While the rat has been used extensively in subarachnoid hemorrhage (SAH)-cerebral vasospasm studies, concerns exist whether this animal represents a usable model because its time course and pattern of cerebral vasospasm following SAH is not comparable to that observed in man. At present, our knowledge of the rat model is based almost exclusively on studies using a 'single hemorrhage' method. Since there is a positive correlation between severity of cerebral vasospasm, and volume of subarachnoid blood, an obvious question is whether the rat will show modifications in vascular responses when insulted by a second SAH. Here, an SAH was produced in rats using a 'double hemorrhage' method. Following SAH, cerebral arteries showed pathological alterations, significant decreases in luminal perimeter, and increases in arterial wall thickness, over a 7-day post-SAH period. The above vascular features are considered to be indicative of cerebral vasospasm and their presence over a 7-day post-SAH period represents a significant time extension when compared to a single hemorrhage. These modified vascular responses made the double hemorrhaged rat a much-improved animal model.

The mRNA upregulation of these proteins indicates that activation of rho A/rho kinase-related signal transduction pathways is involved in the development of long-lasting contraction of cerebral arteries after SAH.

BackgroundLuteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.ObjectiveTo compare BMD change in men receiving either LHRHa or oestradiol patches (OP).Design, setting, and participantsMen with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr.InterventionsLHRHa as per local practice, OP (FemSeven 100 μg/24 h patches).Outcome measurements and statistical analysisThe primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance.Results and limitationsA total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001).ConclusionsTransdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial.Patient summaryThis study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial.Trial registrationISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Background and Purpose-Extracellular ATP might induce cerebral vasospasm after subarachnoid hemorrhage through P 2 receptor. To investigate the roles of P 2 receptor subtypes in vasospasm, we examined the changes in mRNA expression of P 2 receptor subtypes in basilar arteries from double cisternal blood injection rat models. Methods-One hundred male Sprague-Dawley rats, each weighing 350 to 400 g, were divided into 2 groups of 50. In the first group (nϭ50), the autologous arterial blood (0.2 to 0.3 mL) was injected into the cisterna magna on days 0 and 2. The rats were killed on day 3, 5, or 7 (nϭ10 in each group). In the sham group (nϭ10), the rats were injected with saline (0.3 mL) instead of blood. Ten rats were killed without blood or saline injection and served as control. The basilar arteries from rats in each group were used for reverse transcription and polymerase chain reaction. In another group of 50 rats, the same experiment was conducted, and the basilar arteries were collected for transmission electron microscopic study. Results-In the subarachnoid hemorrhage groups, transmission electron microscopy showed the reduction in vessel perimeter on days 5 and 7 to be approximately 30% to 40%. The P 2X1 mRNA level was significantly decreased on day 3 and recovered on days 5 and 7. The P 2Y1 mRNA level was transiently increased on day 5, and the P 2Y2 mRNA level was elevated from day 5 to day 7 (PϽ0.05). Conclusions-The differential expression of the P 2 receptors indicates that P 2X1 subtype might not play an important role in vasospasm. The upregulation of P 2Y1 and P 2Y2 receptors might enable ATP to produce contraction at low levels of concentration. (Stroke. 2001;32:516-522.)Key Words: adenosine triphosphate Ⅲ muscle, smooth Ⅲ phenotype Ⅲ receptors, purinergic P 2 Ⅲ rats C erebral vasospasm is a leading cause and a frequent complication of the morbidity and mortality of subarachnoid hemorrhage (SAH). Cerebral vasospasm is characterized by a delayed, prolonged constriction, occurring mainly in vascular smooth muscle cells, 1,2 and by cell proliferation within the arterial wall. 3 The cause of vasospasm might be vasoactive substances (such as oxyhemoglobin, purine, and pyrimidine nucleotides) released into the subarachnoid space by the dissolution of the resultant blood clot 4,5 or by vasoactive agents released from the vessel wall (such as endothelin). These spasmogens might produce gene expression changes that lead not only to a prolonged contraction but also to cell differentiation, cell proliferation, and cell death. 3,6 The P 2 receptor (P 2 nucleotide receptor) was also referred to as P 2 purinergic receptor (purinoceptor) previously. A large number of P 2 receptor subtypes can be divided into 2 major families: the ligand-gated ion channel P 2X receptors and the G protein-coupled P 2Y receptors. More than 7 P 2X and 8 P 2Y subtypes were identified. P 2 receptors play a central role in the functions of extracellular nucleotides in peripheral and central neuronal tissues, See Editorial Comment, page ...