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Evidence for inhibition of sympathetic neurotransmission by endogenously released acetylcholine in the guinea-pig trachea.

1. Interactions between pulmonary cholinergic and noradrenergic nerves were studied in the innervated tracheal tube preparation isolated from guinea-pigs anaesthetized with urethane. Relaxations of the trachealis smooth muscle in response to postganglionic stimulation of the sympathetic nerve were recorded as decreases in the intraluminal pressure of the tracheal tube after the pressure had been raised with the stable thromboxane-mimetic, U46619. In contrast, contractions following preganglionic stimulation of the vagal nerve trunk were recorded as increases in intraluminal pressure. 2. In app

Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease.

We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer's disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer's disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer's disease

Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats.

Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT +

Protective effect of alpha-lipoic acid against ischaemic acute renal failure in rats.

1. In the present study, we investigated whether treatment with alpha-lipoic acid (LA), a powerful and universal anti-oxidant, has renal protective effects in rats with ischaemic acute renal failure (ARF). 2. Ischaemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Blood urea nitrogen (BUN), plasma concentrations of creatinine (Pcr) and urinary osmolality (Uosm) were measured for the assessment of renal dysfunction. Creatinine clearance (Ccr) and fractional excretion of Na+ (FENa) were used as indicato

Association between Complete Proteinuria Remission and Kidney Function in the Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy.

KEY POINTS: This analysis explored the association between complete remission of proteinuria and kidney function decline during sparsentan or irbesartan treatment. Patients achieving complete remission of proteinuria experienced better eGFR preservation and fewer kidney failure events. These data support Kidney Disease Improving Global Outcomes guideline recommendations to maintain proteinuria levels in IgA nephropathy ideally below 0.3 g/d. BACKGROUND: In the phase 3, randomized, double-blind PROTECT ( NCT03762850 ) trial, sparsentan, a single-molecule dual endothelin angiotensin receptor an

Age-dependent impairment of K(ATP) channel function following brain injury.

Previous studies observed that endothelin-1 (ET-1) contributed to ATP-sensitive K+ (K(ATP)) channel impairment 1 h following fluid percussion brain injury (FPI) in the newborn pig. The present study was designed to determine the effect of FPI on K(ATP) channel activity as a function of time in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. FPI of moderate severity (1.9-2.1 atm) was produced by using a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. Croma

[Carotid body inflammation and carotid sinus nerve afferent activity after intermittent hypoxia exposure of various frequencies in rabbits].

OBJECTIVE: To explore the inflammatory reactions, endothelin level and carotid sinus nerve (CSN) afferent activity of carotid body (CB) after intermittent hypoxia/reoxygenation (IH/ROX) exposure of various frequencies in rabbits. METHODS: Forty-nine male adult New Zealand white rabbits (2.5-3.0 kg) were separated into 7 groups (n = 7 each). After anesthetization, the right carotid artery and CSN were cleared of surrounding tissues without touching the right CB and the left carotid region. The CSN was unenveloped to partially expose the myelin sheath, and electrodes were placed to the "single"

Immune complexes containing scleroderma-specific autoantibodies induce a profibrotic and proinflammatory phenotype in skin fibroblasts.

BACKGROUND: In systemic sclerosis (SSc), autoantibodies provide the most accurate tool to predict the disease subset and pattern of organ involvement. Scleroderma autoantibodies target nucleic acids or DNA/RNA-binding proteins, thus SSc immune complexes (ICs) can embed nucleic acids. Our working hypothesis envisaged that ICs containing scleroderma-specific autoantibodies might elicit proinflammatory and profibrotic effects in skin fibroblasts. METHODS: Fibroblasts were isolated from skin biopsies obtained from healthy subjects and patients with diffuse cutaneous SSc (dcSSc). ICs were purified

Medical decision analysis of endoscopic surveillance of Barrett's oesophagus to prevent oesophageal adenocarcinoma.

BACKGROUND: Although the use of non-heart beating donors (NHBDs) could bridge the widening gap between organ demand and supply, its application to liver transplantation is limited due to the high incidence of primary graft loss. Prevention of liver injury in NHBDs will benefit the results of transplantation. This study was conducted to evaluate the protective effects of L-arginine on liver grafts from NHBDs. METHODS: One hundred and four Wistar rats were randomly divided into 7 groups: normal control (n=8), controls 1, 2 and 3 (C1, C2, C3, n=16), and experimental 1, 2 and 3 (E(1), E(2), E(3),

Alterations in arachidonic acid release and phospholipase C-beta(1) expression in glaucomatous human ciliary muscle cells.

PURPOSE: Prostaglandin (PG) F(2alpha) and other Ca(2+)-mobilizing agonists, such as carbachol (CCh) and endothelin (ET)-1, induce an increase in uveoscleral outflow, in part through receptor-mediated mechanisms in the ciliary muscle. Because changes in uveoscleral outflow across the ciliary muscle could cause elevation of intraocular pressure (IOP) in patients with glaucoma, the present study was conducted to investigate the possibility that basal and agonist-induced second-messenger formation may be altered in glaucomatous human ciliary muscle (g-HCM) cells compared with normal (n)-HCM cells.

Neuroprotection and Enhanced Hemoglobin Excretion by Intrathecal Clazosentan in Mice With Subarachnoid Hemorrhage.

BACKGROUND: Intravenous administration of clazosentan, a selective endothelin receptor subtype A antagonist, has been used as an anti-vasospastic agent. This study aimed to investigate whether intrathecal administration of clazosentan prevents neuroinflammation and affects lymphatic clearance of hemoglobin in a mouse model of acute subarachnoid hemorrhage (SAH). METHODS: Male C57BL/6 mice (n=109) underwent prechiasmatic cisternal injection models of SAH or sham models. From 30 minutes post-modeling, mice randomly received a continuous intracerebroventricular infusion of saline or clazosentan

Motor Impairment and Adaptation in a Novel Nonhuman Primate Model of Internal Capsule Infarct.

BACKGROUND: Loss of hand control is a major source of poststroke disability, particularly when infarcts involve subcortical white matter. Yet, most preclinical models target the cortex and infer recovery from task performance without quantifying whether improvements reflect restoration or adaptation. To address this, we developed a novel nonhuman primate model of focal internal capsule infarct. This study is exploratory and hypothesis-testing, including prespecified hypotheses regarding motor impairment and adaptation. METHODS: Three adult male rhesus macaques (Macaca mulatta, 5-10 years) rec

Review of the clinical, humanistic, and economic burden of focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease characterized by podocyte injury, proteinuria, and risk of kidney failure. Until recently, no medicines had been approved by the FDA or European Medicines Agency, with management focused on supportive care and proteinuria reduction. This supplement explores the burden of FSGS from a clinical, humanistic, and economic perspective, informed by the results of 3 systematic literature reviews. FSGS is associated with poorer quality of life and high health care costs, and these outcomes are correlated with disease severity

Treatment Patterns in Patients With Incident Pulmonary Hypertension: Real-World Data From the Pulmonary Hypertension Association Registry.

BACKGROUND: Current evidence supports risk-based treatment for pulmonary arterial hypertension (PAH) with an endothelin receptor antagonist and phosphodiesterase type 5 inhibitor as initial therapy for patients with low- and intermediate-risk PAH, and triple therapy with the addition of a parenteral prostacyclin for patients with high-risk PAH. RESEARCH QUESTION: What are the current treatment patterns for patients with newly diagnosed PAH in the Pulmonary Hypertension Association Registry (PHAR)? STUDY DESIGN AND METHODS: This analysis was performed in a prospectively collected cohort of pa

RECOVER study: a multicenter retrospective cohort study and comparison of the efficacy and safety of clazosentan and fasudil in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a crucial determinant of the prognosis of patients with aneurysmal subarachnoid hemorrhage (aSAH). In Japan, fasudil has traditionally been used to prevent cerebral vasospasm after aSAH. The effectiveness of clazosentan, a selective endothelin receptor A antagonist, in preventing cerebral vasospasm, a significant contributor to DCI, was recently demonstrated. This study aimed to compare the efficacy and safety of perioperative management using clazosentan- and fasudil-based therapies. METHODS: This multicenter, retrospective observational cohort s

The Potential of the Probiotic Isolate Lactobacillus plantarum SS18-50 to Prevent Colitis in Mice.

The objective of this study was to investigate the effect of the Lactobacillus plantarum (L. plantarum) SS18-50 (an isolate with favorable probiotic properties following space traveling) on dextran sulfate sodium (DSS)-induced colitis in mice. Male ICR mice were randomly assigned to one of six groups: a control group, a model group, and four intervention groups comprising the isolate (SS18-50-L and SS18-50-H) and the wild type (GS18-L and GS18-H) strains. The model group and the intervention groups were administered a 3.5% DSS (w/v) solution to induce acute enteritis. The four intervention gro

IgA Vasculitis (Henoch-Schönlein Purpura): An Update on Treatment.

Objective: IgA vasculitis (IgAV), previously named as Henoch-Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10-30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therap

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… Endothelin Receptor Antagonists Endothelins (ETs) are potent endogenous pressor agents comprising a family of three peptides, each one consisting of 21 amino acids: endothelin-1 (ET1), endothelin-2 (ET2), and endothelin-3 (ET3). …

NCX 470 Exerts Retinal Cell Protection and Enhances Ophthalmic Artery Blood Flow After Ischemia/Reperfusion Injury of Optic Nerve Head and Retina.

PURPOSE: The purpose of this study was to assess the retinal protective activity and ocular hemodynamics after NCX 470 (0.1%) compared to bimatoprost administered as the US Food and Drug Administration (FDA)-approved drug (Lumigan - 0.01% ophthalmic solution, LUM) and at an equimolar dose (0.072%, BIM) to that released by NCX 470. METHODS: Endothelin-1 (ET-1) induced ischemia/reperfusion injury model in rabbits was used. ET-1 was injected nearby the optic nerve head (ONH) twice/week for 6 weeks. Starting on week 3, the animals received vehicle (VEH), NCX 470, LUM, or BIM (30 µL/eye, twice dai

Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial.

BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1-a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A-a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B-

The lncRNA MALAT1 participates in regulating coronary slow flow endothelial dysfunction through the miR-181b-5p-MEF2A-ET-1 axis.

BACKGROUND: Coronary slow flow (CSF) refers to coronary arteries with no obvious stenosis but have slow coronary flow without effective treatment. The main cause of CSF is endothelial dysfunction. The long non-coding RNA (lncRNA) MALAT1 is involved in regulating endothelial dysfunction, but its role in CSF endothelial dysfunction is still unclear. METHODS: We included 41 CSF patients and 37 controls in the study, who all underwent coronary angiography, echocardiography, and brachial artery flow-mediated dilatation (FMD) examination. Human umbilical vein endothelial cells (HUVECs) stimulated b