clazosentan and Cerebral-Infarction

Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH.. Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment.. Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76).. Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan.

Topics: Brain Ischemia; Cerebral Infarction; Dioxanes; Humans; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients.. Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies.. In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously.. Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).

Topics: Cerebral Infarction; Humans; Japan; Morbidity; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Cerebral vasospasm occurs within 4 to 14 days from the onset of aneurysmal subarachnoid hemorrhage (aSAH) in 40 to 70% of patients. Of patients with cerebral vasospasm, 17 to 40% experience delayed ischemic neurological deficits and about half of them develop cerebral infarction. Although the mechanism of the onset of cerebral vasospasm has not been fully elucidated, one of mechanisms is considered that after the onset of aSAH, the level of endothelin, a potent and sustained vasoconstriction substance, increases by production induced by oxyhemoglobin and release from erythrocytes and thus cerebral vasospasm develops via endothelin (ET)

Topics: Cerebral Infarction; Endothelin Receptor Antagonists; Humans; Quality of Life; Receptor, Endothelin A; Sodium; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.. REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.. In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39).

Topics: Brain Ischemia; Cerebral Infarction; Clinical Deterioration; Humans; Prospective Studies; Quality of Life; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Background and Purpose- Anemia after aneurysmal subarachnoid hemorrhage is common and potentially modifiable. Here, we first evaluate the effect of anemia on neurological outcome and death and second, study the effects of packed red blood cell transfusion on outcome. Methods- A secondary analysis on 413 subjects in the CONSCIOUS-1 study (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage). Multivariable logistic regression identified independent risk factors for anemia and determined the effect of anemia on neurological outcome and death, while adjusting for selected covariates. Optimal predictive thresholds for hemoglobin levels were determined using receiver operating characteristic curve analysis. Finally, patients were pseudorandomized to transfusion using propensity score matching to study the effect of transfusions on outcome. Results- Anemia, defined as hemoglobin <10 g/dL, was present in 5% of patients at presentation, in 29% of patients after aneurysm securing (days 1-3), and in 32% of patients during the peak delayed cerebral ischemia risk period (days 5-9). Anemia after aneurysm securing (odds ratio, 1.96; 95% confidence interval, 1.07-3.59; P=0.03) and during the delayed cerebral ischemia window (odds ratio, 2.63; 95% confidence interval, 1.46-4.76; P=0.0014) was independently associated with poor neurological outcome. Anemia postaneurysm securing (odds ratio, 3.50; 95% confidence interval, 1.15-10.62; P=0.027) but not during the delayed cerebral ischemia window was associated with death. Using propensity score-matched cohorts, we found that transfusion of anemic patients did not improve long-term outcome (P=0.8) or mortality rates (P=0.9). Transfusion of patients with a hemoglobin concentration >10 g/dL was associated with improved neurological outcomes (odds ratio, 0.09; 95% confidence interval, 0.002-0.72; P=0.015), with no differences in mortality. Conclusions- Anemia after aneurysmal subarachnoid hemorrhage is associated with poor long-term neurological outcome and death. Transfusion of packed red blood cells is beneficial for patients who are not considerably anemic beforehand, suggesting further work needs to define the threshold but also the time period of anemia that is sufficient and necessary to contribute to poor outcomes. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00111085.

Topics: Adult; Anemia; Blood Transfusion; Brain Ischemia; Cerebral Infarction; Dioxanes; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Mortality; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH.. The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared.. Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003).. These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

Topics: Adult; Aged; Angiography, Digital Subtraction; Cerebral Angiography; Cerebral Infarction; Dioxanes; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Humans; Japan; Male; Middle Aged; Neurosurgical Procedures; Pyridines; Pyrimidines; Republic of Korea; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Treatment Outcome; Vasodilator Agents; Vasospasm, Intracranial; Young Adult

Atrophy in specific brain areas correlates with poor neuropsychological outcome after subarachnoid hemorrhage (SAH). Few studies have compared global atrophy in SAH with outcome. The authors examined the relationship between global brain atrophy, clinical factors, and outcome after SAH.. This study was a post hoc exploratory analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial, a randomized, double-blind, placebo-controlled trial of 413 patients with aneurysmal SAH. Patients with infarctions or areas of encephalomalacia on CT, and those with large clip/coil artifacts, were excluded. The 97 remaining patients underwent CT at baseline and 6 weeks, which was analyzed using voxel-based volumetric measurements. The percentage difference in volume between time points was compared against clinical variables. The relationship with clinical outcome was modeled using univariate and multivariate analysis.. Older age, male sex, and systemic inflammatory response syndrome (SIRS) during intensive care stay were significantly associated with brain atrophy. Greater brain atrophy was significantly associated with poor outcome on the modified Rankin scale (mRS), severity of deficits on the National Institutes of Health Stroke Scale (NIHSS), worse executive functioning, and lower EuroQol Group-5D (EQ-5D) score. Adjusted for confounders, brain atrophy was not significantly associated with Mini-Mental State Examination and Functional Status Examination scores. Brain atrophy was not associated with angiographic vasospasm or delayed ischemic neurological deficit.. Worse mRS score, NIHSS score, executive functioning, and EQ-5D scores were associated with greater brain atrophy and older age, male sex, and SIRS burden. These data suggest outcome is associated with factors that cause global brain injury independent of focal brain injury.

Topics: Adult; Age Distribution; Aged; Atrophy; Brain; Cerebral Infarction; Dioxanes; Double-Blind Method; Embolization, Therapeutic; Encephalitis; Endothelin A Receptor Antagonists; Female; Humans; Male; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Postoperative Complications; Pyridines; Pyrimidines; Recovery of Function; Risk Factors; Sex Distribution; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome

Delayed ischemic neurological deficit (DIND) following aneurysmal subarachnoid hemorrhage (SAH) remains a significant cause of mortality and disability. The administration of colloids and the induction of a positive fluid balance during the vasospasm risk period remain controversial. Here, we compared DIND and outcomes among propensity score-matched cohorts who did and did not receive colloids and also tested the effect of a positive fluid balance on these endpoints.. Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Propensity score matching was performed on the basis of age, gender, pre-existing heart conditions, hypertension, nicotine use, World Federation of Neurosurgical Societies scores, aneurysm location, clazosentan treatment, subarachnoid clot burden, and severity of angiographic vasospasm. Inferential statistics were used for group-wise comparisons.. One hundred twenty-three subjects were matched (41 received colloids, whereas 82 did not). The covariate balance and propensity score distributions were acceptable. There was no difference between the groups with respect to DIND (17 vs. 22%; p = 0.64) or the presence (48 vs. 51%; p = 0.71) or volume of delayed infarcts (volume >7.5 cm3; 62 vs. 48%; p = 0.41). Similarly, no differences were found on multivariate analysis between patients who did and did not have a positive fluid balance, although patients with severe angiographic vasospasm had more delayed infarcts with a negative fluid balance (p = 0.01). Among all subjects, the administration of colloids and a positive fluid balance were associated with worse outcomes on the NIHSS (p = 0.04) and modified Rankin (p = 0.02) scales, respectively.. Colloid administration and induction of a positive fluid balance during the vasospasm risk period may be associated with poor outcomes in specific patient groups. Patient selection is of utmost importance when managing the fluid status of patients with aneurysmal SAH.

Topics: Aged; Cerebral Infarction; Colloids; Critical Care; Dioxanes; Double-Blind Method; Endothelin A Receptor Antagonists; Female; Fluid Therapy; Humans; Male; Middle Aged; Propensity Score; Prospective Studies; Pyridines; Pyrimidines; Radiography; Severity of Illness Index; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasodilator Agents; Vasospasm, Intracranial; Water-Electrolyte Balance

Cerebral vasospasm is a common complication occurring after aneurysmal subarachnoid hemorrhage (SAH). It is recognized as a leading preventable cause of morbidity and mortality in this patient group, but its management is challenging, and new treatments are needed. Clazosentan is an endothelin receptor antagonist designed to prevent endothelin-mediated cerebral vasospasm. Vajkoczy et al. (Neurosurg 103:9-17, 2005) initially demonstrated that clazosentan reduced moderate/severe angiographically proven vasospasm by 55% relative to placebo. These findings led to the initiation of the CONSCIOUS trial program to further examine the efficacy and safety of clazosentan in reducing angiographic vasospasm and improving clinical outcome after aneurysmal SAH. In the first of these studies, CONSCIOUS-1, 413 patients were randomized to placebo or clazosentan 1, 5 or 15 mg/h. Clazosentan reduced angiographic vasospasm dose-dependently relative to placebo with a maximum risk reduction of 65% with the highest dose. Despite this, there was no benefit of clazosentan on the secondary protocol-defined morbidity/mortality endpoint; however, additional post-hoc and modified endpoint analyses provided some evidence for a potential clinical benefit. Two additional large-scale studies (CONSCIOUS-2 and CONSCIOUS-3) are now underway to further investigate the potential of clazosentan to improve long-term clinical outcome.

Topics: Adult; Aged; Cerebral Angiography; Cerebral Infarction; Cohort Studies; Dioxanes; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; International Cooperation; Male; Middle Aged; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography Scanners, X-Ray Computed; Vasospasm, Intracranial; Young Adult

Numerous abnormal findings may be evident on CT scans after aneurysmal subarachnoid hemorrhage (SAH). Here, the authors assess the interobserver variability in the radiological interpretation of the initial CT scan following SAH.. Two experienced reviewers, a neurosurgeon and a neuroradiologist, independently prospectively reviewed the initial CT scans of 413 patients enrolled in the CONSCIOUS-1 trial. Measured variables included SAH, intraventricular hemorrhage, intracerebral hemorrhage, subdural hematoma, chronic infarction, midline shift, and hydrocephalus. To assess interobserver variability, weighted kappa values and intraclass correlation coefficients (ICCs) were calculated and Bland-Altman analysis was performed.. Moderate to substantial agreement was found for most of the CT scanning findings. There was fair to moderate interobserver agreement between reviewers when determining the extent of SAH based on a descriptive categorical classification (kappa 0.41; 95% CI 0.33-0.49), and better agreement when a semiquantitative scale was used (ICC 0.56; 95% CI 0.49-0.62). There was poor agreement between reviewers for the presence of hydrocephalus (kappa 0.34; 95% CI 0.20-0.48), but substantial to near perfect agreement on ventriculocranial ratio measurements (ICC 0.77; 95% CI 0.72-0.81).. The authors' findings suggest that there is considerable interobserver variability in the interpretation of CT scans after SAH. Quantitative measures may reduce interobserver variability in comparison with qualitative or categorical scales. Variability in interpretation of CT scans has implications for patient care and conduct of clinical trials. It may be beneficial to develop standardized assessments to ensure consistent evaluation of measured variables.

Topics: Cerebral Infarction; Cerebral Ventricles; Dioxanes; Humans; Hydrocephalus; Neuroradiography; Neurosurgery; Observer Variation; Prospective Studies; Pyridines; Pyrimidines; Reproducibility of Results; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Vasospasm, Intracranial

Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm.. This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses.. 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS.. SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Topics: Adult; Cerebral Infarction; Databases as Topic; Dioxanes; Double-Blind Method; Female; Fever; Humans; Hypothermia; Leukocytosis; Male; Middle Aged; Placebos; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Systemic Inflammatory Response Syndrome; Tachycardia; Tetrazoles; Treatment Failure; Treatment Outcome; Vasospasm, Intracranial

Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm, significantly associated with morbidity and mortality. In double-blind, placebo-controlled phase 3 studies, clazosentan reduces cerebral vasospasm-related morbidity and all-cause mortality in patients with aSAH. There are no reports about the clinical efficacy of clazosentan combination therapy with some other drugs. Initially, we explored the efficacy of clazosentan combination therapy with cilostazol, statin, and antiepileptic drugs. Subsequently, we assessed the add-on effect of fasudil to clazosentan combination therapy for aSAH patients. This multicenter, retrospective, observational cohort study included Japanese patients with aSAH between June 2022 and March 2023. The primary outcome was the ordinal score on the modified Rankin Scale (mRS; range, 0-6, with elevated scores indicating greater disability) at discharge. Among the 47 cases (women 74.5%; age 64.4 ± 15.0 years) undergoing clazosentan combination therapy, 29 (61.7%) resulted in favorable outcomes. Overall, vasospasm occurred in 16 cases (34.0%), with four cases (8.5%) developing vasospasm-related delayed cerebral ischemia (DCI). Both hypotension and vasospasm-related DCI were related to unfavorable outcome at discharge. Fasudil were added in 18 (38.3%) cases. Despite adding fasudil to clazosentan combination therapy, the incidence of aSAH-related vasospasm did not decrease. Added-on fasudil to combination therapy related to pulmonary edema, vasospasm, and vasospasm-related DCI, and unfavorable outcomes. Clazosentan combination therapy could potentially result in favorable outcomes for aSAH patients to prevent post-aSAH vasospasm-related DCI. The add-on effect of fasudil to combination therapy did not demonstrate a significant impact in reducing aSAH-related vasospasm or improving outcomes at discharge.

Topics: Aged; Brain Ischemia; Cerebral Infarction; Female; Humans; Middle Aged; Retrospective Studies; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Synthesis and release of the potent vasoconstrictor peptide endothelin-1 (ET-1) increases following cerebral ischemia and has previously been shown to mediate the delayed hypoperfusion associated with transient global ischemia. In this study we assessed the impact of ET-1 on perfusion and infarct volume in a focal model of cerebral ischemia by use of the selective ET(A) receptor antagonist Ro 61-1790 (affinity for ET(A) receptor 1000 fold greater than ETB receptor). Control rats subjected to permanent middle cerebral artery occlusion (MCAO) showed extensive reductions in microvascular perfusion 4 h post-MCAO that were significantly attenuated by Ro 61-1790 pretreatment (10 mg/kg, i.v.). Ro 61-1790 concomitantly and significantly reduced the ischemic lesion volume in the same animals. This effect was maintained 24 h post-MCAO providing that the animals received additional i.v. injections of 5 mg/kg Ro 61-1790 at 5 h and 8 h after MCAO. These findings demonstrate that ET(A) receptor antagonism partially preserves tissue perfusion following focal ischemia and that this effect is associated with significant neuroprotection. The results also support the hypothesis that vasoactive mediators, and ET-1 in particular, are important contributors to the pathogenesis of cerebral ischemic injury.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Dioxanes; Endothelin Receptor Antagonists; Endothelin-1; Male; Microcirculation; Middle Cerebral Artery; Pyridines; Pyrimidines; Rats; Rats, Inbred SHR; Receptor, Endothelin A; Sulfonamides; Tetrazoles