clazosentan and Brain-Ischemia

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

A subarachnoid hemorrhage (SAH) is a serious and potentially life-threatening condition where blood leaks out of blood vessels over the surface of the brain. Delayed ischemic neurological deficit (DIND) and the related feature of vasospasm, where patients experience a delayed deterioration, have long been recognized as the leading potentially treatable cause of death and disability in patients with SAH. Endothelin is a potent, long-lasting endogenous vasoconstrictor that has been implicated in the pathogenesis of DIND. Therefore, endothelin receptor antagonists (ETAs) have emerged as a promising therapeutic option for SAH-induced cerebral vasospasm.. To assess the efficacy and tolerability of ETAs for SAH.. We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 11), MEDLINE (1950 to December 2011), EMBASE (1946 to December 2011) and the Chinese Biomedical Database (1978 to December 2011). In an effort to identify further published, unpublished and ongoing trials we searched additional Chinese databases, ongoing trials registers, Google Scholar and Medical Matrix, handsearched journals, scanned reference lists, and contacted researchers and pharmaceutical companies.. We only included randomized controlled trials (RCTs) that compared an ETA with placebo for SAH in adult (18 years of age or older) patients who met the diagnostic criteria for SAH based on clinical symptoms, with confirmation on computerized tomography scan results or angiography. Two review authors independently selected RCTs according to the inclusion criteria. We resolved disagreements by discussion with a third review author.. Two review authors independently selected relevant articles and assessed their eligibility according to the inclusion and exclusion criteria. We resolved disagreements by discussion with a third review author. We used the random-effects model and expressed the results as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI).. We included four RCTs with 2024 participants that compared ETAs with placebo for SAH. All RCTs were multicenter, double-blind studies with a low risk of bias. ETAs reduced the incidence of DIND (RR 0.80; 95% CI 0.67 to 0.95) and angiographic vasospasm (RR 0.62; 95% CI 0.52 to 0.72) but did not reduce the incidence of unfavorable outcomes (RR 0.87; 95% CI 0.74 to 1.02) or mortality (RR 1.05; 95% CI 0.77 to 1.45). ETAs increased the incidence of hypotension (RR 2.53; 95% CI 1.77 to 3.62) and pneumonia (RR 1.56; 95% CI 1.23 to 1.97).. ETAs appear to reduce DIND and angiographic vasospasm but there were adverse events and the impact on clinical outcome is unclear. Additional well-designed RCTs are needed.

Topics: Brain Ischemia; Conflict of Interest; Dioxanes; Endothelin Receptor Antagonists; Humans; Hypotension; Pneumonia; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Research Support as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Cerebral vasospasm is the most important potentially treatable cause of mortality and morbidity following aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan, a selective endothelinreceptor antagonist, has been suggested to help reduce the incidence of vasospasm in patients with aSAH. However, the results were controversial in previous trials. This meta-analysis attempts to assess the effect of clazosentan in patients with aSAH.. We systematically searched Pubmed, Embase, and the Cochrane Library from their inception until June, 2012. All randomized controlled trials (RCTs) related to the effect of clazosentan in aSAH were included. The primary outcomes included the incidence of angiographic vasospasm, new cerebral infarction (NCI), delayed ischemic neurological deficits (DIND), and vasospasm-related morbidity/mortality (M/M); the second outcomes included the occurrence of rescue therapy, all-cause-mortality, and poor outcome. 4 RCTs were included with a total of 2156 patients. The risk of angiographic vasospasm (relative risk [RR] =0.58; 95% CI, 0.48 to 0.71), DIND (RR=0.76; 95% CI, 0.62 to 0.92), and vasospasm-related M/M (RR=0.80; 95% CI, 0.67 to 0.96) were statistically significantly reduced in the clazosentan group. Patients treated with clazosentan had a reduced occurrence of rescue therapy (RR=0.62; 95% CI, 0.49 to 0.79). However, no statistically significant effects were observed in NCI (RR=0.74; 95% CI, 0.52 to 1.04), mortality (RR=1.03; 95% CI, 0.71 to 1.49), and poor outcome (RR=1.12; 95% CI, 0.96 to 1.30).. Our pooling data supports that clazosentan is probably effective in preventing the occurrence of angiographic vasospasm, vasospasm-related DIND, vasospasm related M/M, and rescue therapy. However, no evidence lends significant supports to the benefits of clazosentan in decreasing the occurrence of NCI, mortality or improving the functional outcome.

Topics: Brain Ischemia; Cause of Death; Confidence Intervals; Dioxanes; Humans; Incidence; Placebos; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Treatment Outcome; Vasospasm, Intracranial

Topics: Adult; Brain Ischemia; Cerebral Angiography; Clinical Trials as Topic; Combined Modality Therapy; Dioxanes; Endothelin A Receptor Antagonists; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracranial Aneurysm; Magnesium; Male; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Neuroprotective Agents; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; 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

Predictors of outcome after aneurysmal subarachnoid hemorrhage have been determined previously through hypothesis-driven methods that often exclude putative covariates and require a priori knowledge of potential confounders. Here, we apply a data-driven approach, principal component analysis, to identify baseline patient phenotypes that may predict neurological outcomes.. Principal component analysis was performed on 120 subjects enrolled in a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. Correlation matrices were created using a combination of Pearson, polyserial, and polychoric regressions among 46 variables. Scores of significant components (with eigenvalues>1) were included in multivariate logistic regression models with incidence of severe angiographic vasospasm, delayed ischemic neurological deficit, and long-term outcome as outcomes of interest.. Sixteen significant principal components accounting for 74.6% of the variance were identified. A single component dominated by the patients' initial hemodynamic status, World Federation of Neurosurgical Societies score, neurological injury, and initial neutrophil/leukocyte counts was significantly associated with poor outcome. Two additional components were associated with angiographic vasospasm, of which one was also associated with delayed ischemic neurological deficit. The first was dominated by the aneurysm-securing procedure, subarachnoid clot clearance, and intracerebral hemorrhage, whereas the second had high contributions from markers of anemia and albumin levels.. Principal component analysis, a data-driven approach, identified patient phenotypes that are associated with worse neurological outcomes. Such data reduction methods may provide a better approximation of unique patient phenotypes and may inform clinical care as well as patient recruitment into clinical trials.. http://www.clinicaltrials.gov. Unique identifier: NCT00111085.

Topics: Brain Ischemia; Cerebral Angiography; Dioxanes; Double-Blind Method; Female; Humans; Intracranial Hemorrhages; Male; Middle Aged; Nervous System Diseases; Phenotype; Principal Component Analysis; Prospective Studies; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Tomography, X-Ray Computed; Treatment Outcome; Vasospasm, Intracranial

Early identification of patients at risk of angiographic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may mitigate its sequelae. One mechanism that may contribute to angiographic vasospasm is increased central sympathetic activity, which is also thought to cause electrocardiographic (ECG) changes after SAH. Here, we perform the first study to determine the association between ECG changes and angiographic vasospasm after SAH.. Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm. ECGs were obtained within 24 hours of aneurysm rupture and during the vasospasm risk period. Angiographic vasospasm was assessed using catheter angiography at baseline and 7 to 11 days after SAH. Multivariate logistic regression was used to identify significant associations.. The most prevalent finding on ECG both immediately following SAH and during the vasospasm risk period was QT prolongation (42% and 25%, respectively). A prolonged QT interval and tachycardia on the baseline ECG were associated with angiographic vasospasm (OR, 1.86; 95% CI, 1.00-3.45; and OR, 10.83; 95% CI, 1.17-100.50, respectively). QT prolongation on ECG during the vasospasm risk period was also associated with angiographic vasospasm (OR, 3.53; 95% CI, 1.67-7.39). No ECG findings were associated with delayed ischemic neurological deficit, but tachycardia and ST changes were associated with worse clinical outcome.. QT prolongation and tachycardia on ECG were independently associated with angiographic vasospasm after aneurysmal SAH on multivariate analysis.. URL: http://clinicaltrials.gov. Unique Identifier: NCT00111085.

Topics: Adult; Aged; Aneurysm, Ruptured; Brain Ischemia; Cerebral Angiography; Databases, Factual; Dioxanes; Electrocardiography; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Stunning; Nervous System Diseases; Potassium; Predictive Value of Tests; Prognosis; Prospective Studies; Pyridines; Pyrimidines; Risk Factors; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; 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

Cerebral vasospasm and late cerebral ischemia (LCI) remain leading causes of mortality in patients experiencing a subarachnoid hemorrhage (SAH). This occurs typically 3 to 4 days after the initial bleeding and peaks at 5 to 7 days. The underlying pathophysiology is still poorly understood. Because SAH is associated with elevated levels of endothelin-1 (ET-1), focus has been on counteracting endothelin receptor activation with receptor antagonists like clazosentan, however, with poor outcome in clinical trials. We hypothesize that inhibition of intracellular transcription signaling will be an effective approach to prevent LCI. Here, we compare the effects of clazosentan versus the MEK1/2 blocker U0126 in a rat model of SAH. Although clazosentan directly inhibits the contractile responses in vivo to ET-1, it did not prevent SAH-induced upregulation of ET receptors in cerebral arteries and did not show a beneficial effect on neurologic outcome. U0126 had no vasomotor effect by itself but counteracts SAH-induced receptor upregulation in cerebral arteries and improved outcome after SAH. We suggest that because SAH induces elevated expression of several contractile receptor subtypes, it is not sufficient to block only one of these (ET receptors) but inhibition of transcriptional MEK1/2-mediated upregulation of several contractile receptors may be a viable way towards alleviating LCI.

Topics: Animals; Brain Ischemia; Butadienes; Cerebral Arteries; Dioxanes; Disease Models, Animal; Endothelin-1; Enzyme Inhibitors; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Nitriles; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Up-Regulation

Subarachnoid hemorrhage (SAH) remains a condition with suboptimal functional outcomes, especially in the young population. Pharmacotherapy has an accepted role in several aspects of the disease and an emerging role in several others. No preventive pharmacologic interventions for SAH currently exist. Antiplatelet medications as well as anticoagulation have been used to prevent thromboembolic events after endovascular coiling. However, the main focus of pharmacologic treatment of SAH is the prevention of delayed cerebral ischemia (DCI). Currently the only evidence-based medical intervention is nimodipine. Other calcium channel blockers have been evaluated without convincing efficacy. Anti-inflammatory drugs such as statins have demonstrated early potential; however, they failed to provide significant evidence for the use in preventing DCI. Similar findings have been reported for magnesium, which showed potential in experimental studies and a phase 2 trial. Clazosentane, a potent endothelin receptor antagonist, did not translate to improve functional outcomes. Various other neuroprotective agents have been used to prevent DCI; however, the results have been, at best inconclusive. The prevention of DCI and improvement in functional outcome remain the goals of pharmacotherapy after the culprit lesion has been treated in aneurysmal SAH. Therefore, further research to elucidate the exact mechanisms by which DCI is propagated is clearly needed. In this article, we review the current pharmacologic approaches that have been evaluated in SAH and highlight the areas in which further research is needed.

Topics: Adrenal Cortex Hormones; Animals; Anticoagulants; Apoptosis; Brain Ischemia; Calcium Channel Blockers; Clinical Trials as Topic; Dexamethasone; Dioxanes; Disease Models, Animal; Drugs, Chinese Herbal; Estrogens; Evidence-Based Medicine; Free Radical Scavengers; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Magnesium Sulfate; Neuroprotective Agents; Nimodipine; Platelet Aggregation Inhibitors; Pregnatrienes; Progesterone; Pyridines; Pyrimidines; Receptor, Endothelin A; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Topics: Animals; Aquaporins; Blotting, Western; Brain Edema; Brain Ischemia; Dioxanes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Evoked Potentials, Somatosensory; Image Processing, Computer-Assisted; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuroprotective Agents; Oligopeptides; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Stroke; Sulfonamides; Tetrazoles

Topics: Brain Ischemia; Cerebral Angiography; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dioxanes; Endpoint Determination; Humans; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial

Topics: Brain Ischemia; Dioxanes; Endothelin Receptor Antagonists; Endpoint Determination; Humans; Meta-Analysis as Topic; Outcome Assessment, Health Care; Pyridines; Pyrimidines; Receptors, Endothelin; Reproducibility of Results; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Time Factors; Vasospasm, Intracranial

The authors examined the effect of selective endothelin (ET) receptor type A (ET(A)) antagonism on histological and functional recovery in cat at 24 hours after reversible middle cerebral artery occlusion (MCAO). A novel and specific ET(A) antagonist, Ro 61-1790 [5-methylpyridine-2-sulfonic acid-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-1H-tetrazol-5-y l-pyridin-4-yl)-pyrimidin-4-ylamide sodium salt (1:2)] (Roche, Basel, Switzerland), was used at doses that produced steady-state plasma concentrations and abolished ET-induced pial arteriolar vasoconstriction. In a cranial window preparation, 8 nmol/L ET constricted pial arterioles by 33 +/- 18% (mean +/- SD), but this response was ablated by intravenous Ro 61-1790 treatment (10-mg/kg bolus, 4-mg/kg/h infusion). In additional animal cohorts, halothane-anesthetized cats were treated with 90 minutes of MCAO and 24 hours of reperfusion. Animals received Ro 61-1790 infusion beginning at the onset of reperfusion and continuing for 6 or 24 hours (n = 41). Control cats were treated with 0.9% saline by intravenous infusion throughout reperfusion. There was no difference in injury volume or neurologic evaluation score in saline-treated cats (n = 11; caudate 24 +/- 28%, cortical injury 7.5 +/- 5% of ipsilateral structure; score 52 +/- 8) versus the results in cats treated with Ro 61-1790 for either 24 hours (n = 6; caudate 22 +/- 23%, cortex 6 +/- 5%, injury volume of ipsilateral structure; score 55 +/- 3) or 6 hours (n = 11; caudate 33 +/- 30%, cortex 12 +/- 14%, injury volume of ipsilateral structure; score 50 +/- 10). Mortality was greatest in the 24-hour drug treatment group. These data suggest that blockade of ET(A) receptor activity is not beneficial to tissue or functional outcomes from experimental stroke in cat.

Topics: Animals; Arterial Occlusive Diseases; Arterioles; Brain Ischemia; Cats; Cerebral Arteries; Dioxanes; Endothelin Receptor Antagonists; Endothelins; Male; Pia Mater; Pyridines; Pyrimidines; Receptor, Endothelin A; Sulfonamides; Tetrazoles; Treatment Failure; Vasoconstriction

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