Overall the aim has been to characterise the in vitro upregulation of the 5-hydroxytryptamine 1B/1D (5-HT(1B/1D)) and endothelin (ET) receptors in the cerebral circulation as well as demonstrating phenotypic changes in a pathophysiological model mimicking subarachnoid haemorrhage. The first part describes receptor upregulation using organ culture of whole vessel segments from both rat and man. The upregulation is dependent on gene transcription and translation; thus, an active signalling pathway is involved. Further analysis of this pathway revealed that protein kinase C is especially important in the upregulation process of the ET(B) receptor. The second part attempts to take the concept of receptor upregulation into the pathophysiological realm, especially focusing on experimental subarachnoid haemorrhage. Changes similar to those observed using the in vitro organ culture technique were observed in vivo. Especially the ET(B) receptor upregulates and perhaps more importantly, this appears to be associated with a generally increased sensitivity towards ET-1. Now, even at physiological concentrations of ET-1 were appreciable contraction observed. Similar results were obtained when studying the upregulation of the 5-HT(1B) receptor; the upregulation imparts increased sensitivity of the cerebral arteries towards serotonin. The increased functional responses represent a significant contribution towards the understanding of cerebral vasospasm after subarachnoid haemorrhage. Finally, it is revealed that the ET(B) receptor is more frequently present in human arteries from patients with cerebrovascular disease thus substantiating the idea of receptor upregulation as part of human cerebrovascular pathology.
|Award date||2003 Jan 10|
|Publication status||Published - 2003|
Bibliographical noteDefence details
Place: Segerfalksalen, Wallenberg Neurocentrum
Name: Astrup, Jens
Article: Hansen-Schwartz J, Edvinsson L. Increased sensitivity to ET-1 in rat cerebral arteries following organ culture. Neuroreport 2000; 11(3):649-652.
Article: Hoel NL, Hansen-Schwartz J, Edvinsson L. Selective up-regulation of 5-HT(1B/1D) receptors during organ culture of cerebral arteries. Neuroreport 2001; 12(8):1605-1608.
Article: Hansen-Schwartz J, Nordström C-H, Edvinsson L. Human endothelin subtype A receptor enhancement during tissue culture via de novo transcription. Neurosurgery 2002; 50(1):127-133.
Article: Hansen-Schwartz J, Svensson C-L, Xu C-B, Edvinsson L. 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 2002; 137(1): 118-126.
Article: Hansen-Schwartz J, Hoel NL, Xu C-B, Svendgaard N-A, Edvinsson L. Experimental subarachnoid haemorrhage upregulates the 5-HT(1B) receptor in rat cerebral arteries. J Neurosurg (submitted)
Article: Hansen-Schwartz J, Hoel NL, Zhou M, Xu C-B, Svendgaard N-A, Edvinsson L. Subarachnoid haemorrhage enhances endothelin receptor expression and function in rat cerebral arteries. Neurosurgery 2003 (in press)
Article: Hansen-Schwartz J, Szok D, Edvinsson L. Expression of ET(A) and ET(B) receptor mRNA in human cerebral arteries. Br J Neurosurg 2002; 16(2):149-153.
Subject classification (UKÄ)
- Other Clinical Medicine
- Pharmacological sciences
- subarachnoid haemorrhage
- reverse transcriptase polymerase chain reaction
- in vitro pharmacology
- organ culture
- Endothelin receptors
- 5-HT receptors