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J Damas

Publications and source records attributed to J Damas.

At least 37 records · Page 2Linked to original sources
PubMed1999

Thromboxane A2 receptor antagonism in man and rat by a sulphonylcyanoguanidine (BM-144) and a sulphonylurea (BM-500).

Torasemide, a loop diuretic, has been reported to relax dog coronary artery precontracted by thromboxane A2 (TXA2), an endogenous prostanoid involved in cardiovascular and pulmonary diseases. N-cyano-N'-[[4-(3'-methylphenylamino)pyrid-3-yl]sulphonyl] homopiperidinoamidine (BM-144) and N-isopropyl-N'-[5-nitro-2-(3'-methylphenylamino)-benzenesulphon yl]urea (BM-500), chemically related to torasemide, have been examined for their TXA2 antagonism. The affinity (IC50, the concentration resulting in 50% inhibition) of BM-144 and BM-500 for the TXA2 receptor of washed platelets from man was 0.28 and 0.079 microM, respectively. This is better than for sulotroban (IC50 = 0.93 microM) but less than for SQ-29548 (IC50 = 0.021 microM), two TXA2 antagonists used as reference. The aggregation of platelets from man induced by arachidonic acid was prevented by BM-144 (IC50 = 9.0 microM) and by BM-500 (IC50 = 14.2 microM). Similar results were obtained by use of U-46619, a TXA agonist, as aggregating agent (BM-144, IC50 = 12.9 microM and BM-500, IC50 = 9.9 microM). The contracting effect of U-46619 on rat stomach strip was abolished by BM-144 (IC50 = 1.01 microM) and BM-500 (IC50 = 2.54 microM). Both drugs (BM-144: IC50 = 0.12 microM and BM-500: IC50 = 0.19 microM) also relaxed rat aorta precontracted by U-46619; both were more potent than sulotroban (IC50 = 1.62 microM). The two torasemide derivatives (100 microM) did not significantly affect the myo-stimulating effect of some prostaglandins (PGE2, PGI2, PGF2alpha) or aorta contraction elicited by KCl (30 mM). They did not modify rat diuresis after administration of a 30-mg kg(-1) dose. In conclusion, BM-144 and BM-500 can be regarded as novel non-carboxylic TXA2 receptor antagonists and offer a novel template for the design of more potent molecules.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

[Inflammation and stress].

In the face of the tissue injury, the human organism builds three kinds of responses: inflammation, acute phase phenomena and stress. These responses correspond to three lines of a gradual defense against aggressive stimuli. However, the stress can be induced in the absence of any kind of inflammation. As the effects of these responses are often confounded, we think it was useful to recall the main repercussions of these responses, the links between them and the aspects which separate them.

Acute Disease↗
PubMed1998

The fate of plasma kallikrein in normal and kininogen-deficient rats.

The clearance of exogenous plasma kallikrein, its uptake by liver, spleen, kidneys, lungs and its extravasation in the paws were determined in normal Wistar rats, normal and kininogen-deficient Brown Norway rats. Kallikrein was purified from rat plasma and labelled with 125I. After intravenous injection of 125I-kallikrein, the disappearance of acid-precipitable kallikrein from the blood fits a biexponential curve similar in the three groups of rats: a rapid initial clearance (T1/2 around 3 min) followed by a phase of slower elimination (T1/2 around 50 min). Removal of kallikrein from the blood was associated with a large uptake of radioactivity by the liver: 67% of the 125I-kallikrein cleared from the blood at 10 min. The kidneys and the spleen accumulated small amounts of the radioactivity. The uptake of kallikrein by the spleen was slightly reduced in kininogen-deficient rats. The kininogen deficiency in Brown Norway rats from the strain BN/May Pfd was confirmed by the low levels of kinins released by tissue kallikrein and by a prolongation of activated thromboplastin times in the plasma of these animals. We concluded that plasma kallikrein is rapidly cleared from the circulation of the rat. The liver is the main clearing organ of plasma kallikrein. The disappearance of kallikrein from the circulation is not affected by the lack of high molecular weight kininogen, except in the case of the uptake of the enzyme performed by the cells of the spleen, which is reduced.

Animals↗
PubMed1998

Comparative study of pirlindole, a selective RIMA, and its two enantiomers using biochemical and behavioural techniques.

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim of this study was to compare the effects of the racemic pirlindole (a selective and reversible MAO-A inhibitor) and its two enantiomers using biochemical techniques (in vitro and ex vivo determination of rat brain MAO-A and MAO-B activity) and behavioural models (forced swimming test and reserpine-induced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of (+/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 microM, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, with a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test and the reserpine-induced hypothermia and ptosis model, the three compounds had an antidepressant profile. In the forced swimming test, the minimal effective dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance with the biochemical data.

Animals↗
PubMed1998

[Starling's law in 1998].

This paper reexamines the law of Starling on the exchanges of liquids through the capillaries at the light of the most recent data available in the literature.

Capillary Permeability↗
PubMed1997

Involvement of 5-hydroxytryptamine and bradykinin in the hyperalgesia induced in rats by collagenase from Clostridium histolyticum.

The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight hyperalgesia in kininogen deficient rats in comparison with the behavioural response obtained in normal rats. Lisinopril (10(-5) M), and angiotensin-converting enzyme inhibitor, increased the duration of the hyperalgesia elicited in normal rats. Ondansetron (0.5 to 5 mumol/kg), a 5-HT3 antagonist, suppressed the hyperalgesia as did methysergide (1.1 to 11 mumol/kg), a mixed 5-HT1 and 5-HT2 receptor antagonist. However, the hyperalgesia was not modified by RP 67580 (1.8 to 18 mumol/kg), a NK1 receptor antagonist, and was only slightly delayed by indomethacin (2 mg/kg), a cyclo-oxygenase inhibitor. The oedema-promoting effect of 5-HT (6 nmol) was inhibited by methysergide but not by ondansetron. The swelling induced by collagenase in rat paw was reduced by methysergide but not by ondansetron. We conclude that the behavioural response induced by collagenase depends on an interactions between bradykinin and 5-HT. Prostanoids play a minor role in the beginning of the reaction whereas substance P is not significantly involved in this hyperalgesia.

Analgesics↗
PubMed1996

Dibenzoazepine analogues: the electrophysiological properties of JL3, a potential atypical antidepressant.

JL3, 10-(4-methylpiperazin-1-yl)pyrido[4,3-b][1,4]benzothiazepine, has potent antidepressant-like activity in Porsolt's test in mice. Therefore, its influence on the electrical activity of central monoaminergic neurons was investigated in rats anaesthetized with chloral hydrate. JL3 induced a marked decrease of the firing rate of dorsal raphe serotonergic neurons (ID50 = 3.87 +/- 0.57 mg kg-1) and of locus coeruleus noradrenergic neurons (ID50 = 2.63 +/- 0.35 mg kg-1). The drug did not modify the electrical activity of A10 dopaminergic neurons. JL3 does not block amine uptake but it has affinity for 5-HT1A and 5-HT2 receptors. It is speculated that serotonergic mechanisms could play a role in the electrophysiological effects of JL3.

Animals↗
PubMed1996

Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase.

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.

Albumins↗
PubMed1996

Potentiation of the pro-inflammatory effects of bradykinin by inhibition of angiotensin-converting enzyme and aminopeptidase P in rat paws.

The influence of some peptidase inhibitors on oedema and plasma extravasation induced by bradykinin and carrageenan in rat paw was evaluate. Bradykinin-induced oedema in normal rats was increased by o-phenanthroline (3.10(-2) M), by captopril (10(-6) M to 10(-4) M), by lisinopril (10(-6) M to 10(-4), or by lisinopril (10(-5) M) in combination with apstatin (8.10(-5) M or 1.4 10(-4) M). It was not modified by phosphoramidon (10(-6) M to 10(-5) M) and by diprotin A (10(-3) M). It was increased by mergepta at high concentrations (2.10(-4) M). Mergepta did not increase the potentiating effect of captopril. Carrageenan-oedema in normal rats was increased by captopril (10(-5) M), lisinopril (10(-5) M) and apstatin (1.4 10(-4) M. It was not modified by mergepta (10(-4) M), phosphoramidon (10 (-5) M) and diprotin A (109-3) M). Des-Arg1-bradykinin and Des-Arg9-bradykinin have low oedema-promoting effects. Captopril (10(-5) M) increased the effects of bradykinin but not those of carrageenan in kininogen-deficit Brown Norway rats. Angiotensin-converting enzyme and aminopeptidase P appear to be main kinin-inactivating enzymes in rat paws. Carboxypeptidase N, neutral endopeptidase 24.11 and dipeptidyl(amino)peptidase IV do not play a significant role in this inactivation.

Aminopeptidases↗
PubMed1996

Kallikrein and salivary secretion in rats during heat exposure.

RP 67850, a NK1 receptor antagonist, inhibited the sialogogic effect of Substance P (SP). Heat-induced salivation was indirectly measured through the changes in body weight. Thermolytic salivation was reduced by atropine and RP 67580 and thus would be mainly controlled by acetylcholine and tachykinins. This salivation was associated with a large depletion of kallikrein in submaxillary glands. This depletion was not inhibited by atropine and RP 67580. Feeding has been reported to reduce amylase activity in parotid glands but did not modify the kallikrein content in submaxillary glands. Heat exposure did not modify amylase activity. There is a dissociation between the releases of amylase and kallikrein from salivary glands.

Animals↗
PubMed1996

The brown Norway rats and the kinin system.

In 1979, we found a strain of kininogen-deficient Brown Norway rats. Since then, several studies have used these animals as negative controls of the involvement of the kinin system in physiological and pathophysiological processes. The cause of this deficiency has now been elucidated. This article reviews studies performed with these kininogen-deficient rats. These investigations have mainly focused on the links between the kinin system and the kidneys, hypertension, salivary glands, acute inflammatory reactions, cysteine proteinase inhibition, lymphatic tissues, coagulation, and cardiovascular shock states.

Animals↗
PubMed1995

Collagenase-induced oedema in the rat paw and the kinin system.

Collagenase (100 micrograms) induced a large plasma extravasation, during the first 15 min after its injection in rat paw, associated with the rapid development of oedema which subsided after 6 h. The extent of the oedema was similar in normal and kininogen-deficient rats. The swelling induced in normal rats was reduced by HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and by three serine protease inhibitors, soybean trypsin inhibitor (SBTI), Leucaena leucocephala trypsin inhibitor 1 (LLTI-1) and Leucaena leucocephala trypsin inhibitor 2 (LLTI-2). These agents had no effect on the oedema induced in kininogen-deficient rats. The swelling was also reduced by methysergide, indomethacin, ketoprofen and methylprednisolone. It was increased by heparin, but it was not modified by mepyramine, WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo- [4,3-a][1,4]-diazepine-2-yl]-1-(4-morpholinyl)-1-propanone) and NG-nitro-L-arginine. In vitro, collagenase did not release kinins from rat plasma or from purified T-kininogen. LLTI-1 and LLTI-2 did not inhibit collagenase activity for one of its specific substrates. Kinins are thus involved in the development of collagenase oedema in normal rats. Their generation would be indirect following changes in matrix proteins in extravascular spaces. Nevertheless, kinins are not the decisive mediators of the swelling. Serotonin, possibly released from platelets, and prostanoids participate in the inflammatory process.

Animals↗
PubMed1995

Modulation of the clozapine structure increases its selectivity for the dopamine D4 receptor.

Clozapine has a more marked affinity for the recently cloned dopamine D4 receptor than for the dopamine D2 receptor. In the search for a selective ligand for the dopamine D4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido [2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepine class. Indeed, JL 18 binds to the dopamine D4 receptor with affinity up to 25 times superior to that for the dopamine D2 receptor and presents reduced affinities for other receptors.

Apomorphine↗
PubMed1995

The myostimulating effect of tissue kallikrein on rat uterus.

The mechanism of the myostimulating activity of rat tissue kallikrein on rat uterus was re-examined using uterus from kininogen-deficient rats and HOE 140 (D-Arg[Hyp3, Thi5, D-Tic7, Oic8]bradykinin), a specific bradykinin receptor-B2 antagonist. The uterus from kininogen-deficient rats was 50 times less sensitive to rat kallikrein than that from normal rats. HOE 140 (6 to 60 nM) inhibited the contracting effects of bradykinin and of rat kallikrein. Porcine kallikrein had no effect on rat uterus. Bradykinin and rat kallikrein induced a relaxation of rat duodenum. The duodenum from kininogen-deficient rats was 100 times less sensitive to rat kallikrein than the duodenum from normal rats. HOE 140 (0.6 to 3 nM) inhibited the relaxing effects of bradykinin and of kallikrein. Preincubation of rat kallikrein with aprotinin (Trasylol) abolished the effects of kallikrein on smooth muscles. HOE 140 inhibited the amidolytic activity of tissue kallikrein with a Ki value of 220 microM. HOE 140, at micromolar concentrations, suppressed the kininogenase activity of tissue kallikrein. Plasma of deficient rats contained 0.7% of the normal levels of kininogens. After washing the blood vessels with saline, kininogens were present in uterine homogenates but not in duodenal homogenates from both rat strains.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Antipsychotics and neuropeptides: the atypical profile of CI-943 and its relationship to neurotensin.

CI-943 is a new drug candidate with antipsychotic-like activity in a variety of behavioural tests in rodents and primates, but without any affinity for brain dopamine receptors. CI-943 does not cause dystonia in monkeys, a predictive symptom of extrapyramidal side effects (EPS). Its mechanism of action remains unclear. Neurotensin (NT) concentration in nucleus accumbens and caudate is increased by CI-943; this may be associated with its antipsychotic effect. Indeed various observations suggest that the clinical action of antipsychotic drugs may at least be partially mediated by some neuropeptides. Various actions of neurotensin are reviewed. The hypothesis on the role of neurotensin represents a new strategy in the development of pharmacological tools for the treatment of schizophrenia.

Animals↗