An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs

Nirei, Hisataka; Hamada, Kaori; Shoubo, Miwako; Sogabe, Keizo; Notsu, Yoshitada; Ono, Takaharu

doi:10.1016/0024-3205(93)90007-p

Cited by 106 publications

(38 citation statements)

References 17 publications

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“…Several animal studies suggested a beneficial effect of EDNRA inhibition in treating vasospasm, leading to human clinical trials (26). The use of clazosentan, a selective EDNRA antagonist with a predilection for the central nervous system, has demonstrated reduction in angiographically demonstrated vasospasm, even though there was no improvement in clinical outcome (27,28).…”

Section: −7mentioning

confidence: 99%

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Yasuno

Bakırcıoğlu

Low

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

104

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The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by metaanalysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5′ of the endothelin receptor type A with P = 2.2 × 10 −8 [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10 −7, PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10 −7, PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.subarachnoid hemorrhage | stroke | genetic risk loci I ntracranial aneurysms (IAs) are balloon-like dilations of cerebral arteries and affect 2-5% of the population (1). Although most of these lesions are clinically silent, their rupture and consequent subarachnoid hemorrhage usually occurs between ages 40 and 60 without prior warning, resulting in substantial morbidity and mortality (2, 3).Aside from the well-established risk factors, such as hypertension, smoking, female sex (4), and high shear stress imposed on the cerebrovasculature (5), there is evidence for significant genetic contribution to IA pathogenesis (6). As is the case for other multifactorial diseases, both common and rare variants are thought to contribute to IA. In an attempt to identify common variants that confer risk of IA, we previously completed two genome-wide association studies of IA (6, 7). The larger, second genome-wide association study (7) implemented a discovery and a replication phase using samples of European and Japanese descent, respectively. Using a discovery cohort of 2,780 cases and 12,515 controls, we analyzed 831,532 genotyped and imputed autosomal SNPs for association with IA. We used a Bayesian measure of the strength of association-the posterior probability of association (PPA)-to prioritize SNPs by calculating to what extent the data supports association with IA (7). This analysis revealed five loci with PPA > 0.5. Following replication genotyping using two independent Japanese cohorts and combining the discov...

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Section: −7mentioning

confidence: 99%

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Yasuno

Bakırcıoğlu

Low

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

104

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“…[9,11,14,19,24,33,37,40,[47][48][49] This controversial [5,19] hypothesis is supported by a delayed onset of long-lasting spasm of the intracranial vessels produced by intracisternal administration of ET-1, [3,47] by an increase in ET-1 levels in CSF after SAH in humans, [11,14,48,49] and by a decrease in the incidence of vasospasm after use of ET-1 receptor antagonists. [8,23,34,38,57] Astrocytes, neurons, and pituitary cells produce ET-1. [10,17,26,29,56] However, ET-1 is also released by endothelial and smooth-muscle cells when they are stimulated by oxyhemoglobin [9,24,40] and by astrocytes when they are stimulated by thrombin.…”

Section: Discussionmentioning

confidence: 99%

“…The combination of the continuous presence of low levels of ET-1 in the perivascular space, such as those observed in our experiments, with decreased NO production due to the concomitant disappearance of NO synthase activity from the adventitia of the vessel [43] or a decrease in NO availability due to a "sink effect" of hemoglobin, [18,22] could be responsible for vasospasm. Because a decrease in NO availability results in increased ET-1 production, [28,37] the decrease of vasospasm in response to ET-1 receptor antagonists [8,23,34,38,57] as well as to NO [1] may occur because both approaches tend to recover the normal balance between ET-1 and NO.…”

Section: Vasospasm and Et-1mentioning

confidence: 99%

Source and cause of endothelin-1 release to cerebrospinal fluid after subarachnoid hemorrhage

Pagnanelli

Barrer²

1997

FOC

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Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 μM), methemoglobin (10 μM), or hypoxia (11% oxygen). There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 ± 2.2 pg/ml and ET-1 plasma levels were 1.2 ± 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 ± 1.7 pg/ml in CSF and 2.7 ± 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 ± 0.4 pg/ml at the occlusion vs. 3.1 ± 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 ± 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 ± 0.8 pg/ml vs. 0.1 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 ± 0.6 pg/ml vs. 0 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 ± 0.6 vs. 6.4 ± 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05). Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

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“…In addition to this indirect evidence, more direct demonstrations have been made in various animal models of cerebral vasospasm using endothelin receptor antagonists. In dogs (mostly double-hemorrhage model), cerebral vasospasm was effectively ameliorated by the following treatments: intracisternal administration of FR139317 (211) or phosphoramidon (212), continuous intrathecal infusion of BQ-123 (209,213), intracisternal administration of SB 209670 (214) or intravenous administration of bosentan (215). With respect to the pathogenesis of cerebral vasospasm, the attractively straightforward "endothelin hypothesis" appears to be supported by several different lines of experimental data, and suggests that an abluminal clot may stimulate endothelial cells in a cerebral artery to produce endothPlin-1…”

Section: V-4 Brain Injury and Cerebral Vasospasmmentioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs

Cited by 106 publications

References 17 publications

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Common variant near the endothelin receptor type A ( EDNRA ) gene is associated with intracranial aneurysm risk

Source and cause of endothelin-1 release to cerebrospinal fluid after subarachnoid hemorrhage

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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