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Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.

ABSTRACT: Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known about the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ET1 increases cerebrovascular risk by disrupting critical mechanisms regulating cerebral blood flow. Male C57Bl6/J mice equipped with a cranial window were infused intravenously with vehicle or ET1, and somatosensory cortex blood flow was assessed by laser Doppler flowmetry. ET1 infusion increased mean arterial pressure and attenuated the blood flow increase produced by neural activity (whisker stimulation) or neocortical application of the endothelium-dependent vasodilator acetylcholine but not A23187. The cerebrovascular effects of ET1 were abrogated by the ET(A) receptor antagonist BQ123 and were not related to vascular oxidative stress. Rather, the dysfunction was dependent on Rho-associated protein kinase activity. Furthermore, in vitro studies demonstrated that ET1 suppresses endothelial nitric oxide (NO) production, assessed by its metabolite nitrite, an effect associated with Rho-associated protein kinase-dependent changes in the phosphorylation state of endothelial NO synthase. Collectively, these novel observations demonstrate that increased ET1 plasma levels alter key regulatory mechanisms of the cerebral circulation by modulating endothelial NO synthase phosphorylation and NO production through Rho-associated protein kinase. The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia.

SUBMITTER: Faraco G

PROVIDER: S-EPMC3874144 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.

Faraco Giuseppe G Moraga Ana A Moore Jamie J Anrather Joseph J Pickel Virginia M VM Iadecola Costantino C

Hypertension (Dallas, Tex. : 1979) 20130819 4

Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known about the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ...[more]

PMID: 23959559

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Project description:BackgroundCerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining.ResultsA mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value <?0.001).ConclusionsAfter severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted.

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Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.

Publications

Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.

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