ETB receptor-mediated vasodilation is regulated by estradiol in young women

The endothelin-B (ETB) receptor mediates vasodilation in young women, an effect lost following menopause. It is unclear whether these alterations are due to aging or changes in estradiol (E2). During endogenous hormone suppression (GnRH antagonist), blockade of ETB receptors enhanced cutaneous microvascular vasodilation. However, during E2 administration, blockade of ETB receptors attenuated vasodilation, indicating that the ETB receptor mediates dilation in the presence of E2. In young women, ETB receptors mediate vasodilation in the presence of E2, an effect that is lost when E2 is suppressed.

Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

Abstract P148: Role of Endothelin B Receptors in Neuronal Progenitor Cell Differentiation and Mitochondrial Function in Ischemic Stroke

Neuronal progenitor cells (NPCs) and mitochondria are well known to play roles in regeneration and functions of the brain, respectively. However, stimulation of endothelin-B receptors (ETBR) using an agonist, sovateltide (IRL-1620) on their fate in the brain after stroke remains elusive. We evaluated the effect of sovateltide mediated ETBR stimulation on differentiation of NPCs and fate of mitochondria after stroke. Ischemic stroke was induced by performing permanent right middle cerebral artery occlusion (MCAO) in rats. Sovateltide (5 μg/kg) or saline (equal volume) was injected intravenously; neurological and motor function evaluation was done at 24 hrs and day 7 post MCAO. Brain tissues were analyzed for NPCs differentiation and mitochondrial fate using techniques such as western blots, immunofluorescence, transmission electron microscopy and in situ PCR. In vitro hypoxia experiment was carried out to confirm sovateltide mediated neuronal differentiation. Neurological and motor functions were significantly improved in sovateltide treated rats at 24 hrs and day 7 post MCAO. Differentiation of NPCs was evident with upregulation of neuronal differentiation markers Neuro D1 (p=0.00002) as well as HuC/HuD (p=0.0037) along with neuronal marker Doublecortin (DCX) (p=0.00011) at 24 hrs post MCAO. However, significant upregulation only in HuC/HuD (p=0.043) was observed at day 7. Better preserved mitochondrial fate was observed in sovateltide rat brains with downregulation of mitochondrial fission marker, DRP1 (p<0.001), increase in fusion marker, MFN2 (p<0.0001) and increase in cross-sectional area x number (p<0.05) as well as mitochondrial/tissue area (p<0.05) at 24 hrs and day 7 post MCAO. In situ PCR analysis showed increased mitochondrial DNA (p=0.0418), indicating better mitochondrial biogenesis at day 7 post MCAO. In vitro exposure of sovateltide and hypoxia to cultured NPCs showed higher NeuroD1 and NeuN (a mature neuronal marker) expression confirming NPCs differentiation. Sovateltide mediated ETBR stimulation promotes differentiation of NPCs and mitochondrial fusion as well as biogenesis and helps in neuronal regeneration and function restoration in acute ischemic brains.

High salt intake induces collecting duct HDAC1-dependent NO signaling

We reported that high salt intake stimulates renal collecting duct (CD) endothelin B receptor (ETBR)/NOS1β-dependent NO production inhibiting the epithelial sodium channel (ENaC) promoting natriuresis. However, the mechanism underlying the high salt (HS) induced increase of NO production is unclear. Histone deacetylase 1 (HDAC1) responds to increased fluid flow, as can occur in the CD during HS intake. The renal inner medulla (IM), in particular the IMCD, has the highest NOS1 activity within the kidney. Hence, we hypothesized that HS intake provokes HDAC1 activation of NO production in the IM. HS intake for one week significantly increased HDAC1 abundance in the IM. Ex vivo treatment of dissociated IM from HS mice with a selective HDAC1 inhibitor (MS-275) decreased NO production with no change in endothelin-1 (ET-1) peptide or mRNA levels. We further investigated the role of the ET-1/ETBR/NOS1β signaling pathway with chronic ETBR blockade (A-192621). Although NO was decreased and ET-1 levels were elevated in dissociated IM from HS mice treated with A-192621, ex vivo MS-275 did not further change NO or ET-1 levels suggesting that HDAC1 mediated NO production is regulated at the level or downstream of ETBR activation. In split-open CDs from HS mice, patch clamp analysis revealed significantly higher ENaC activity after MS-275 pretreatment, which was abrogated by an exogenous NO donor. Moreover, flow-induced increases in mIMCD-3 cell NO production were blunted by HDAC1 or calcium inhibition. Taken together, these findings indicate that HS intake induces HDAC1-dependent activation of the ETBR/NO pathway contributing to the natriuretic response.