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Biomedical subjects

R A Lefebvre

Publications and source records attributed to R A Lefebvre.

At least 109 records · Page 6Linked to original sources
PubMed1991

Influence of fenoldopam and quinpirole in the guinea-pig stomach.

1. The influence of the selective DA1-agonist fenoldopam and the selective DA2-agonist quinpirole was investigated in the guinea-pig intact stomach model and in guinea-pig gastric corpus muscle strips. 2. In the intact stomach model, quinpirole induced a relaxation from 10(-6) M on. The relaxation by quinpirole (3 x 10(-5) M) was significantly inhibited by rauwolscine (10(-7) M), yohimbine (10(-7) M) and domperidone (10(-6) M). In the presence of tetrodotoxin, quinpirole (3 x 10(-5) M) induced a contraction. 3. In the same model, fenoldopam induced a relaxation but only at 3 x 10(-5) M. The relaxation by fenoldopam (3 x 10(-5) M) was not inhibited by SCH 23390 (10(-6) M). The relaxant effect of dopamine (3 x 10(-6) M) was significantly inhibited by rauwolscine (10(-7) M), yohimbine (3 x 10(-7) M), haloperidol (10(-6) M) and domperidone (10(-6) M). 4. In circular muscle strips of the gastric corpus, the electrically induced cholinergic contractions were inhibited by dopamine but not consistently influenced by quinpirole or fenoldopam. 5. Dopamine, fenoldopam and quinpirole induced an increase in basal tone of the strips. The contraction by dopamine (10(-5) M) was significantly antagonized by prazosin and methysergide. 6. No evidence was thus found for the presence of DA1-receptors in both guinea-pig stomach models. Equally, no evidence for the presence of DA2-receptors was found when studying quinpirole in the strips. Although the relaxant effect of quinpirole in the intact stomach seems predominantly mediated via alpha 2-adrenoceptors, an involvement of DA2-receptors cannot be excluded.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Effects of the dopamine receptor agonists, fenoldopam and quinpirole, in the rat stomach.

The effects of the DA1-receptor agonist, fenoldopam, and the DA2-receptor agonist, quinpirole, were studied with the longitudinal muscle of rat gastric fundus and circular muscle of rat gastric corpus, as there are contrasting reports about the receptors involved in the inhibitory effect of dopamine in these tissues. Quinpirole had no effect on basal tone in the longitudinal muscle of the rat gastric fundus and did not inhibit the sustained contractions induced by electrical field stimulation or by methacholine. Fenoldopam had no effect on the tone increased by methacholine but slightly potentiated the electrically induced contraction at the highest concentrations; it concentration dependently (10(-7)-3 X 10(-5) M) increased the basal tone. The contractile effect of fenoldopam was clearly antagonized by rauwolscine 10(-6) M, yohimbine 10(-6) M and phentolamine 3 X 10(-6) M plus propranolol 10(-5) M. The 5-HT receptor antagonist, methysergide, antagonized the fenoldopam-induced contractions in a non-competitive way. Fenoldopam and quinpirole had no effect on contractions induced in the circular muscle of the rat gastric corpus by methacholine or electrical field stimulation. They induced some contraction at basal tone, at their highest concentrations. As fenoldopam and quinpirole did not mimic the inhibitory effect observed with dopamine in the same models, no evidence was found for the presence of inhibitory dopamine receptors in rat gastric muscle. The contractile effect of fenoldopam in the longitudinal muscle of the fundus is probably due to an interaction with 5-HT receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

High-performance liquid chromatographic determination of propylthiouracil in plasma.

A high-performance liquid chromatographic method for the determination of the antithyroid drug propylthiouracil in dog plasma has been developed. Propylthiouracil and the internal standard, methylthiouracil, are extracted from plasma with methylene chloride at pH 6 and the organic layer is evaporated to dryness. The residue is chromatographed on a Chromspher C18 reversed-phase column using Pic B-7 (0.005 M 1-heptanesulphonic acid in water)-1% acetic acid-methanol (40:45:15, v/v/v) as the mobile phase. Quantification is achieved by monitoring the UV absorbance at 300 nm. The response is linear (0.1-15 micrograms/ml) and using 100 microliters of plasma the detection limit is 50 ng/ml. The within-run coefficient of variation is less than or equal to 5% and the accuracy is within 10% of the theoretical value at concentrations between 0.1 and 15 micrograms/ml plasma.

Animals↗
PubMed1990

Investigation of possible pharmacokinetic and pharmacodynamic interactions between epanolol and digoxin.

The possibility of a pharmacokinetic and/or pharmacodynamic interaction between epanolol and digoxin has been investigated in 10 healthy male subjects taking digoxin 0.375 mg daily for 14 days. During that period epanolol 200 mg daily or matching placebo was also given, each for 7 days, according to a double-blind, randomized cross-over plan. The plasma digoxin concentration-time profiles after 7 days of concomitant placebo or epanolol were comparable. Trough and peak plasma digoxin levels were similar (placebo: 0.84 and 2.62 ng.ml-1; epanolol: 0.87 and 2.46 ng.ml-1). The renal clearances of digoxin and creatinine were lower during treatment with epanolol, but the differences were not significant (placebo 142.0 and 126.5 ml.min-1; epanolol 105.7 and 109.3 ml.min-1). STI indexes were lower during treatment with digoxin plus epanolol, than after digoxin alone. The difference was significant for QS2I (513 versus 503 ms), PEPI (119 versus 112 ms) and PEP/LVET (0.286 versus 0.304). The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between epanolol and digoxin, and that epanolol does not interfere with the positive inotropic action of digoxin.

Adrenergic beta-Antagonists↗
PubMed1990

Influence of exercise on nitroglycerin plasma concentrations after transdermal application.

Nitroglycerin plasma concentrations following transdermal application were measured in nine healthy subjects during supine rest position or during supine rest interrupted by sitting or exercising for 20 min. Sitting led to almost doubling of the average plasma concentrations (0.31 ng ml-1 before sitting, 0.55 ng ml-1 at the end of the sitting period), but exercise was accompanied by a much more marked increase in average plasma concentrations, which reached its maximum 5 min after ending exercise (0.22 ng ml-1 before exercise, 1.26 ng ml-1 5 min after the exercise period). Changes of bioavailability as well as of systemic clearance might be involved in the exercise-induced increase in plasma nitroglycerin concentrations.

Administration, Cutaneous↗
PubMed1990

Influence of the DA2-receptor agonist quinpirole on the guinea pig ileum.

The influence of the dopamine-receptor agonist quinpirole was studied in segments of the guinea pig ileum, mounted to measure longitudinal muscle activity. In concentrations selective for dopamine receptors (10(-9)-10(-7) M), quinpirole did not influence cholinergic twitch responses induced by transmural stimulation at supramaximal voltage, but it concentration-dependently facilitated them in the concentration range 10(-6) to 10(-4) M; the potency of quinpirole was similar to that of metoclopramide (ED50 values, 6.0 x 10(-6) M and 2.2 x 10(-6) M, respectively). Pretreatment of the tissues with 5-hydroxytryptamine or with the 5-hydroxytryptamine receptor antagonists methysergide, ketanserin and R53434 did not influence the facilitatory effect of quinpirole. It was also not influenced by drugs blocking adrenoceptors, dopamine receptors, opioid receptors, muscarinic M1 receptors, GABAA receptors and inhibiting the synthesis of prostaglandins. It was antagonized by the nicotinic receptor antagonist hexamethonium but not by pentolinium. Quinpirole did not enhance contractile responses to acetylcholine and carbachol, but in high concentrations induced contractions in unstimulated preparations. It is concluded that quinpirole facilitates twitch responses in the guinea pig ileum via a prejunctional site of action. This effect is not related to activation of dopamine receptors, but the exact mechanism remains unclear.

Acetylcholine↗
PubMed1989

Influence of differentiation on muscarinic receptors in N1E 115 neuroblastoma cells.

The effect of inducing morphological differentiation in N1E 115 mouse neuroblastoma cells on the number of muscarinic receptors and the ligand binding affinity was investigated using the lipophylic quinuclidinyl benzylate and the hydrophylic N-methylscopolamine as tritiated ligands. Induction of morphological differentiation was accompanied by a two- to three-fold increase of the number of receptors when assayed in a broken cell preparation; the ligand binding affinity was unaffected by differentiation. Using intact cells, this increase was not paralleled by a similar increase in binding sites accessible for N-methylscopolamine, which binds preferentially to extracellular sites.

Animals↗
PubMed1989

Influence of GABA and ethylenediamine in the guinea-pig duodenum.

1. GABA induced concentration-dependent transient contractions of the guinea-pig duodenum, but only occasionally evoked small relaxatory responses. The GABA-induced contractions were blocked by atropine and tetrodotoxin but were not influenced by hexamethonium; during electrically evoked twitch contractions, GABA had a concentration-dependent inhibitory effect. 2. The concentration-response curve for the contractile effect of GABA was shifted to the right in a dose-dependent manner by bicuculline and picrotoxin, with a clear reduction of the maximal effect in the presence of picrotoxin. 3. Homotaurine and delta-aminovaleric acid but not baclofen mimicked the GABA-induced contractions; the responses induced by these GABAA receptor agonists were antagonized by atropine, tetrodotoxin and bicuculline. Baclofen concentration-dependently inhibited electrically evoked twitch contractions. 4. Ethylenediamine also had a GABA-like effect, and cross-desensitization developed between GABA and ethylenediamine. 5. The ethylenediamine-induced contractions were not antagonized by thiosemicarbazide; they were reduced by 3-mercaptopropionic acid but the GABA-induced contractions were reduced to the same extent. 6. It is concluded that GABA induces contraction of the guinea-pig duodenum by excitation of GABAA receptors on postganglionic cholinergic neurones; a GABAB receptor-mediated inhibitory effect can be observed during electrically evoked twitch contractions. Ethylenediamine mimicks the GABAA receptor-mediated effect probably by a direct effect on the GABAA receptors.

3-Mercaptopropionic Acid↗
PubMed1988

Comparison of the effect of vasoactive intestinal polypeptide and non-adrenergic non-cholinergic neurone stimulation in the cat gastric fundus.

The possible involvement of vasoactive intestinal polypeptide (VIP) in the non-adrenergic non-cholinergic (NANC) relaxation of the cat gastric fundus was studied in circular and longitudinal muscle strips. Cumulative transmural stimulation induced a frequency-dependent relaxation, while cumulative administration of VIP induced a concentration-dependent relaxation. Tetrodotoxin almost completely antagonized the relaxation induced by transmural stimulation (1 Hz), but did not influence the relaxation induced by VIP (10(-7) M); the latter was not influenced by hexamethonium or propranolol plus phentolamine. Trypsin (30 min incubation) and VIP antiserum (1 h incubation) prevented the relaxation induced by VIP and reduced that induced by transmural stimulation, but did not influence the relaxation induced by isopropylnoradrenaline. Two putative VIP receptor antagonists, [AcTyr1]hGRF-(1-40)OH and [4Cl-D-Phe6,Leu17]VIP, did not influence the relaxation induced by VIP or transmural stimulation. These results are compatible with the hypothesis that VIP is involved in the NANC relaxation of the cat gastric fundus, although participation of a non-VIP component cannot be excluded.

Animals↗
PubMed1988

Influence of exercise on plasma concentrations of isosorbide dinitrate.

As the fall in hepatic blood flow caused by exercise is expected to decrease the elimination of high extraction drugs, the influence of exercise on the fate of the anti-anginal drug isosorbide dinitrate has been assessed. Isosorbide dinitrate 10 mg was given orally, after an overnight fast, on 2 different days to 7 healthy volunteers and the plasma concentrations of the parent compound and its mononitrate metabolites were measured. Heavy bicycle exercise from the 45th to the 105th min after intake of the drug on one of the experimental days did not change the plasma isosorbide dinitrate concentrations as compared to those on the rest day. The concentrations of both mononitrates were lower on the exercise day, but the difference was already present before the exercise started.

Administration, Oral↗
PubMed1988

Vasoactive intestinal polypeptide as possible mediator of relaxation in the rat gastric fundus.

Relaxations were induced in longitudinal muscle strips of the rat gastric fundus by stimulation of non-adrenergic non-cholinergic (NANC) neurons and by administration of vasoactive intestinal polypeptide (VIP) or isoprenaline. The effect of antiserum against vasoactive intestinal polypeptide (VIP antiserum) and of control serum on these relaxations was investigated. Incubation with VIP antiserum (dilution 1/50) for 1 h almost completely prevented the relaxation by VIP. It partially prevented the relaxation evoked by electrical stimulation while the relaxation induced by isoprenaline was not influenced. Control serum decreased the VIP- and stimulation-induced relaxations much less than did VIP antiserum. In addition, the effect of the putative VIP antagonist (4Cl-D-Phe6, Leu17) VIP was studied on the relaxations induced by NANC neuron stimulation and by VIP. The VIP antagonist (3 x 10(-5) M, incubation time 10 min) had a relaxatory effect itself but had no influence on either VIP- or stimulation-induced relaxations. The results with VIP antiserum confirm the involvement of VIP in the inhibitory NANC neurotransmission of the rat gastric fundus.

Animals↗
PubMed1988

Single dose pharmacokinetics of cetirizine in young and elderly volunteers.

The pharmacokinetics of the H1-receptor antagonist cetirizine were studied from 0 to 48 h after a single oral intake of 10 mg in 10 elderly volunteers (60 to 90 years) and in 10 young healthy volunteers (21 to 29 years). In young healthy volunteers about 60% of an oral dose of cetirizine was excreted in the urine in unchanged form. Mean plasma concentrations were slightly higher in the elderly subjects. Cmax (362 ng/ml), Tmax (1.30 h), terminal half-life (11.8 h) and AUC infinity (4316 ng.h/ml) in the elderly subjects were somewhat higher than in the young subjects (Cmax: 337 ng/ml, Tmax: 1.12 h, terminal half-life: 10.6 h, AUC: 3721 ng.h/ml), but the difference was not significant. The mean cumulative urinary excretion at 32 h was significantly lower in the elderly subjects. It is concluded that the slight differences in pharmacokinetics of cetirizine between young and elderly subjects after single oral intake can be attributed to the decreased renal clearance in the elderly.

Administration, Oral↗
PubMed1988

Influence of food on steady state serum concentrations of theophylline from two controlled-release preparations.

The influence of food on the bioavailability of the controlled-release theophylline preparations Theostat and Theolair was studied in 12 healthy subjects after multiple dosing (b.i.d. for 6 days). On the morning of days 5 and 6, the volunteers took these products once after overnight fasting and once after a high-fat breakfast. For Theostat, serum theophylline levels and pharmacokinetic parameters were not affected by the intake of breakfast. For Theolair, serum theophylline concentrations were markedly lower after breakfast, with a significant decrease of Cmax and AUC. This study confirms the necessity of studying the influence of food on the bioavailability of theophylline controlled-release preparations.

Adult↗
PubMed1987

Antiaversive properties of opioids in the conditioned taste aversion test in the rat.

The antiaversive effect of mu-, kappa- and delta-opioid receptor agonists against conditioned taste aversion (CTA) induced by apomorphine, lithium chloride and copper sulphate in the rat was studied, in order to evaluate whether prevention of CTA is a suitable model for the study of antiemetics. Anti-aversion was not a general characteristic of all opioid substances tested. Only one dose of the mu-agonist morphine and only one dose of the kappa-agonist ethylketocyclazocine had a consistent antiaversive effect against CTA induced by apomorphine; one dose of the delta-agonist [D-Ala2, Met5]enkephalinamide antagonized the aversion induced by lithium chloride. As the results do not correspond to our previous findings on the antiemetic effects of these opioids in the dog (all mu- and kappa-agonists tested having an antiemetic effect), we conclude that the CTA test cannot be used as a screening test for potentially antiemetic drugs.

Animals↗
PubMed1987

Neurogenic vasodilatation produced by fenoldopam in the rat hindquarters vascular bed.

1 The effects of local administration of the selective DA1-receptor agonist fenoldopam into the isolated autoperfused rat hindquarters were studied in order to investigate the site of action of fenoldopam in this vascular bed. 2 Bolus injections of fenoldopam produced reductions in perfusion pressure in the preconstricted, constant flow perfused rat hindquarters vascular bed. 3 The vasodilator effect of fenoldopam was abolished by sectioning of the lumbar sympathetic nerves and by pretreatment with the ganglion-blocker hexamethonium or the alpha-adrenoreceptor antagonists phentolamine and prazosin. At the same concentration, local infusion of fenoldopam had no effect on vasoconstrictor responses to locally administered noradrenaline and phenylephrine. 4 The vasodilator effect of fenoldopam was antagonized by the non-selective dopamine receptor antagonist RS-sulpiride and by the selective DA1-receptor antagonist SCH 23390, but not by the selective DA2-receptor antagonist domperidone. 5 These results provide no evidence for the presence of postsynaptic DA1-receptors in the rat hindquarters vascular bed; they show that fenoldopam induces neurogenic vasodilatation in this vascular bed, probably via stimulation of ganglionic DA1-receptors.

Animals↗
PubMed1987

Influence of alpha-chymotrypsin and trypsin on the non-adrenergic non-cholinergic relaxation in the rat gastric fundus.

Relaxations of the rat gastric fundus were induced by electrical stimulation of the non-adrenergic non-cholinergic (NANC) neurones, by vasoactive intestinal polypeptide (VIP), by noradrenaline and by isopropylnoradrenaline. The influence of alpha-chymotrypsin and trypsin thereupon was studied. alpha-Chymotrypsin 2 u ml-1, present for 30 min, antagonized completely the VIP-induced relaxation, but not the stimulation-induced relaxation; alpha-chymotrypsin 10 u ml-1 also partially antagonized the stimulation-induced relaxation. When alpha-chymotrypsin 2 u ml-1 was added after the relaxation had occurred, it antagonized completely the VIP-induced relaxation, but it also partially antagonized the stimulation-induced relaxation. The partial antagonism of the stimulation-induced relaxation was more pronounced with alpha-chymotrypsin 10 u ml-1. Trypsin, 10(-6) M and 3 X 10(-6) M, had effects on VIP- and stimulation-induced relaxations similar to those of alpha-chymotrypsin. The relaxations induced by noradrenaline and isopropylnoradrenaline were not influenced by alpha-chymotrypsin or trypsin, respectively. The results suggest that a peptide, possibly VIP, is involved in the NANC relaxation of the rat gastric fundus.

Animals↗
PubMed1987

Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed.

The effect of local administration of the dopamine 2 (DA2)-receptor agonist quinpirole and of the DA1-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. Local infusion of quinpirole (30 micrograms kg-1 min-1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 +/- 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 micrograms kg-1) but not by the selective DA1-receptor antagonist SCH 23390 (50 micrograms kg-1). Local infusion of fenoldopam (30 micrograms kg-1 min-1 for 5 min) reduced baseline perfusion pressure to 89.9 +/- 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 +/- 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 +/- 8.2%. Similar pressor responses induced by the selective alpha 1-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 +/- 6.4%), but responses to locally administered angiotensin II were not modified. Pretreatment with SCH 23390 (50 micrograms kg-1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. Pretreatment with the selective alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation. 7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2-receptors while fenoldopam stimulates postsynaptic vasodilatory DA,-receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic alpha-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic alpha 2-adrenoceptors.

Angiotensin II↗