Selective antagonism of the hepatic glucocorticoid receptor reduces hepatic glucose production.

A liver-selective glucocorticoid (GC) receptor antagonist (A-348441) was used to determine the effect of reduced hepatic GC signaling on hepatic glucose production. Fasted conscious dogs were studied in the presence (GRA, n = 6) or absence (CON, n = 6) of the intraduodenally administered GC receptor antagonist (100 mg/kg). All dogs were maintained on a pancreatic clamp and in a euglycemic state for 7 hours to ensure that any changes in glucose metabolism were the direct result of the effects of A-348441, which was given at the start of a 5-hour experimental period.

Blood pressure regulation by ETA and ETB receptors in conscious, telemetry-instrumented mice and role of ETA in hypertension produced by selective ETB blockade.

The net contribution of endothelin type A (ET(A)) and type B (ET(B)) receptors in blood pressure regulation in humans and experimental animals, including the conscious mouse, remains undefined. Thus we assessed the role of ET(A) and ET(B) receptors in the control of basal blood pressure and also the role of ET(A) receptors in maintaining the hypertensive effects of systemic ET(B) blockade in telemetry-instrumented mice. Mean arterial pressure (MAP) and heart rate were recorded continuously from the carotid artery and daily (24 h) values determined.

Delivery of RNAi reagents in murine models of obesity and diabetes.

RNA interference (RNAi) is an exciting new tool to effect acute in vivo knockdown of genes for pharmacological target validation. Testing the application of this technology to metabolic disease targets, three RNAi delivery methods were compared in two frequently utilized preclinical models of obesity and diabetes, the diet-induced obese (DIO) and B6.V-Lep/J (ob/ob) mouse.

Metabolic responses with endothelin antagonism in a model of insulin resistance.

Atrasentan, an endothelin antagonist, would have beneficial effects on metabolic responses in a model of insulin resistance. Zucker lean or fatty rats were maintained either on regular (lean and fatty control, n = 12) or atrasentan-treated water (5 mg/kg/d, fatty atrasentan, n = 13) for 6 weeks. There was no significant difference in water intake and body weight with the atrasentan-treated group compared with fatty controls.

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects.

Hypertension induced by blockade of ET(B) receptors in conscious nonhuman primates: role of ET(A) receptors.

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.

Effects of a selective endothelin A receptor antagonist, ABT-627, in healthy normotensive anaesthetized rats developing acute pulmonary air embolism.

Acute pulmonary air embolism (APAE) injures the vascular endothelium in the lung and results in pulmonary hypertension (PH). Endothelins (ETs), a family of potent vasoactive peptides, are known to be associated with PH of various aetiologies. We evaluated the effects of ABT-627, a selective ET(A) receptor (ET(A)-R) antagonist in a rat model of APAE over 3 h.

Effects of a selective ET(A)-receptor antagonist, atrasentan (ABT-627), in murine models of allergic asthma: demonstration of mouse strain specificity.

Asthma is a chronic respiratory disease that is characterized by airway inflammation, bronchoconstriction and the influx of pro-inflammatory cells, mostly eosinophils in the lung tissue and bronchoalveolar space. Amongst the many physiopathological roles attributed to endothelins (ETs), one is to modulate pulmonary functions. It is established that Balb/c mice develop allergen-induced Th(2)-cytokine gene expression, airway inflammation and hyper-responsiveness whereas C57Bl/6 mice are much less reactive.

Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: ex vivo and in vivo studies.

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.

Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: in vitro studies.

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627, ABT-546, A-182086 and A-192621, which exhibit difference in selectivity for ET(A) and ET(B) receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting (125)I-labelled ET-1 binding to cloned human ET(A) and ET(B) receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice.

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity.