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At least 1,009 records · Page 56Linked to original sources
PubMed1985

Effects of atriopeptin on particulate guanylate cyclase from rat adrenal.

Atriopeptin II activated particulate guanylate cyclase 5-10-fold in a concentration- and time-dependent fashion in crude membranes obtained from homogenates of rat adrenal cortex or medulla. Similar effects were observed with other atriopeptin analogs. Soluble guanylate cyclase and adenylate cyclase in these preparations were not activated. Accumulation of cyclic GMP in minces of adrenal cortex or medulla was increased 6-8-fold due to atriopeptin II activation of particulate guanylate cyclase. Several thiol-reactive agents blocked the activation of particulate guanylate cyclase, suggesting that free thiol groups on membrane proteins may be important in atriopeptin receptor-guanylate cyclase coupling.

Adrenal Cortex↗
PubMed1992

Role of alpha-adrenoceptors in the effects of buspirone and 5-carboxamidotryptamine in rabbit isolated thoracic aorta.

1. The role of alpha-adrenoceptors in the vascular effects of buspirone (BUS) and 5-carboxamidotryptamine (5-CT) was investigated in rabbit thoracic aorta. 2. Buspirone produced a concentration-dependent contraction. The non-selective 5-HT1 and 5-HT2-receptor antagonist methysergide and the 5-HT2 receptor antagonist ketanserin did not alter the contractile effect of buspirone. However, the competitive antagonist of alpha 1-adrenoceptors, prazosin, shifted the concentration-response curve of buspirone to the right without changing the maximal response. 3. Benextramine tetrahydrochloride monohydrate (BHC), a noncompetitive antagonist of alpha 1-adrenoceptors, inhibited the contraction induced by buspirone in a noncompetitive manner. After pretreatment with two different concentrations of BHC, the estimated apparent dissociation constants of buspirone were found to be identical. 4. In addition, buspirone antagonized the concentration-response curve of phenylephrine again showing a similar dissociation constant, suggesting a partial agonistic action of buspirone at the level of alpha 1-adrenoceptors. 5. The concentration-response curve of 5-HT showed two components in the thoracic aorta obtained from reserpine treated and untreated animals as verified by different pD2 values. The second component was observed with relatively higher concentrations of 5-CT and could be blocked by prazosin or BHC. Neither of these compounds altered the first component. After Pretreatment with BHC, the first component of 5-CT was competitively antagonized by methysergide and ketanserin, having pA2 values of 8.81 and 9.1 respectively. 6. These results suggest that the contraction induced by buspirone is mainly mediated by alpha 1-adrenoceptors, while the higher concentrations of 5-CT caused contraction via alpha 1-adrenoceptor stimulation in addition to its 5-HT2 agonistic effect.

Adrenergic alpha-Antagonists↗
PubMed1989

Effect of aging on presynaptic alpha 2-adrenoceptor mechanisms in guinea pig ileum.

1. Presynaptic alpha 2-adrenoceptor mechanisms in electrically stimulated longitudinal muscles of ilea isolated from 3, 10, 20 and 47 week-old guinea pigs were studied by analysis of the concentration-response curves of noradrenaline, a full agonist, and clonidine, a partial agonist, and the Scatchard plot of specific binding of [3H]-p-aminoclonidine to synaptosomal fractions from the longitudinal muscle of guinea pig ileum. 2. The pD2 value of noradrenaline and the maximum contraction induced by clonidine increased with age from 3 to 20 weeks and there after decreased to 47 weeks, while the pA2 value of yohimbine against noradrenaline did not alter with age. 3. The capacity of the maximum binding sites of [3H]-p-aminoclonidine increased with increasing age (3-20 weeks), while the dissociation constant (Kd) of [3H]-p-aminoclonidine did not change during the same period. 4. The changes in the presynaptic alpha 2-adrenoceptor mechanisms with age are considered to be due to the change in the total concentration of presynaptic of alpha 2-adrenoceptors.

Aging↗
PubMed1995

Cytolysis of human erythrocytes by a covalent antibody-selenium immunoconjugate.

A selenium (Se)-containing immunoconjugate of a human anti-erythrocyte membrane antibody (Ab-Se) has been synthesized via oxidation of the carbohydrate moieties of the antibody and covalent coupling with selenocystamine. The isolated Ab-Se immunoconjugate is shown to be more hemolytic than is selenocystamine when expressed on equivalent selenium basis. Native antibody preincubated with the human erythrocytes prevented hemolysis induced by the Ab-Se immunoconjugate. As observed microscopically, the Ab-Se immunoconjugate caused extensive damage to the erythrocyte membrane and lysis. The cytotoxicity of Se toward the human erythrocytes is believed to be caused initially by the localized generation of superoxide (O2.-) within the cell membrane. This is the first demonstration of site-directed immunoselectivity of Se cytotoxicity and demonstrates the potential for a free radical pharmacology based on localized Se-generated O2.-.

Cystamine↗
PubMed1994

Selective enrichment with alpha 1A- and alpha 1B-adrenoceptor subtypes in rat brain cortical membranes.

Recent evidences from molecular biology, radioreceptor binding and functional studies indicate that the alpha 1-adrenoceptor population is heterogeneous and can at least be divided into two subclasses named alpha 1A and alpha 1B. The present study was designed to obtain, a selective enrichment of rat brain cortical membranes with each subtype of alpha 1-adrenoceptor using alkylating agents. [3H]prazosin binding to rat cortical membranes was saturable and of high affinity (KD = 0.11 +/- 0.02 nM; Bmax = 132.5 +/- 7.2 fmol/mg protein). All ligands competed for specific [3H]prazosin binding in a statistically significant biphasic manner (%Rhigh = 30-40%; %Rlow = 60-70%). These sites meet generally accepted and recently described pharmacologic criteria for their identification as the alpha 1A- and alpha 1B-adrenoceptors. After pretreatment of membranes with benextramine (1 microM) in the presence of clonidine (1 microM), the antagonists, WB4101, (+)-niguldipine and phentolamine, displaced the radioligand with an inhibition curve steeper than in control membranes and with Ki values that agree with those obtained for the low affinity site present in control membranes. On the other hand, after pretreatment with chloroethylclonidine (10 microM) in the presence of WB4101 (1 nM), Hill coefficients for the displacement of the radioligand by WB4101, (+)-niguldipine, and phentolamine, were also increased, but in contrast to the situation described above, the Ki values agree with those obtained for the high affinity site present in control membranes. In conclusion, this method of partial alkylation of receptors could be a valuable tool for separately studying the pharmacological characteristics of the alpha 1-adrenoceptor subtypes in native membranes of cerebral tissue.

Adrenergic alpha-Antagonists↗
PubMed2003

Induction of the mitochondrial permeability transition by selenium compounds mediated by oxidation of the protein thiol groups and generation of the superoxide.

The cancer chemopreventive effect of selenium compounds cannot be fully explained by the role of selenium as a component of antioxidant enzymes, suggesting that other mechanisms, such as thiol oxidation or free radical generation, also underlie this effect. The toxicities of six different selenium compounds (selenite, selenate, selenocystine, selenocystamine, selenodioxide, and selenomethionine) have now been compared in HepG2 human hepatoma cells and isolated rat liver mitochondria. Selenite, selenocystine, and selenodioxide induced apoptosis in HepG2 cells and mediated oxidation of protein thiol groups in both HepG2 cells and isolated mitochondria. Selenocystamine oxidized protein thiol groups in isolated mitochondria and crude extracts of HepG2 cells but not in intact HepG2 cells, suggesting that this compound is not able to cross the cell membrane. The selenium compounds capable of oxidizing thiol groups also induced the mitochondrial permeability transition (MPT) in isolated mitochondria. Furthermore, they generated the superoxide (O(2) .-) on reaction with glutathione in the presence of mitochondria, and an O(2) .-) scavenger inhibited their induction of the MPT. These results suggest that the pro-apoptotic action of selenium compounds is mediated by both thiol oxidation and the generation of O(2) .-), both of which contribute to opening of the MPT pore.

Cystamine↗
PubMed2006

Osteopontin promotes pathologic mineralization in articular cartilage.

Calcium pyrophosphate dihydrate (CPPD) crystals are commonly found in osteoarthritic joint tissues, where they predict severe disease. Unlike other types of calcium phosphate crystals, CPPD crystals form almost exclusively in the pericellular matrix of damaged articular cartilage, suggesting a key role for the extracellular matrix milieu in their development. Osteopontin is a matricellular protein found in increased quantities in the pericellular matrix of osteoarthritic cartilage. Osteopontin modulates the formation of calcium-containing crystals in many settings. We show here that osteopontin stimulates ATP-induced CPPD crystal formation by chondrocytes in vitro. This effect is augmented by osteopontin's incorporation into extracellular matrix by transglutaminase enzymes, is only modestly affected by its phosphorylation state, and is inhibited by integrin blockers. Surprisingly, osteopontin stimulates transglutaminase activity in cultured chondrocytes in a dose-responsive manner. As elevated levels of transglutaminase activity promote extracellular matrix changes that permit CPPD crystal formation, this is one possible mechanism of action. We demonstrate the presence of osteopontin in the pericellular matrix of chondrocytes adjacent to CPPD deposits and near active transglutaminases. Thus, osteopontin may play an important role in facilitating CPPD crystal formation in articular cartilage.

Adenosine Triphosphate↗
PubMed2004

Production of dromedary (Camelus dromedarius) embryos by IVM and IVF and co-culture with oviductal or granulosa cells.

The general objective of this work was to produce dromedary embryos from cumulus-oocyte complexes (COCs) that were matured, fertilized and co-cultured in vitro. A total of 1598 COCs were recovered from 457 ovaries; 1308 were deemed suitable for IVM and were cultured at 38.5 degrees C, 5% CO2, and >95% humidity for 36 h in TCM-199 supplemented with 10% heat-treated fetal calf serum (FCS), 10 ng/ml epidermal growth factor (EGF), 1 microg/ml FSH, and 500 microM cysteamine. Matured COCs (n = 88) were denuded, fixed, and stained to determine nuclear status; 63% (56/88) had reached metaphase II (MII) at 36 h. Overall, 1135 COCs were inseminated with ejaculated fresh semen (0.5 x 10(6)spermatozoa/ml in modified TALP-solution). Inseminated oocytes (n = 155) were examined for evidence of fertilization; 68% (106/155) were penetrated by spermatozoa, including 52% (55/106) with two pronuclei and 34% (36/106) with polyspermy. Inseminated, denuded oocytes (n = 819) were co-cultured with dromedary oviductal epithelial or granulosa cells in TCM-199 supplemented with 10% heat-treated FCS. Although the rate of first cleavage (two to eight cells) was similar for the two co-culture systems (32 versus 33%, respectively), more embryos (two-cell to blastocyst stage) were obtained from oocytes co-cultured with oviductal versus granulosa cells (61 versus 45%; P < 0.05). The proportions of fertilized oocytes developing to the early morula stage were 19% (80/417) and 12% (48/402) for oocytes co-cultured for 7 days with oviductal or granulosa cells, respectively (P > 0.05). However, development to the blastocyst stage (10% of fertilized oocytes) occurred only in oocytes co-cultured with oviductal cells. In conclusion, dromedary embryos were produced in vitro using abattoir-derived oocytes, fresh (ejaculated) semen, and oviductal cell co-culture.

Animals↗
PubMed1998

Synthesis and antitumour effect of the melanogenesis-based antimelanoma agent N-propionyl-4-S-cysteaminylphenol.

Chemotherapy of malignant melanoma is still a great challenge, as no effective drugs are available. The development of melanogenesis-based drugs is a promising area of research because melanogenesis is a unique biochemical pathway operating only in melanoma cells (and their normal counterparts) so that the tumour can be targeted. We have been using cysteinylphenol, a sulphur-containing analogue of tyrosine, and derivatives for that purpose. N-Acetyl-4-S-cysteaminylphenol was found to have the best antimelanoma effect in cell culture systems and in mice bearing B16 melanoma tumours. It also caused depigmentation of the skin, suggesting the possibility of use as a hypopigmenting agent. To improve the efficiency of the drug, we thought of replacing the acetyl group in N-acetyl-4-S-cysteaminylphenol with a propionyl group in the hope that increased hydrophobicity would increase the cellular uptake of the drug. N-Propionyl-4-S-cysteaminylphenol was synthesized by condensing 4-hydroxythiophenol with 2-ethyl-2-oxazoline. The drug showed both cytostatic and cytocidal effects in a human melanotic melanoma cell line. The drug was found to be a good depigmenting agent for the black hair follicles of C57 black mice when given s.c. for 14 days. A 10-day treatment with N-propionyl-4-S-cysteaminylphenol at 300 mg/kg body weight reduced the growth rate of B16 melanoma s.c. tumours in mice by 36%. The propionyl derivative was found to increase the life span of mice bearing melanoma more effectively than did the acetyl derivative.

Animals↗
PubMed1997

Characterisation of a cloned human 5-HT1A receptor cell line using [35S]GTP gamma S binding.

Compound potencies and efficacies depend upon receptor reserve and hence estimating this parameter in assay systems allows for a more meaningful interpretation of the data generated. This study describes a method whereby the degree of receptor reserve, with respect to 5-hydroxytryptamine (5-HT), was determined for a HeLa cell line expressing the human 5-HT1A receptor using the agonist-induced [35S]guanosine 5'[gamma-thio]triphosphate ([35S]GTP gamma S) binding assay, followed by a comparison of the potencies and relative efficacies of several compounds. Following irreversible antagonism with benextramine 5-HT yielded a pKA of 7.3, compared with a pKobs of 8.4 from saturation analysis, indicating the presence of high and low affinity state receptors. A 20% receptor occupancy elicited a half-maximal functional response consistent with the presence of receptor reserve. 5-HT, 5-carboxamidotryptamine (5-CT), 8-hydoxy-dipropylamino-tetralin (8-OH-DPAT), 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1 H-indole (RU24969), buspirone, gepirone, mesulergine and sumatriptan were equally efficacious. 1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN 190) displayed reduced relative efficacy and methiothepin inverse agonism.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Pressor effect of the putative M1 muscarinic receptor agonist MCN-A-343 in the conscious rat.

The putative M1 muscarinic receptor agonist McN-A-343 evoked a dose-dependent increase in mean arterial pressure (MAP) when administered intravenously to conscious freely-moving rats pretreated with the ganglionic nicotinic receptor antagonist pentolinium. A tachycardia accompanied the increase in MAP which was blocked by the beta-adrenergic receptor antagonist propranolol. The increase in MAP was attenuated by the alpha 1-adrenergic receptor antagonist prazosin combined with the alpha 2-adrenergic receptor antagonist yohimbine. Adding propranolol to alpha-adrenergic receptor blockade uncovered a latent pressor response. Replacing prazosin with benextramine (which blocks NPY in addition to alpha-adrenergic receptors) attenuated the pressor response unmasked by propranolol. This attenuation was comparable to that provided by benextramine of the pressor response to intravenous administration of NPY. Adrenal demedullation only slightly attenuated the pressor response while having no effect on the tachycardia. The catecholamine depletor guanethidine greatly attenuated the McN-A-343-evoked increase in MAP and heart rate. The combination of adrenal demedullation and guanethidine did not further attenuate the increase in MAP but did provide better attenuation of the tachycardia than guanethidine alone. These results show that McN-A-343-evokes an increase in MAP and heart rate of conscious freely-moving rats primarily by causing the release of catecholamines, and possibly NPY, from sympathetic neurons with the adrenal glands playing a minor role.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1998

Oxidation of cysteamine induced by gas-phase radicals from combustion smoke of poly (methyl methacrylate).

In order to obtain fundamental knowledge on biological damage caused by the smoke from combustion of poly(methyl-methacrylate) (PMMA), we investigated the oxidation of cysteamine induced by PMMA smoke. We suggest that the long-lived and oxygen-centered radicals involved in PMMA smoke should play an important role in the oxidation of cysteamine. The mechanism for the oxidation of cysteamine by combustion smoke of PMMA was postulated as radical initiated chain reactions, taking into account the effect of pH, oxygen and radical concentrations.

Chromatography, High Pressure Liquid↗