1 OPC-31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol-anaesthetized rats and for diuretic action in conscious normal rats. 2 OPC-31260 caused a competitive displacement of [3H]-AVP binding to both V1 and V2 receptors with IC50 values of 1.2 + 0.2 x 106M and 1.4 + 0.2 x 10-8M, respectively. 3 OPC-31260 at doses of 10 to 100pg kg-', i.v., inhibited the antidiuretic action of exogenously administered AVP in water-loaded, alcohol-anaesthetized rats in a dose-dependent manner. OPC-31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist. 4 After oral administration at doses of 1 to 30mgkg-1 in normal conscious rats, OPC-31260 dosedependently increased urine flow and decreased urine osmolality. The diuretic action of OPC-31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone. 5 The results indicate that OPC-31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC-31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.
An orally effective, nonpeptide, vasopressin V1 receptor antagonist, OPC-21268, has been identified. This compound selectively antagonized binding to the V1 subtype of the vasopressin receptor in a competitive manner. In vivo, the compound acted as a specific antagonist of arginine vasopressin (AVP)-induced vasoconstriction. After oral administration in conscious rats, the compound also antagonized pressor responses to AVP. OPC-21268 can be used to study the physiological role of AVP and may be therapeutically useful in the treatment of hypertension and congestive heart failure.
NADPH oxidase 4 (Nox4) is constitutively active, while Nox2 requires the cytosolic regulatory subunits p47phox and p67phox and activated Rac with activation by phorbol 12-myristate 13-acetate (PMA). This study was undertaken to identify the domain on Nox4 that confers constitutive activity. Lysates from Nox4-expressing cells exhibited constitutive NADPH- but not NADH-dependent hydrogen peroxide production with a Km for NADPH of 55 ± 10 μM. The concentration of Nox4 in cell lysates was estimated using Western blotting and allowed calculation of a turnover of ∼200 mol of H2O2 min−1 (mol of Nox4)−1. A chimeric protein (Nox2/4) consisting of the Nox2 transmembrane (TM) domain and the Nox4 dehydrogenase (DH) domain showed H2O2 production in the absence of cytosolic regulatory subunits. In contrast, chimera Nox4/2, consisting of the Nox4 TM and Nox2 DH domains, exhibited PMA-dependent activation that required coexpression of regulatory subunits. Nox DH domains from several Nox isoforms were purified and evaluated for their electron transferase activities. Nox1 DH, Nox2 DH, and Nox5 DH domains exhibited barely detectable activities toward artificial electron acceptors, while the Nox4 DH domain exhibited significant rates of reduction of cytochrome c (160 min−1, largely superoxide dismutase-independent), ferricyanide (470 min−1), and other electron acceptors (artificial dyes and cytochrome b5). Rates were similar to those observed for H2O2 production by the Nox4 holoenzyme in cell lysates. The activity required added FAD and was seen with NADPH but not NADH. These results indicate that the Nox4 DH domain exists in an intrinsically activated state and that electron transfer from NADPH to FAD is likely to be rate-limiting in the NADPH-dependent reduction of oxygen by holo-Nox4.
Phenotypes of Caenorhabditis elegans unc-18 and unc-64 gene mutations are similar. While unc-18 is known to be essential for normal synaptic transmission (Hosono, R., Hekimi, S., Kamiya, Y., Sassa, T., Murakami, S., Nishiwaki, S., Miwa, J., Taketo
A new cis-element, trophoblast-specific element 2 (TSE2) is located in the placenta-specific enhancer of the human aromatase gene that dictates its tissue-specific expression. In the minimum enhancer region, an element similar to the trophoblast-specific element (TSE), originally described for the human chorionic gonadotropin ␣-subunit gene, also exists (Yamada, K., Harada, N., Honda, S., and Takagi, Y. (1995) J. Biol. Chem. 270, 25064 -25069). The co-presence of TSE and TSE2 is required to direct trophoblast-specific expression driven by a heterologous thymidine kinase promoter. A 2562-base pair cDNA clone encoding a 436-amino acid protein that binds to TSE2 was isolated from a human placental cDNA library using a yeast one-hybrid system with the TSE2 as a reporter sequence. The protein was revealed to be identical to hGCMa, a mammalian homologue of the Drosophila GCM (glia cells missing) protein. Expression of hGCMa is restricted to the placenta. The protein also binds to PLE1 in the leptin promoter among other cis-elements reported to confer placenta-specific expression, suggesting that hGCMa is a placenta-specific transcription regulator, possibly involved in the expression of multiple placenta-specific genes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.