Different contributions of endothelin-A and endothelin-B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats.
(1/1906)
We investigated the involvement of actions mediated by endothelin-A (ETA) and endothelin-B (ETB) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ETA receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ETB receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-beta-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621-treated animals. These results strongly support the view that ETA receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that the ETB receptor-mediated action protects against vascular and renal injuries in this model of hypertension. A selective ETA receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ETB-selective antagonism alone is detrimental to such cases. (+info)
S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol.
(2/1906)
S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924. CLZ, S-16924, clozapine, and haloperidol decreased aggressive interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100, 635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors. (+info)
Increased lipophilicity and subsequent cell partitioning decrease passive transcellular diffusion of novel, highly lipophilic antioxidants.
(3/1906)
Oxidative stress is considered a cause or propagator of acute and chronic disorders of the central nervous system. Novel 2, 4-diamino-pyrrolo[2,3-d]pyrimidines are potent inhibitors of iron-dependent lipid peroxidation, are cytoprotective in cell culture models of oxidative injury, and are neuroprotective in brain injury and ischemia models. The selection of lead candidates from this series required that they reach target cells deep within brain tissue in efficacious amounts after oral dosing. A homologous series of 26 highly lipophilic pyrrolopyrimidines was examined using cultured cell monolayers to understand the structure-permeability relationship and to use this information to predict brain penetration and residence time. Pyrrolopyrimidines were shown to be a more permeable structural class of membrane-interactive antioxidants where transepithelial permeability was inversely related to lipophilicity or to cell partitioning. Pyrrole substitutions influence cell partitioning where bulky hydrophobic groups increased partitioning and decreased permeability and smaller hydrophobic groups and more hydrophilic groups, especially those capable of weak hydrogen bonding, decreased partitioning, and increased permeability. Transmonolayer diffusion for these membrane-interactive antioxidants was limited mostly by desorption from the receiver-side membrane into the buffer. Thus, in this case, these in vitro cell monolayer models do not adequately mimic the in vivo situation by underestimating in vivo bioavailability of highly lipophilic compounds unless acceptors, such as serum proteins, are added to the receiving buffer. (+info)
Novel, highly lipophilic antioxidants readily diffuse across the blood-brain barrier and access intracellular sites.
(4/1906)
In an accompanying article, an in vitro assay for permeability predicts that membrane-protective, antioxidant 2,4-diamino-pyrrolo[2, 3-d]pyrimidines should have improved blood-brain barrier (BBB) permeation over previously described lipophilic antioxidants. Using a first-pass extraction method and brain/plasma quantification, we show here that two of the pyrrolopyrimidines, one of which is markedly less permeable, readily partition into rat brain. The efficiency of extraction was dependent on serum protein binding, and in situ efflux confirms the in vitro data showing that PNU-87663 is retained in brain longer than PNU-89843. By exploiting inherent fluorescence properties of PNU-87663, its distribution within brain and within cells in culture was demonstrated using confocal scanning laser microscopy. PNU-87663 rapidly partitioned into the cell membrane and equilibrates with cytoplasmic compartments via passive diffusion. Although partitioning of PNU-87663 favors intracytoplasmic lipid storage droplets, the compound was readily exchangeable as shown by efflux of compound from cells to buffer when protein was present. The results demonstrated that pyrrolopyrimidines were well suited for quickly accessing target cells within the central nervous system as well as in other target tissues. (+info)
Pyrrolidine dithiocarbamate up-regulates the expression of the genes encoding the catalytic and regulatory subunits of gamma-glutamylcysteine synthetase and increases intracellular glutathione levels.
(5/1906)
Time- and dose-dependent increases in the steady-state mRNA levels of the genes encoding the catalytic and regulatory subunits of the enzyme gamma-glutamylcysteine synthetase (GCS) were observed in HepG2 human hepatocarcinoma cells after exposure to pyrrolidine dithiocarbamate (PDTC). PDTC was demonstrated to manifest both antioxidant and pro-oxidant properties in HepG2 cells, as assessed by the decreased fluorescence of the redox-sensitive dye Dihydrorhodamine 123 and by the oxidation of glutathione respectively. Attempts to characterize the signalling pathway from PDTC exposure to increases in the expression of the GCS catalytic and regulatory subunit genes demonstrated that induction by PDTC could be partially blocked by treatment with the thiol agent N-acetylcysteine and by the copper chelator bathocuproine disulphonic acid. These findings suggested that the up-regulation of the two genes resulted from a PDTC-induced pro-oxidant signal, which was partially copper-dependent. In summary, these studies demonstrate that PDTC exposure elicits a cellular response in HepG2 cells, characterized by the induction of the genes encoding the two subunits of the enzyme GCS and increased de novo synthesis of the cellular protectant GSH. (+info)
Endothelin stimulates glucose uptake and GLUT4 translocation via activation of endothelin ETA receptor in 3T3-L1 adipocytes.
(6/1906)
Endothelin-1 (ET-1) is a 21-amino acid peptide that binds to G-protein-coupled receptors to evoke biological responses. This report studies the effect of ET-1 on regulating glucose transport in 3T3-L1 adipocytes. ET-1, but not angiotensin II, stimulated glucose uptake in a dose-dependent manner with an EC50 value of 0.29 nM and a 2.47-fold stimulation at 100 nM. ET-1 stimulated glucose uptake in differentiated 3T3-L1 cells but had no effect in undifferentiated cells, although ET-1 stimulated phosphatidylinositol hydrolysis to a similar degree in both. The 3T3-L1 cells expressed approximately 560,000 sites/cell of ETA receptor, which was not altered during differentiation. Western blot analysis and immunofluorescence staining show that ET-1 stimulated the translocation of insulin-responsive aminopeptidase and GLUT4 to the plasma membrane. The effect of ET-1 on glucose uptake was blocked by A-216546, an antagonist selective for the ETA receptor. ET-1 treatment did not induce phosphorylation of insulin receptor beta-subunit, insulin receptor substrate-1, or Akt but stimulated the tyrosyl phosphorylation of a 75-kDa protein. Genistein (100 microM), an inhibitor of tyrosine kinases, inhibited ET-1-stimulated glucose uptake. Our results show that ET-1 stimulates GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes via activation of ETA receptor. (+info)
Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.
(7/1906)
kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention. (+info)
S-16924, a novel, potential antipsychotic with marked serotonin1A agonist properties. IV. A drug discrimination comparison with clozapine.
(8/1906)
The novel benzodioxopyrrolidine (S-16924) displays a clozapine-like profile of interaction with multiple monoaminergic receptors, in addition to potent agonist activity at serotonin (5-HT)1A receptors. S-16924 (2.5 mg/kg i.p.) and clozapine (5.0 mg/kg i.p.) generated robust discriminative stimuli (DS) and displayed full mutual generalization. The D4 antagonists L-745,870 and S-18126, the D1/D5 antagonist SCH-39166, and the D3 antagonist S-14297 showed at most partial generalization to S-16924 and clozapine. The D2/D3 antagonist raclopride fully generalized to S-16924, but only partially generalized to clozapine. The 5-HT2A antagonist MDL-100, 907 fully generalized to S-16924 and two further 5-HT2A antagonists, fananserin and SR-46349, showed partial generalization. However, MDL-100,907, fananserin, and SR-46349 showed less pronounced generalization to clozapine. Similarly, the 5-HT2C antagonists SB-200,646 and SB-206,553 more markedly generalized to S-16924 than to clozapine. The 5-HT1A receptor agonist (+/-)-8-dihydroxy-2-(di-n-propylamino) tetralin generalized fully to S-16924 but not to clozapine. Full generalization was obtained to both S-16924 and clozapine for the clozapine congeners, olanzapine and quetiapine. In distinction, the benzisoxazole, risperidone, and the phenylindole, sertindole, weakly generalized to S-16924 and clozapine. However, the benzisoxazole ziprasidone, which possesses 5-HT1A agonist properties, generalized fully to S-16924 but not to clozapine. Finally, the muscarinic antagonist scopolamine generalized fully to clozapine and partially to S-16924. In conclusion, S-16924 and clozapine display both communalities and differences in their "compound" DS; this likely reflects their respective complex patterns of interaction with multiple monoaminergic receptors. Although no specific receptor was identified as underlying the clozapine DS, 5-HT1A agonist as well as D2 and 5-HT2A/2C antagonist properties contribute to the S-16924 DS. (+info)