Background and Purpose-Elevated levels of endothelin-1 (ET-1) have been reported in cerebral ischemia. A role for ET may prove more important if the vascular receptors were changed. We addressed whether there is any change in ET receptor expression in cerebral ischemia. Methods-The right middle cerebral artery (MCA) was occluded in male Wistar rats for 2 hours with the intraluminal filament method. The basilar artery and both MCAs were removed after 46 hours of recirculation. The contractile responses to ET-1, a combined ET A and ET B receptor agonist, and sarafotoxin 6c (S6c), a selective ET B receptor agonist, were examined in vitro, and ET receptor mRNA was quantified by real-time polymerase chain reaction. Results-S6c, which had no contractile effect per se on fresh or sham-operated rat cerebral arteries, induced a marked contraction in the occluded MCA (E max [maximum contraction, calculated as percentage of the contractile capacity of 63.5 mmol/L K ϩ ]ϭ68Ϯ68%; PϽ0.0001), while there was no difference in the responses to ET-1 after cerebral ischemia. Real-time polymerase chain reaction revealed a significant upregulation of both the ET A and ET B receptors (both PϽ0.05) in the occluded MCA compared with the nonoccluded MCA from the same rats. Conclusions-Focal cerebral ischemia in rat induces increased transcription of both ET A and ET B receptors, which results in the appearance of a contractile response to the ET B receptor agonist S6c. These results suggest a role for ET receptors in the pathogenesis of a vascular component after cerebral ischemia.

Background: Fast-track referral is an increasingly used method for diagnostic evaluation of patients suspected of having cancer. This approach is challenging and not used as often for patients with only nonspecific symptoms. In order to expedite the diagnostics for these patients, we established Sweden's first Diagnostic Center (DC) focusing on outcomes related to diagnoses and diagnostic time intervals. Material and Methods: The study was designed as a prospective cohort study. Patients aged 18 years who presented in primary care with nonspecific symptoms of a serious disease were eligible for referral to the DC after having completed an initial investigation. Acceptable diagnostic time intervals were defined to be a maximum of 15 days in primary care and 22 days at the DC. Diagnostic outcome, length of diagnostic time intervals and patient satisfaction were evaluated. Results: A total of 290 patients were included in the study. Cancer was diagnosed in 22.1%, other diseases in 64.1%, and no diagnosis was identified in 13.8% of these patients. Patients diagnosed with cancer were older, had shorter patient interval (time from first symptom to help-seeking), shorter DCinterval (time from referral decision in primary care to diagnosis) and showed a greater number of symptoms compared to patients with no diagnosis. The median primary care interval was 21 days and the median DC interval was 11 days. Few symptoms, no diagnosis, female sex, longer patient interval, and incomplete investigations were associated with prolonged diagnostic time intervals. Patient satisfaction was high; 86% of patients reported a positive degree of satisfaction with the diagnostic procedures. Conclusions: We demonstrated that the DC concept is feasible with a diagnosis reached in 86.2% of the patients in addition to favorable diagnostic time intervals at the DC and a high degree of patient satisfaction. ARTICLE HISTORY

Background and Purpose-The aim of the study was to examine how focal cerebral ischemia affects the expression and function of vascular angiotensin II receptors. Materials and Methods-We used an intraluminal filament occlusion technique to occlude the right middle cerebral artery (MCA) of the rat. Myographs were used for functional studies of the MCA and real-time polymerase chain reaction, for determination of relative mRNA levels. Results-The contractile responses to angiotensin II were stronger in the right occluded MCA compared with the left MCA and the MCA from sham-operated rats 48 hours after MCA occlusion (PϽ0.05). The angiotensin II type 1 (AT 1 ) receptor antagonists candesartan and losartan abolished the enhanced responses to angiotensin II (PϽ0.05), whereas the AT 2 receptor antagonist PD123319 had no effect. The amount of AT 1 receptor mRNA was lower in the occluded MCAs compared with nonoccluded MCAs 48 hours after occlusion (PϽ0.05), whereas the mRNA levels of angiotensin converting enzyme (ACE) were higher in the occluded arteries. The mRNA levels of the AT 2 receptor and nuclear factor-B were unchanged. Conclusions-Focal cerebral ischemia in the rat upregulated the contractile responses to angiotensin II in the ipsilateral MCA, and this contraction was mediated by AT 1 receptors. Real-time polymerase chain reaction revealed decreased AT 1 receptor mRNA levels in the occluded MCA, whereas the amount of ACE mRNA was increased, suggesting locally enhanced angiotensin II production. These results support a role for AT 1 receptors in cerebral ischemia, and we think that AT 1 receptors might be a future therapeutic target in ischemic stroke. Key Words: angiotensins Ⅲ receptors, angiotensin Ⅲ angiotensin converting enzyme inhibitors Ⅲ cerebral ischemia A ngiotensin II (Ang II) is an octapeptide that acts at different sites in the brain (eg, the vascular, neuroendocrine, and behavioral systems). Angiotensin converting enzyme (ACE), which converts Ang I to Ang II, is expressed in cerebral microvessels of the rat 1 suggesting local formation of Ang II in addition to circulating Ang II. In cerebral vessels, Ang II has been found to induce vasoconstriction 2,3 and vasodilatation, 4 depending on the species studied and methods used. The responses to Ang II are predominantly mediated by the Ang II type 1 (AT 1 ) and type 2 (AT 2 ) receptor subtypes, of which the AT 1 receptor subtype mediates contraction of cerebral arteries in adult rats. 5 The present study is based on the hypothesis that cerebral ischemia induces a change in local vascular receptor expression and function, which might influence the ischemia and have a role in the development of the penumbral zone. In a previous study, we revealed an upregulation of contractile endothelin type B (ET B ) receptors with enhanced transcription in the middle cerebral artery (MCA) of the rat 48 hours after temporal MCA occlusion. 6 In the present study we used the same experimental model. The functional responses to Ang II in the MCA were examined by myographs, a...

The results suggest that, in fresh MCA, the ETA receptor is the most prominent subtype, while after organ culture ETB receptors also contribute to the contraction. This upregulation is due to de novo transcription of receptors. Protein kinase C is involved in the upregulation as Ro-31-8220 attenuates the contraction and the mRNA increase.