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Cerebrovascular ET_B, 5-HT_1B, and AT₁ receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage

¹Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden; and ²Department of Clinical Experimental Research, Glostrup University Hospital, Glostrup, Denmark

Submitted 23 July 2007 ; accepted in final form 10 September 2007

We hypothesize that cerebral ischemia leads to enhanced expression of endothelin (ET), 5-hydroxytryptamine (5-HT), and angiotensin II (ANG II) receptors in the vascular smooth muscle cells. Our aim is to correlate the upregulation of cerebrovascular receptors and the underlying molecular mechanisms with the reduction in regional and global cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). SAH was induced by injecting 250 µl blood into the prechiasmatic cistern in rats. The cerebral arteries were removed 0, 1, 3, 6, 12, 24, and 48 h after the SAH for functional and molecular studies. The contractile responses to ET-1, 5-carboxamidotryptamine (5-CT), and ANG II were investigated with myograph. The receptor mRNA and protein levels were analyzed by quantitative real-time PCR and immunohistochemistry, respectively. In addition, regional and global CBFs were measured by an autoradiographic method. As a result, SAH resulted in enhanced contractions to ET-1 and 5-CT. ANG II [via ANG II type 1 (AT₁) receptors] induced increased contractile responses [in the presence of the ANG II type 2 (AT₂) receptor antagonist PD-123319]. In parallel the ET_B, 5-HT_1B, and AT₁ receptor, mRNA and protein levels were elevated by time. The regional and global CBF showed a successive reduction with time after SAH. In conclusion, the results demonstrate for the first time that SAH induces the upregulation of ET_B, 5-HT_1B, and AT₁ receptors in a time-dependent manner both at functional, mRNA, and protein levels. These changes occur in parallel with a successive decrease in CBF. Thus there is a temporal correlation between the changes in receptor expression and CBF reduction, suggesting a linkage.

cerebral blood flow; cerebral ischemia

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