Disease relevance of

• In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension [1].
• This finding indicates that the pretreatment of TAK-044 is useful as a hepatoprotective agent against ischemia-reperfusion injury, which is otherwise produced by a pathway involving ET-1 [2].
• TAK-044 was given intravenously at a dose of 3 mg/kg before ischemia [3].
• In the treated group, an endothelin antagonist TAK-044 was added to the UW solutions (10 mg/L), and TAK-044 (10 mg/kg body weight) and a platelet activating factor antagonist E5880 (0.3 mg/kg body weight) were also administered to the recipients [4].
• After cardiac arrest of the donors, liver allografts were subjected to 90 min of warm ischemia, flushed, and preserved for 4 hr at 4 degrees C. The pigs were divided into two groups: a control group (no drug treatment) and a drug-treated group, in which donors and recipients were treated with TAK-044 (10 mg/kg body, drip intravenous injection) [5].

High impact information on

• We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men [1].
• Brachial artery infusion of TAK-044 caused local forearm vasodilation [1].
• ET receptor blocker (TAK-044) and NO donor (FK409) were used to improve the hepatic microcirculation following ischemia-reperfusion injury [6].
• Hepatoprotective effect of the endothelin receptor antagonist TAK-044 against ischemia-reperfusion injury in the canine liver [2].
• The nonselective ETA/ETB receptor antagonist TAK-044 inhibited the specific binding of ET-1 to the receptors in a concentration-dependent manner [2].

Chemical compound and disease context of

• In contrast, the receptor antagonist prevented LPS-induced metabolic acidosis and hypoxemia, and improved LPS-induced decreases in urine volume, renal blood flow, creatinine clearance, and urine osmolality, whereas TAK-044 or vehicle administered alone resulted in no significant hemodynamic or blood gas changes [7].
• An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats [8].
• In conclusion, TAK-044 in combination with temocaprilat had a significant potentiation on myocardial metabolism during both ischemia and reperfusion [9].

Biological context of

• In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1 [1].
• Elevation of the portal venous pressure was also suppressed significantly during the portal triad occlusion, and a rapid restoration of oxygen pressure in the liver tissue after reperfusion was observed in the TAK-044-treated group [2].
• Effects of the ET(A)/ET(B) antagonist, TAK-044, on blood pressure and renal excretory function after unclipping of conscious one-kidney-one-clip hypertensive rats [10].
• TAK-044 also reduced MAP (by up to 11+/-3%) and increased effective renal blood flow in the contralateral kidney (by up to 46+/-27%) [11].
• 2. Binding of [125I]-ET-1 to ET receptors on rabbit ventricular and cerebellar membrane fractions was inhibited by TAK-044 with IC50 values of 3.8 nM and 130 nM, respectively [12].

Anatomical context of

• Effects of the endothelin receptor antagonist TAK-044 on hepatocyte element alterations in the ischemic-reperfused liver in Beagle dogs [3].
• Elemental alterations in the nucleus and mitochondria were similar to those in the cytoplasm in both the control and TAK-044 groups [3].
• BACKGROUND/AIMS: This study was designed to investigate elemental alterations of subcellular organelles (cytoplasm, nucleus, mitochondria) after ischemia of the liver, and the effects of the pre-ischemic administration of an endothelin ETA/ETB receptor antagonist (TAK-044) on subcellular elements [3].
• The strongest inhibitory effects were obtained in coronary arteries; an EC50 value for ET-1 was 5.2 +/- 0.77 nM (n = 12) in the control and 24 +/- 3.8 nM (n = 4) in the presence of TAK-044 at 10 nM [13].
• TAK-044 (10 nM, 100 nM) inhibited this ET-1-induced vasoconstriction except in the case of mesenteric arteries [13].

Associations of with other chemical compounds

• Vasodilation to TAK-044 was abolished after treatment with candesartan cilexetil; this effect is associated with a reduced plasma ET-1 concentration [14].
• METHODS: We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days [15].
• In addition, the ETB-mediated vasoconstriction and pressor responses were inhibited by TAK-044 and not by BQ-123 [16].
• The influence of a nonselective antagonist of endothelin receptors, TAK-044 (cyclo-[d-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-l-alanyl-l-alpha-aspartyl-d-2-(2-thienyl)glycyl-l-leucyl-d-tryptophyl] disodium), on the positive inotropic effect of endothelin-1 and endothelin-3 was investigated in isolated rabbit myocardium [17].
• Treatment with TAK-044 resulted in a significant decrease in systolic blood pressure (SBP), blood urea nitrogen (BUN), serum creatinine concentration, plasma aldosterone level, heart weight, and kidney weight [18].

Gene context of

• The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044 [19].
• The Kd values of TAK-044 for the ETA receptor was comparable to that of ET-1 [20].
• The Ki values of TAK-044 for the cellular ETA and ETB receptors were 130 pM and 130 nM at 5,000 cells/well and 1.3 and 590 nM at 50,000 cells/well, respectively [20].
• 1. The aims of the present study were to characterize the pharmacological profile of a new endothelin (ET) receptor antagonist, TAK-044 and to consider whether it limits the extension of myocardial infarct size in rats [12].
• Similarly, a non-selective ETA/ETB receptor antagonist, TAK-044 (12.5 mumol kg-1, for 20 min) slightly decreased blood pressure [21].

Analytical, diagnostic and therapeutic context of

• TAK-044 dose-dependently reversed the effects of ET-1 on RBFprobe and cortical perfusion [11].
• METHODS: In a porcine orthotopic liver transplantation model, changes in the serum and liver tissue ET-1 concentration were measured and the effects of an ET receptor antagonist, TAK-044, were evaluated [5].
• CONCLUSIONS: These findings indicate TAK-044 treatment has protective effects on postoperative function of hepatic allografts procured from NHBDs [5].
• 6. Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-1, respectively [12].
• 3. A 15 min intravenous infusion of placebo or 30 mg TAK-044 (giving a serum concentration of 2 nM, calculated to block > 95% of ETA but < 5% ETB receptors) had no effect on the immunoreactive plasma concentrations of the three peptides [19].

References