Vascular receptor changes in ischemic stroke

Emelie Stenman

Research output: ThesisDoctoral Thesis (compilation)

64 Downloads (Pure)

Abstract

The present thesis aimed to examine how ischemic stroke affects the vascular endothelin and angiotensin systems in cerebral arteries. To study vascular receptor changes in ischemic stroke transient focal ischemia was induced in rats. In addition, rat cerebral arteries and arterial smooth muscle cells were cultured for further analysis of cerebrovascular receptor regulation. For functional studies of cerebral arteries, sensitive myographs were used. mRNA levels were quantitatively measured by real time PCR and protein density was studied by immunohistochemistry.

Main results:

1. Ischemic stroke in rat induces a contractile endothelin ET(B) receptor mediated response in the ipsilateral middle cerebral artery (MCA), which is accompanied by an increased expression of ET(B) receptors.

2. Organ culture of rat MCAs induces a time-dependent upregulation of contractile ET(B) receptors. The phenomenon is due to de novo transcription of the receptors and is partly dependent on PKC.

3. bFGF increases the ET(A) and ET(B) receptor mRNA expression in rat cerebral smooth muscle cells.

4. TNF-alpha and EGF can potentiate the ET(B) receptor mediated contraction in the rat MCA, whereas bFGF enhances the maximal ET(A) receptor mediated contraction and increases the mRNA and protein levels for the ET(B) receptors.

5. Ischemic stroke in rat enhances the contractile response to angiotensin II in the ipsilateral MCA. This contraction is mediated by angiotensin AT1 receptors. In addition the mRNA levels for angiotensin converting enzyme were increased, which may suggest an enhanced production of angiotensin II.

6. A low dose of the AT1 receptor blocker candesartan (0.05 mg/kg and day) in the acute phase of ischemic stroke can decrease the size of brain damage significantly.

Our hypothesis suggests that ischemic stroke can activate contractile mediators in cerebral arteries, and that this phenomenon may be detrimental if it implies a decreased perfusion of the already ischemic hemisphere. The present thesis confirms that there is indeed an increased ET(B) and AT1 receptor mediated contraction in the ipsilateral MCA after ischemic stroke.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Medicine, Lund
Supervisors/Advisors
  • Edvinsson, Lars, Supervisor
Award date2005 Dec 10
Publisher
ISBN (Print)91-85481-12-2
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-12-10
Time: 10:00
Place: Segerfalksalen Wallenberg Neuroscience centre Sölvegatan 17 Lund

External reviewer(s)

Name: Wester, Per
Title: Professor
Affiliation: Department of Public Health and Clinical Medicine, Umeå University

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<div class="article_info">E Stenman, M Malmsjö, E Uddman, G Gidö, T Wieloch and L Edvinsson. <span class="article_issue_date">2002</span>. <span class="article_title">Cerebral ischemia upregulates vascular endothelin ET(B) receptors in rat.</span> <span class="journal_series_title">Stroke.</span>, <span class="journal_volume">vol 33</span> <span class="journal_pages">pp 2311-2316</span>.</div>
<div class="article_info">M Henriksson, E Stenman and L Edvinsson. <span class="article_issue_date">2003</span>. <span class="article_title">Intracellular pathways involved in upregulation of vascular endothelin type B receptors in cerebral arteries of the rat.</span> <span class="journal_series_title">Stroke.</span>, <span class="journal_volume">vol 34</span> <span class="journal_pages">pp 1479-1483</span>.</div>
<div class="article_info">E Stenman and L Edvinsson. <span class="article_issue_date">2004</span>. <span class="article_title">Cerebral ischemia enhances the vascular angiotensin AT1 receptor mediated contraction in rat.</span> <span class="journal_series_title">Stroke.</span>, <span class="journal_volume">vol 35</span> <span class="journal_pages">pp 970-974</span>.</div>
<div class="article_info">CB Xu, E Stenman and L Edvinsson. <span class="article_issue_date">2002</span>. <span class="article_title">Reduction of bFGF-induced smooth muscle cell proliferation and endothelin receptor mRNA expression by mevastatin and atorvastatin.</span> <span class="journal_series_title">Biochem Pharmacol.</span>, <span class="journal_volume">vol 64</span> <span class="journal_pages">pp 497-505</span>.</div>
<div class="article_info">E Stenman, M Henriksson, P Vikman and L Edvinsson. <span class="article_issue_date"></span>. <span class="article_title">Impact of cytokines and growth factors on contractile endothelin responses in rat cerebral arteries.</span> (submitted)</div>
<div class="article_info">E Stenman, M Henriksson and L Edvinsson. <span class="article_issue_date"></span>. <span class="article_title">Low dose inhibition of AT1 receptors decreases ischemic brain damage in rat.</span> (submitted)</div>

Subject classification (UKÄ)

  • Other Clinical Medicine

Keywords

  • Vascular receptor changes
  • Ischemic stroke
  • Endothelin
  • Angiotensin
  • Cardiovascular system
  • Kardiovaskulära systemet
  • Pharmacological sciences
  • pharmacognosy
  • pharmacy
  • farmakognosi
  • farmaci
  • toxikologi
  • toxicology
  • Farmakologi

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