Vascular receptor changes in ischemic stroke

University dissertation from Department of Clinical Sciences, Lund University

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.