Endothelin-1 inhibits sodium reabsorption in the thick ascending limb (THAL) via stimulation of nitric oxide (NO) production. The mechanism whereby endothelin-1 stimulates THAL NO is unknown. We hypothesized that endothelin-1 stimulates THAL NO production by activating phosphatidylinositol 3-kinase (PI3K), stimulating Akt activity, and phosphorylating NOS3 at Ser1177. This enhances NO productio...

AIMS The two-pore-domain potassium channel TASK-1 is robustly inhibited by the activation of receptors coupled to the Gα(q) subgroup of G-proteins, but the signal transduction pathway is still unclear. We have studied the mechanisms by which endothelin receptors inhibit the current carried by TASK-1 channels (I(TASK)) in cardiomyocytes. METHODS AND RESULTS Patch-clamp measurements were carrie...

We used laser-Doppler flowmetry to study the effects of endothelin-1 on local cortical microvascular perfusion and resistance in 29 pentobarbital-anesthetized rats. Intravenous administration of 10-300 pmol endothelin-1 reduced arterial blood pressure and microvascular resistance and increased microvascular perfusion. However, intracarotid administration of low doses of endothelin-1 increased m...

Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-chole...

Increased pulmonary vascular resistance in preterm newborn infants with respiratory distress syndrome is suggested, and endothelin-1 plays an important role in pulmonary vascular reactivity in newborns. We determined umbilical cord blood and neonatal (second sample) levels of endothelin-1 in 18 preterm newborns with respiratory distress syndrome who had no clinical or echocardiographic diagnosi...

Endothelin is a potent vasoconstrictor peptide which has recently been localized in the gastrointestinal tract. We have investigated the transmembrane signaling properties of endothelin in isolated smooth muscle cells of the rabbit rectosigmoid. Endothelin induced a dose dependent contraction of smooth muscle cells in a range of 10(-10) to 10(-6)M. In normal buffer, contraction peaked at 30 sec...

Background—Capillary leakage with fluid loss into the third space contributes to many of the early systemic complications in severe acute pancreatitis. There has been increasing interest in endothelin as one of the factors aVecting capillary permeability. Aim—To elucidate further the role of endothelin in the development of capillary leakage in acute pancreatitis by investigating the eVect of e...

Chronic ethanol feeding decreases insulin-stimulated glucose uptake in rat adipocytes. Here, we show that chronic ethanol also decreases endothelin-stimulated glucose uptake. Endothelin-1 increased uptake of 2-deoxyglucose 2.4-fold in adipocytes isolated from pair-fed rats. However, in adipocytes isolated from rats that had consumed a diet containing 35% ethanol for 4 wk, endothelin-1 did not i...

In cultured endothelial cells, endothelin is produced after stimulation with angiotensin II. The effects of angiotensin II and endothelin-1 on vascular sensitivity to norepinephrine were studied in perfused rat mesenteric resistance arteries. Expression of endothelin messenger RNA (mRNA) was determined in endothelial cells obtained from the mesenteric circulation. Perfusion (5 hours) of the art...

The effect of endothelin, a novel vasoconstrictor peptide, on the adrenergic neuroeffector junction was investigated in isolated perfused mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The vasoconstrictor responses to periarterial sympathetic nerve stimulation and exogenous norepinephrine were determined. Infusion of endothelin-1 increased the baseline...