA expression of novel CGRP1 receptors and their activity-modifying proteins in hypoxic rat lung. Am J Physiol Lung Cell Mol Physiol 280:L547–L554, 2001

    • Search Google Scholar
    • Export Citation
  • 31.

    Sawchenko PE, & Swanson LW: Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses. Science 214:685687, 1981 Sawchenko PE, Swanson LW: Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses. Science 214:685–687, 1981

    • Search Google Scholar
    • Export Citation
  • 32.

    Suzuki S, , Kimura M, & Souma M, et al: Cerebral microthrombosis in symptomatic cerebral vasospasm—a quantitative histological study in autopsy cases. Neurol Med Chir 30:309316, 1990 Suzuki S, Kimura M, Souma M, et al: Cerebral microthrombosis in symptomatic cerebral vasospasm—a quantitative histological study in autopsy cases. Neurol Med Chir 30:309–316, 1990

    • Search Google Scholar
    • Export Citation
  • 33.

    Svendgaard NA, , Delgado TJ, & Arbab MA: Cathecolaminergic and peptidergic systems underlying cerebral vasospasm: CBF and CMRgl changes following an experimental subarachnoid hemorrhage in the rat, in Wilkins RH (ed): Cerebral Vasospasm. New York: Raven Press, 1988, pp 175186 Svendgaard NA, Delgado TJ, Arbab MA: Cathecolaminergic and peptidergic systems underlying cerebral vasospasm: CBF and CMRgl changes following an experimental subarachnoid hemorrhage in the rat, in Wilkins RH (ed): Cerebral Vasospasm. New York: Raven Press, 1988, pp 175–186

    • Search Google Scholar
    • Export Citation
  • 34.

    Svendgaard NA, , Edvinsson L, & Olin T, et al: On the pathophysiology of cerebral vasospasm: transmitter changes in perivascular sympathetic nerves, and increased pial artery sensitivity to norepinephrine and serotonin, in Edvinsson L, & Owman C (eds): Neurogenic Control of Brain Circulation. New York: Pergamon Press, 1977, pp 143152 Svendgaard NA, Edvinsson L, Olin T, et al: On the pathophysiology of cerebral vasospasm: transmitter changes in perivascular sympathetic nerves, and increased pial artery sensitivity to norepinephrine and serotonin, in Edvinsson L, Owman C (eds): Neurogenic Control of Brain Circulation. New York: Pergamon Press, 1977, pp 143–152

    • Search Google Scholar
    • Export Citation
  • 35.

    Svendgaard NA, , Edvinsson L, & Owman C, et al: Increased sensitivity of the basilar artery to norepinephrine and 5-hydroxytryptamine following experimental subarachnoid hemorrhage. Surg Neurol 8:191195, 1977 Svendgaard NA, Edvinsson L, Owman C, et al: Increased sensitivity of the basilar artery to norepinephrine and 5-hydroxytryptamine following experimental subarachnoid hemorrhage. Surg Neurol 8:191–195, 1977

    • Search Google Scholar
    • Export Citation
  • 36.

    Tagari PC, , Kaye AH, & Teddy PJ, et al: The 5-hydroxytryptamine antagonist ketanserin inhibits the vasoconstrictor activity of peroperative CSF, from subarachnoid haemorrhage patients, on isolated tissues. J Neurol Neurosurg Psychiatry 46:214220, 1983 Tagari PC, Kaye AH, Teddy PJ, et al: The 5-hydroxytryptamine antagonist ketanserin inhibits the vasoconstrictor activity of peroperative CSF, from subarachnoid haemorrhage patients, on isolated tissues. J Neurol Neurosurg Psychiatry 46:214–220, 1983

    • Search Google Scholar
    • Export Citation
  • 37.

    Toda N: Mechanisms of contracting action of oxyhemoglobin in isolated monkey and dog cerebral arteries. Am J Physiol 258:H57H63, 1990 Toda N: Mechanisms of contracting action of oxyhemoglobin in isolated monkey and dog cerebral arteries. Am J Physiol 258:H57–H63, 1990

    • Search Google Scholar
    • Export Citation
  • 38.

    Wever R, , Oudega B, & van Gelder BF: Generation of superoxide radicals during the autoxidation of mammalian oxyhemoglobin. Biochim Biophys Acta 302:475478, 1973 Wever R, Oudega B, van Gelder BF: Generation of superoxide radicals during the autoxidation of mammalian oxyhemoglobin. Biochim Biophys Acta 302:475–478, 1973

    • Search Google Scholar
    • Export Citation
  • 39.

    Wilkins RH: Attempted prevention or treatment of intracranial arterial spasm: a survey. Neurosurgery 6:198210, 1980 Wilkins RH: Attempted prevention or treatment of intracranial arterial spasm: a survey. Neurosurgery 6:198–210, 1980

    • Search Google Scholar
    • Export Citation
  • 40.

    Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 18:808825, 1986 Wilkins RH: Attempts at prevention or treatment of intracranial arterial spasm: an update. Neurosurgery 18:808–825, 1986

    • Search Google Scholar
    • Export Citation
  • 41.

    Wilkins RH: Cerebral vasospasm. Crit Rev Neurobiol 6:5177, 1990 Wilkins RH: Cerebral vasospasm. Crit Rev Neurobiol 6:51–77, 1990

  • 42.

    Zervas NT: Vasospasm: an update. Clin Neurosurg 26:643656, 1979 Zervas NT: Vasospasm: an update. Clin Neurosurg 26:643–656, 1979

  • 43.

    Zervas NT, , Lavyne MH, & Negoro M: Neurotransmitters and the normal and ischemic cerebral circulation. N Engl J Med 293:812816, 1975 Zervas NT, Lavyne MH, Negoro M: Neurotransmitters and the normal and ischemic cerebral circulation. N Engl J Med 293:812–816, 1975

    • Search Google Scholar
    • Export Citation

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