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519 records · Page 29Linked to original sources
PubMed1987

Metofenazate as a more selective calmodulin inhibitor than trifluoperazine.

The interaction of several phenothiazines, benzodiazepines, butyrophenones, polycyclic neuroleptics and tricyclic antidepressants with calmodulin and troponin C was investigated using the fluorescent dye 3,3'-dipropylthiocarbocyanine iodide. In the presence of Ca2+, trifluoperazine (2-trifluoromethyl-10-[3-(1-methylpiperazinyl-4)propyl]-phenothiaz ine dihydrochloride, TFP), which is commonly used as a selective calmodulin inhibitor, half maximally increased the fluorescence of the complex formed of the fluorescent dye with calmodulin at a concentration of 4 mumol/l, and with troponin C at 24 mumol/l. TFP completely inhibited the calmodulin dependent stimulation of cyclic nucleotide phosphodiesterase with a Ki of 4 mumol/l and decreased the maximum Ca2+ dependent troponin C mediated activation of actomyosin ATPase by 35% at a concentration of 100 mumol/l. Metofenazate (3,4,5-trimethoxybenzoate-2-chlor-10-(3-[(beta-oxyethyl) piperazinyl-4]-propyl)phenothiazine diethanesulfonate, methophenazine, MP) produced half maximal fluorescence enhancement of the calmodulin dye complex at a concentration of 6 mumol/l and did not influence the fluorescence of the troponin C dye complex at concentrations of up to 1000 mumol/l. MP also completely inhibited the calmodulin dependent stimulation of phosphodiesterase with a Ki of 7 mumol/l but it had not effect on maximum Ca2+ stimulation of actomyosin ATPase. MP increased the Ca2+ sensitivity of skinned cardiac muscle with an about 10fold lower potency than TFP. In view of these results, we propose MP as a useful tool for distinction between processes mediated by either calmodulin or troponin C.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Dopamine selectively inhibits angiotensin II-induced aldosterone secretion by interacting with D-2 receptors.

Aldosterone secretion is subject to both stimulatory and inhibitory controls. Angiotensin II (AII) is the primary stimulator of aldosterone production and an inhibitory role of dopamine (DA) has been suggested recently. In this study we investigated the interactions between DA and AII in the intracellular events leading to aldosterone secretion. By measuring aldosterone secretion and cyclic AMP (cAMP) formation in intact adrenal glomerulosa cells we show that AII induced a sustained stimulation of aldosterone secretion (EC50, 0.41 nM) and a rapid and transient increase in intracellular cAMP content (EC50, 4 nM). DA inhibited both aldosterone secretion (IC50, 300 nM) and cAMP formation (IC50, 100 nM) elicited by submaximal concentrations of AII; in contrast, DA did not attenuate either basal or adrenocorticotropic hormone-stimulated cell activity. The pharmacological characterization of DA effects with dopaminergic agonists and antagonists strongly indicated an involvement of D-2 receptors. Indeed, selective D-2 agonists were more effective than DA in inhibiting the glomerulosa cell responses to AII; in addition, the effects of DA on both aldosterone secretion and cAMP formation were prevented by D-2 antagonists, such as (-)-sulpiride and domperidone, but not by the selective D-1 antagonist SCH 23390. These data suggest a specific functional interaction between D-2 receptors apparently associated with inhibition of cAMP formation and AII in the regulation of aldosterone production.

Adrenal Cortex↗
PubMed1985

Dopamine stimulated increase of GTP levels in the rat retina.

Dopamine stimulates a 7-10-fold increase of GTP concentration in whole rat retina maintained in vitro. Half-maximal stimulation of GTP levels were obtained with 10(-6) M dopamine, and significant increases in GTP levels were seen with 10(-7) M dopamine. Intracellular GTP levels were significantly increased within 4 min after exposure to dopamine and maximal effects were reached within 30 min. Dopamine agonists, apomorphine and bromocriptine, also stimulate a 7-10-fold increase in GTP concentration, whereas other catecholamines (norepinephrine, epinephrine, and isoproterenol) were less potent. Several other neurotransmitters present in rat retina (gamma-aminobutyric acid, glycine, glutamine, and taurine) had no effect on GTP levels. Although dopamine also stimulates increases in cyclic AMP levels in the retina, dibutyryl cyclic AMP and 8-bromo-cyclic AMP had no effect on GTP levels, indicating that the dopamine-stimulated increase of GTP is independent of the catalytic production of cyclic AMP by adenylate cyclase. Since dopamine-stimulated adenylate cyclase activity requires GTP, the dopamine-stimulated increase in GTP concentration described in this report may serve to facilitate dopamine stimulation of adenylate cyclase activity.

Animals↗
PubMedDate not supplied

Effects of SK&F 82526 and SK&F 83742 on the renal vascular dopamine receptor.

The renal vascular effects of benzazepine derivatives were studied on the isolated perfused rat kidney in the presence of phenoxybenzamine and sotalol after contraction of the vascular bed with prostaglandin F2 alpha. SK&F 82526 was a very potent dopaminomimetic drug (ED50 = 7.6 +/- 0.8 X 10(-9) M) on the renal vascular dopamine receptor. It displayed partial agonist activity (similar to SK&F 38393) and was devoid of alpha-adrenomimetic effects. SK&F 83742 was a potent dopaminolytic drug. It antagonized dopamine-induced relaxation of the renal vascular bed in a competitive way, with an apparent pA2 of 7.47 +/- 0.23.

Animals↗
PubMed1981

Characterization of catecholamine binding sites in the rat brain.

A systematic study of the effect of neurotoxic agents upon neurotransmitter binding to specific receptors requires the simultaneous assay of several closely related ligand-receptor interactions. Conditions are presented which allow the determination of dopaminergic, alpha-noradrenergic and beta-noradrenergic receptor sites within the same brain areas without major overlap of selectivity. As a result, regional distribution of catecholaminergic receptor sites and some characteristics of such binding are described.

Animals↗
PubMed1982

Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor.

The interactions of dopaminergic agonists and antagonists with binding sites in bovine anterior pituitary membranes have been investigated with radioligand-binding techniques and computer-modeling procedures. 3H-labeled agonist binding is stereospecific, reversible, saturable, and of high affinity. The rank order of catecholamines, phenothiazines, and related drugs in competing for 3H-agonist binding is indicative of interactions with a D-2 dopamine receptor. Both agonist/3H-agonist and antagonist/3H-agonist competition curves are monophasic and noncooperative (nH = 1) with computer analysis indicating a single class of binding sites. Specific 3H-agonist binding can be completely inhibited by guanine nucleotides. GppNHp us the most potent nucleotide followed by GTP and GDP which are equipotent. The equilibrium binding capacity for 3H-labeled antagonists is twice that for 3H-agonists. Unlabeled antagonists inhibit 3H-antagonist binding competitively and exhibit antagonist/3H-antagonist competition curves which model best to a state of homogeneous affinity. In contrast, unlabeled agonists inhibit 3H-antagonist binding in a heterogeneous fashion displaying multiphasic (nH less than 1) competition curves which can be resolved into high and low affinity binding sites. In the presence of saturating concentrations of guanine nucleotides, however, the agonist/3H-antagonist curves model best to a single affinity state which is identical with the low affinity state seen in control curves. The binding data can be explained by postulating two states of the D-2 dopamine receptor, inducible by agonists but not antagonists and modulated by guanine nucleotides.

Animals↗
PubMed1984

Dopamine modulation of active ion transport in rabbit corneal epithelium.

The addition of micromolar quantities of dopamine stimulated ion transport in the isolated rabbit corneal epithelium. This response was blocked by pretreatment with the dopamine antagonist, haloperidol, and by the elimination of Cl- from the bathing solutions. The beta-adrenergic antagonist, timolol, was also a potent inhibitor of the epithelial response to dopamine. The presence of the serotonin antagonist, methysergide, or the dopamine beta-hydroxylase inhibitor, FLA-63, did not significantly alter the corneal response to dopamine. Following superior cervical ganglionectomy, the epithelial response to dopamine was abolished. These findings are consistent with the idea that Cl- secretion in the rabbit corneal epithelium can be modulated by preterminal dopamine receptors located on the sympathetic nerve fibers; therefore, dopamine stimulation appears to be a serial process mediated by the release of norepinephrine from sympathetic nerve terminals in the epithelium.

Animals↗
PubMed1978

[3H] 2-Amino-6,7-dihydroxy 1,2,3,4-tetrahydronapthalene (ADTN): a potential specific dopamine receptor ligand.

The characteristics of [3H] 2-amino-6,7-dihydroxy 1,2,3,4-tetrahydronapthalene (ADTN) binding to calf striatal membranes were investigated. [3H]ADTN was observed to bind with high affinity and stereospecificity to a preparation of crude synaptic membranes. A number of dopamine agonists and antagonists were studied for their ability to displace bound [3H]ADTN. Dopamine agonists were found to be more potent inhibitors of ADTN binding than were dopamine antagonists. Kinetic analysis indicates that [3H]ADTN binds to dopamine recognition sites in a manner comparable to dopamine itself. Overall, the data suggest that ADTN may be a useful ligand for the characterization of agonist requirements for recognition by dopamine binding sites.

Animals↗
PubMed1994

D4 dopamine receptor-mediated signaling events determined in transfected Chinese hamster ovary cells.

A Chinese hamster ovary (CHO) cell line stably expressing a recombinant human D4 dopamine receptor made from a synthetic gene has been used to determine potential D4-mediated signaling events. We designed and synthesized a modified gene coding for a human D4 receptor with reduced G + C content but unaltered encoded amino acids. Stable expression of this gene was obtained in two cell lines, inducible expression in CHO lacI cells and constitutive expression in HEK293 cells. In CHO lacI cells induced to express D4 receptors but not in uninduced cells, dopamine and quinpirole inhibit forskolin-stimulated cAMP accumulation and potentiate ATP-stimulated [3H]arachidonic acid release through a mechanism that requires protein kinase C but is unaffected by membrane-soluble cAMP analogs. In addition, D4 receptor activation causes an increase in the rate of extracellular acidification measured by microphysiometry. This response is unaffected by protein kinase C down-regulation but is inhibited by removal of extracellular sodium and inhibitors of NaH-1 exchange, suggesting the involvement of a Na+/H+ exchanger. All responses are blocked by clozapine and are sensitive to pertussis toxin. D4 receptors, like other G(i)/G(o)-linked receptors, mediate multiple signaling events, and the pathways activated are similar to those used by D2 and D3 receptors expressed in similar cells.

Amiloride↗
PubMed1994

High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype.

Dopamine D1A and D1B receptor subtypes belong to the superfamily of G protein-coupled receptors. Both receptors are coupled to the activation of adenylyl cyclase and exhibit distinct brain distribution. To identify functional differences, binding and stimulation of adenylyl cyclase were assessed in 293 cells expressing transiently either dopamine D1A or D1B receptors. Membranes expressing D1B receptors displayed higher affinities for agonists than those expressing D1A receptors, whereas antagonist affinities were lower at the D1B than at the D1A receptor. Basal activity of adenylyl cyclase in whole 293 cells expressing various levels of D1B receptors was significantly higher than the basal activity measured in cells expressing D1A receptors. Maximal activation of adenylyl cyclase resulting from stimulation of the D1B receptor was less than that obtained following agonist activation of the D1A receptor. In cells expressing D1B receptors, agonists displayed an increased potency for stimulating adenylyl cyclase in comparison with the potencies determined for the D1A receptor. On the other hand, certain antagonists displayed "negative efficacy" at both receptor subtypes but had a more profound inhibition on the agonist-independent signaling activity of the D1B receptor. The properties described here are reminiscent of those of constitutively active G protein-coupled receptors obtained by site-directed mutations. Thus, the D1B receptor may represent a naturally occurring receptor subtype with properties akin to those of constitutively active G protein-coupled receptors. The different anatomical distribution and biochemical properties of these D1 receptors strengthen the functional distinctions between the two subtypes and could account for the basis of heterogeneity within a given class of neurotransmitter or hormone receptors. In addition, if these properties are recapitulated in cells expressing the D1B receptors, they may underlie important role in the regulation of physiological effects by dopamine. Finally, these results raise the interesting possibility that psychotropic antagonist drugs used in the management of certain brain disorders may have their beneficial actions as negative efficacy compounds.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗