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C Renault

Publications and source records attributed to C Renault.

36 records · Page 2Linked to original sources
PubMed1984

Opposite effects of an agonist, RO5-4864, and an antagonist, PK 11195, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J mice.

Two compounds with high affinity for the "peripheral type" benzodiazepine binding sites, PK 11195 (an isoquinoline derivative) and RO5-4864 (a benzodiazepine derivative) can modify the sensitivity of DBA/2J mice to audiogenic seizures. RO5-4864 (1-15 mg/kg) facilitates in a dose-dependent manner the audiogenic seizures and PK 11195 (2-5 mg/kg) antagonizes the RO5-4864 effects. At these doses PK 11195 alone does not modify the sensitivity to audiogenic seizures, but at doses between 20-80 mg/kg it protects DBA/2J mice against audiogenic seizures. By contrast PK 11195 is inactive against the facilitation of audiogenic seizures by ethyl-beta-carboline-3-carboxylate (a brain benzodiazepine receptor inverse agonist) and against the seizure elicited in absence of noise stimuli by RO5-4864 at doses between 20-40 mg/kg. These results suggest that facilitation by RO5-4864 of the audiogenic seizures and its antagonism by PK 11195 are mediated by the peripheral type benzodiazepine binding sites and agree with the thermodynamic analysis of the binding data which suggested that RO5-4864 might be an agonist and PK 11195 an antagonist. The good correlation between pharmacological effects and the occupancy degree of the binding sites as measured by the displacement of the "in vivo" [3H]-PK 11195 binding give an additional support to binding sites mediated effects.

Acoustic Stimulation↗
PubMed1984

In vivo labelling in several rat tissues of 'peripheral type' benzodiazepine binding sites.

'Peripheral type' benzodiazepine binding sites in several rat tissues were labelled by intravenous injection of [3H]PK 11195 and [3H] RO5 -4864. Binding was saturable in all tissues studied and regional distribution paralleled the in vitro binding. A similar potency order of displacing compounds was found in vivo and in vitro PK 11195 greater than PK 11211 greater than RO5 -4864 greater than diazepam greater than dipyridamole greater than clonazepam. These results demonstrate the feasibility of using this technique to examine the effects of pharmacological manipulation on the binding sites in their native state. However some properties (broader maximum during time course, higher percentage of particulate binding in the brain and independence of temperature) make [3H]PK 11195 the most suitable ligand for this kind of studies.

Animals↗
PubMed1984

Autoradiographic localization of peripheral benzodiazepine binding sites in the cat brain with [3H]PK 11195.

"Peripheral type" benzodiazepine binding sites were labelled in cat brain membranes by using [3H]PK 11195. This ligand binds to the "peripheral type" binding sites in a reversible, specific and saturable manner. Cat brain binding sites density (congruent to 6 pmol/mg prot.) was higher than in the rat. Pharmacological specificity was demonstrated by the potency order of displacing agents: PK 11195 greater than RO5-4864 greater than dipyridamole greater than diazepam greater than clonazepam. A similar characterization was performed in slide mounted brain sections where [3H]PK 11195 also labelled the "peripheral type" benzodiazepine binding sites. The high percentage of specific binding (80%) at 1 nM of [3H]PK 11195 made possible the autoradiographic studies on binding sites distribution. These sites were heterogeneously distributed in the grey matter and absent in white matter. Visual, auditory and other specific sensory relay stations were highly labelled. The blood pressure regulating nuclei, the vestibulo-cerebellar and the extrapyramidal motor system also presented a very high binding density. As previously described in the rat brain, choroid plexus was also strongly labelled by [3H]PK 11195 in the cat.

Animals↗
PubMed1984

Pharmacological evidence that PK 8165 behaves as a partial agonist of brain type benzodiazepine receptors.

PK 8165, a new quinoline derivative, has a good affinity for brain type benzodiazepine binding sites and an anticonflict activity in the Vogel Test. However, contrarily to classical benzodiazepines (BZ) this compound is devoid of anticonvulsant and sedative properties. As biochemical studies suggested that PK 8165 is a partial agonist for BZ receptors, its interactions with convulsant, sedative and muscle relaxant properties of diazepam (DZ) were investigated. PK 8165 potentiates (12.5 to 50 mg/kg i.p.) the antagonistic effect of DZ on M.E.S.-induced seizures and footshock-induced fighting in mice. Moreover, PK 8165 potentiates in the same dose range the muscle relaxant and hypnotic effects of DZ in mice. These potentiations are specific since PK 8165 does not interfere with phenobarbital and mebubarbital effects in M.E.S. and righting reflex in mice. Also, PK 8165's anticonflict activity (punished drinking in thirsty rats) is antagonized by RO15-1788, a specific antagonist of centrally active BZ.

Aggression↗
PubMed1984

[Right intraventricular tumors. Apropos of a case].

The authors report a case of right ventricular tumour in a 16 year old girl who presented with dyspnoea on effort, chest pain on exertion and loss of consciousness. The diagnosis was made on the basis of abnormal right intraventricular echoes on two dimensional echocardiography and was confirmed by angiography. The patient was operated with success. Histology revealed a mesenchymoma, a benign tumour, but whose infiltrating nature calls for a reserved prognosis. The echocardiogram can be used for regular post-operative surveillance. The young patient is well after 18 months' follow-up.

Adolescent↗
PubMed1984

The 5-hydroxytryptamine-releasing properties of two epimer quinoline derivatives.

Two epimer quinoline derivatives, PK 5078 and PK 7059, have been shown to be potent at releasing 5-HT from blood platelets. Moreover PK 5078 was also a potent and selective inhibitor of the uptake of 5-HT, being about 20 times as active as clomipramine. Both drugs, like p-chloroamphetamine, released 5-HT but did not inhibit MAO-A. Whilst p-chloroamphetamine seemed to be active on the cytoplasmic pool of 5-HT and reserpine on the vesicular pool, PK 5078 and PK 7059 were effective first on the vesicular pool and then on the cytoplasmic pool. The quinoline derivatives were devoid of the typical side-effects of amphetamine-like drugs, i.e. hyperactivity, anorexia and group toxicity. For these reasons PK 5078 and PK 7059 can be considered to be a new type of selective 5.HT-releasing drug.

Animals↗
PubMed1983

Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies.

The [3H]PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinolinecarboxamide, binding sites in rat cardiac membranes are saturable, with high affinity, specific GABA-independent and correspond to the peripheral type of benzodiazepine. The order of potency of displacing agents was: PK 11195 greater than RO5-4864 greater than dipyridamole greater than diazepam greater than clonazepam. The Bmax obtained with [3H]PK 11195 was equivalent of the Bmax obtained with [3H]RO5-4864 in the same experimental conditions. However thermodynamic analysis indicates that the [3H]PK 11195 binding was entropy driven whereas the [3H]RO5-4864 binding was enthalpy driven. Consequently PK 11195 might be an antagonist of these binding sites and RO5-4864 an agonist or a partial agonist. The simultaneous use of both drugs might help to elucidate the physiological relevance of peripheral benzodiazepine binding sites.

Animals↗
PubMed1983

Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies.

[3H] RO5-4864 binding sites have been characterized in kidney, heart, brain, adrenals and platelets in the rat. In all these organs the following order of potency in the RO5-4864 displacement was found: RO5-4864 greater than diazepam greater than clonazepam indicating that they correspond to the "peripheral type" of benzodiazepine binding sites. PK 11195, an isoquinoline carboxamide derivative, displaces [3H] RO5-4864 from its binding sites in all the organs. PK 11195 was as potent as RO5-4864 in the platelets, heart, adrenals, kidney and several brain regions (midbrain, hypothalamus, medulla + pons and hippocampus. However it was 5 to 10 times more effective in cortex and striatum. In conclusion PK 11195 might represent a new tool to elucidate the physiological relevance of "peripheral type" benzodiazepine binding sites and might help to discriminate the hypothetical subclasses of these binding sites.

Adrenal Glands↗
PubMed1983

Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies.

Peripheral type of benzodiazepine binding sites were labelled in the kidney, the heart and the brain with [3H] RO5-4864 following intravenous injection in mice. The regional distribution of this in vivo binding parallels the in vitro binding: heart and kidney were more labelled than brain. Benzodiazepine potencies in reducing [3H] RO5-4864 binding in vivo parallel relative affinities for [3H] RO5-4864 binding sites in isolated organs membranes: RO5-4864 greater than diazepam greater than clonazepam. PK 11195 a new compound, chemically unrelated to benzodiazepines, which is a potent inhibitor of [3H] RO5-4864 in vitro is also very effective (more than RO5-4864) after I.P. injection and oral administration. These results emphasize the feasibility of using this technique to examine the effects on various pharmacological and physiological manipulations of these binding sites in vivo. Moreover the fact that PK 11195 binds to these sites in vivo might indicate that this compound could help to elucidate the physiological relevance of the peripheral type of benzodiazepine binding sites.

Animals↗
PubMed1983

Labelling of "peripheral-type" benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization.

PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide] is a new ligand for the "peripheral-type" benzodiazepine binding sites, chemically unrelated to benzodiazepines. It displaces with a very high potency (IC50 congruent to 10(-9) M) [3H]-RO5-4864 (a benzodiazepine which specifically labels the peripheral-type sites) from its binding sites. [3H]PK 11195 binds to a membrane fraction from rat brain cortex and rat olfactory bulb in a saturable and reversible manner with a very high affinity (KD = 10(-9) M). The number of maximal binding sites was ten times greater in the olfactory bulb than in the brain cortex. The order of potency of several compounds as displacers at 25 degrees C (PK 11195 greater than RO5-4864 greater than diazepam greater than dipyridamole greater than clonazepam) demonstrates that [3H]PK 11195 binds to the peripheral-type benzodiazepine binding sites. The KD value for the [3H]PK 11195 binding is not affected by temperature changes, whereas RO5-4864 and diazepam affinities decrease with increasing temperatures. Autoradiographic images of [3H]PK 11195 binding to rat brain sections show that binding sites are mainly localized in the olfactory bulb, median eminence, choroid plexus, and ependyma. This ligand could be a useful tool to elucidate the physiological and pharmacological relevance of these binding sites.

Animals↗
PubMed1983

"Peripheral type" benzodiazepine binding sites in rat adrenals: binding studies with [3H]PK 11195 and autoradiographic localization.

PK 11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinec arboxamide] is a compound chemically unrelated to benzodiazepines with a high affinity for the "peripheral type" binding sites for benzodiazepines (Le Fur et al., 1983a). [3H]PK 11195 binds to the adrenal membranes with a high affinity (KD congruent to 3 nM) in a specific, reversible and GABA-independent manner. Binding is also characterized by very high Bmax (34 pmol/mg protein). These binding sites are the "peripheral type" benzodiazepine binding sites as demonstrated by the potency order of displacement of the [3H]PK 11195 bound: PK 11195 greater than R05-4864 greater than diazepam greater than dipyridamole greater than clonazepam. The biochemical characteristic of the binding to rat adrenal sections has also been studied. In these conditions the affinity for [3H]PK 11195 is ten times smaller, but the potency order of displacing agents was the same, demonstrating the identity of the section binding sites. Using tritium sensitive film these sites have been visualized in adrenal sections. [3H]PK 11195 binding sites are localized in the adrenal cortex with some spare labelling in the medulla.

Adrenal Glands↗
PubMed1983

1-[4-(2-ter-butyl-quinolyl)]-3-(4-piperidyl)propanol (PK 10139): a new potent and long-acting antiarrhythmic agent.

PK 10139 is a new synthetic quinoline antiarrhythmic agent 10 times more potent and at least 2 to 3 times longer acting than quinidine sulfate. In the dog, the near 100% active dose (1.5 mg/kg i.v.) completely converted to sinus rhythm ouabain-induced ventricular tachycardia for over 30 min. The efficacy of this compound against multifocal beats induced by two-stage ligation of the left coronary artery (Harris) in the conscious dog was demonstrated after i.v. and oral administration with no peripheral and central nervous system side effects after the higher effective dose contrary to quinidine. In the anesthetized dog, PK 10139 like quinidine, increased atrial, atrioventricular nodal and ventricular refractory periods as determined with the programmed extrastimulus technique. PK 10139 also increased electrical stimulus threshold and intracardiac conduction times evaluated by measurement of A-H nodal conduction time, H-V conduction time and QRS interval as seen with all the class I antiarrhythmic agents. Thus, PK 10139 is a much more potent and long-acting agent than quinidine, with better tolerance.

Animals↗
PubMed1976

Fluorogenic labeling of organophosphate pesticides with dansyl chloride. Application to residue analysis by high-pressure liquid chromatography and thin-layer chromatography.

The analysis of some organophosphorus pesticides by fluorogenic labeling with dansyl chloride (5-dimethylaminonaphthalene--l-sulfonyl chloride) was investigated. The pesticides were hydrolysed in sodium hydroxide to the corresponding phenols. The reaction of dansyl chloride with the phenols was accomplished in a two-phase system. The resulting fluorescent derivatives were separated and analysed quantitatively by in situ thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC). As little as 10-25 ng/spot of pesticide was detected by both TLC and HPLC.

Chemical Phenomena↗
PubMedDate not supplied

Modulation of voltage-operated, but not receptor-operated, calcium channels in the rabbit aorta by PK 11195, an antagonist of peripheral-type benzodiazepine receptors.

We compared the effects of PK 11195, an antagonist of peripheral benzodiazepine receptors, on contractions of rabbit aorta by activation of either voltage-operated calcium channels (VOC) using BAY K 8644 (a calcium "agonist") and KCl or receptor-operated channels (ROC) using phenylephrine and B-HT 920, (alpha 1- and alpha 2-adrenoceptor agonist, respectively). In partially depolarized muscle strips, BAY K 8644 induced contractions that were noncompetitively inhibited by PK 11195 (pD'2 = 5.6 +/- 0.15). The effect of this calcium agonist was also antagonized by nitrendipine (competitively) and by yohimbine (noncompetitively), while prazosin was inactive. Contractions induced by KCl were inhibited by nitrendipine and, weakly, by PK 11195. Contractions induced by phenylephrine and B-HT 920 were inhibited competitively by prazosin and yohimbine and noncompetitively by nitrendipine, while PK 11195 was ineffective. It is concluded that PK 11195 behaves as an antagonist of VOC activated by BAY K 8644 and to a lesser extent by KCl depolarization but not of ROC coupled to alpha 1- and alpha 2-receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

[Clinical study of the action of dobutamine in acute cardiac insufficiency].

78 patients were treated with dobutamine for a severe episode of heart failure at a mean dose of 9.51 micrograms . kg-1 . min-1 for an average of 5 days. 59 of these patients had ischaemic heart disease, including 34 with recent infarcts. The monitoring of treatment was essentially clinical, consisting of repeated measurement of the heart rate, the systolic and diastolic blood pressure and the diuresis. A haemodynamic survey was performed in only 25 cases. 48 patients were improved. 24 of these patients had no clinical or radiological signs of heart failure at the end of the treatment. Dobutamine significantly increases the blood pressure (97.7 +/- 24.9 to 105.8 +/- 21 mm Hg), the diuresis and the cardiac index (2.02 +/- 0.51 to 2.52 +/- 0.54 l . min-1 . m-2) and it significantly decreases the mean capillary pressure (25.36 +/- 6.20 to 21.03 +/- 6.94 mm Hg). The tolerance was very satisfactory, particularly in terms of the heart rate, ventricular excitability and the progression of the coronary disease. This clinical study confirms the value of dobutamine in the treatment of severe heart failure, either alone or in combination with vasodilators. The authors do not believe tha haemodynamic monitoring is essential at the doses used, which means that dobutamine could be used more widely in these indications.

Acute Disease↗