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Biomedical subjects

J Velly

Publications and source records attributed to J Velly.

At least 19 recordsLinked to original sources
PubMed1991

Facilitation of learning consecutive to electrical stimulation of the locus coeruleus: cognitive alteration or stress-reduction?

This chapter summarizes behavioral and neurochemical data on the delayed effect of locus coeruleus stimulation on learning capabilities in the rat. The initial observation showed that electrical stimulation of the locus coeruleus of a 15-day-old-rat improved the early stages of acquisition and extinction of a food-reinforced task performed 4 weeks later. Neurochemical lesion of the dorsal noradrenergic bundle performed 10 days before the stimulation did not attenuate the behavioral effect, whereas the lesion of the locus coeruleus proper suppressed the subsequent behavioral improvement. More recently we showed that the increase of adrenocorticotrophin release consecutive to a moderate stressful situation was significantly lower in previously stimulated rats than in implanted non-stimulated animals. Furthermore, we demonstrated that the neurochemical lesion of the locus coeruleus increased neophobia in the open-field as well as in a specific exploration task. Taken together these data strongly suggest that the long-term improvement in acquisition and extinction of locus coeruleus-stimulated rats results mainly from an attenuated stress reaction when these animals are confronted with a new environment (beginning of acquisition) or a new situation (beginning of extinction). Finally, we were interested in investigating the possibility of some long-term neurochemical modifications that could be related to the observed behavioral effects. The most significant modification observed concerned certain subpopulations of adrenoceptors in specific brain regions. By using specific ligands of the beta-, alpha 1- and alpha 2-adrenoceptors, we studied the long-term effect (4 weeks) of the locus coeruleus stimulation on the kinetic characteristics of these three sub-types of receptors in four brain areas (the cortex, hippocampus, hypothalamus and brainstem). No significant alteration in the density of beta binding sites was observed in any of the four structures analyzed; likewise locus coeruleus stimulation did not modify the density or affinity of the beta-, alpha 1- and alpha 2-receptors in the brainstem. The density of alpha 1- and alpha 2-receptors was significantly increased in the cortex whereas in the hippocampus only the density of the alpha 2-receptors was increased. Finally, a very large increase of the density of alpha 2-adrenoceptors was observed in the hypothalamus (113%). In each case the increase in receptor density was also associated with a decreased affinity. A behavioral counterpart of these changes in the kinetic properties of the alpha 2-receptors has been observed by using a pharmacological approach.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Effects of dopamine prodrugs and fenoldopam on glomerular hyperfiltration in streptozotocin-induced diabetes in rats.

The effects of dopamine (DA) prodrugs (L-dopa and gludopa) and of a D1-selective agonist (fenoldopam) on glomerular hyperfiltration were studied in the early stage of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) and were treated 1 week later with L-dopa (2 x 10 mg/kg/day, s.c.), gludopa (2 x 3 or 2 x 10 mg/kg/day, s.c.), or fenoldopam (2 x 0.3 or 2 x 1 mg/kg/day, s.c.). Their renal functions were compared with those of untreated diabetic and nondiabetic control rats. STZ injection led to hyperglycemia that was kept moderate (20-25 mmol/L) by daily insulin therapy (2-4 U of NPH insulin). Within 2 weeks, glomerular hyperfiltration (polyfructosan clearance) developed in diabetic rats (30% increase vs. nondiabetic control). A rise in renal plasma flow (PAH clearance) was sometimes observed. One week of treatment with either L-dopa, gludopa, or fenoldopam normalized the glomerular filtration rate and decreased filtration fraction. These corrections occurred despite similar metabolic disturbance and kidney hypertrophy. Gludopa was less well tolerated by diabetic rats than L-dopa. Results with L-dopa showed that the normalization of glomerular hyperfiltration was linked to DA synthesis and stimulation of D1 receptors, since it was reversed by carbidopa, a dopa decarboxylase inhibitor, and by SCH 23390, a D1-selective antagonist. These data show that DA prodrugs and a D1 agonist can suppress diabetic glomerular hyperfiltration in the very early course of the disease in rats.

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

Metabolism and vascular effects of gamma-L-glutamyl-L-dopa on the isolated rat kidney.

Gamma-L-glutamyl-L-dopa (or gludopa), a dopamine (DA) prodrug, is selectively metabolized in vivo by the kidney through the sequential action of two renal enzymes, gamma-glutamyl transpeptidase (gamma-GT) and aromatic L-amino acid decarboxylase (AADC). This study was designed to analyze, in vitro, the factors regulating gludopa metabolism and its renal vascular effects. Rat kidneys were perfused in closed circuit with a cell-free perfusion buffer containing 6% bovine serum albumin (BSA). Adding gludopa (final concentration 10(-5) M in the perfusate) led to the release of DA both into urine and perfusate (0.53 +/- 0.21 and 1.38 +/- 0.28 nmol/min/g kidney wt, respectively, during the first 5 min after substrate addition, N = 5, mean +/- SEM). Total DA release (urine plus perfusate) was 73.7 +/- 15.8 nmol/g kidney wt within 30 minutes of recirculation. In non-filtering kidneys, total DA release in the recirculating medium was lower (12.5 +/- 1.4 nmol/g kidney wt, P less than 0.01). Glomerular filtration and access to the gamma-GT on the brush border membrane of proximal tubular cells are therefore required for the maximal conversion rate of gludopa. On filtering kidneys, L-dopa was also converted to DA, but at a higher rate than gludopa (total DA formed within 30 min of recirculation = 131.2 +/- 31.9 nmol/g kidney wt) and this rate was not reduced in non-filtering kidneys (224.2 +/- 41.7 nmol/g kidney wt DA formed within 30 min). Metabolic conversion of L-dopa by AADC is thus preserved in the case of an approach via the basolateral side of the proximal tubular cells. The renal vascular effects of gludopa were studied after vascular tone had been restored by continuous perfusion of PGF2 alpha and after the inhibition of alpha- and beta-adrenoceptors. Gludopa (3.10(-6) to 4.10(-5) M) elicited concentration-dependent renal vasodilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Renal dopamine synthesis from precursors.

In the Wistar rat in vivo L-dopa (10 mg/kg, subcutaneously) was shown to have the characteristics of a kidney-directed dopamine (DA) prodrug: two daily injections increased 24 h urinary DA excretion 450-fold but had no systemic effects on blood pressure and heart rate. In inactin-anesthesized rats, L-dopa increased natriuresis, diuresis and renal blood flow; these effects were linked to endorenal DA synthesis and to DA-1 receptor stimulation since they were suppressed by both carbidopa and SCH 23390. In the isolated perfused rat kidney, DA was synthesized from L-dopa with a greater yield than from gludopa. In nonfiltering kidneys, L-dopa metabolism was not limited when the access to dopa decarboxylase was restricted to the basolateral membrane. The same was not true for gludopa, for which the basolateral metabolism was low.

Animals↗
PubMed1990

L-dopa and streptozotocin-induced diabetic nephropathy in rats.

The purpose of the present study was to determine whether the physiological dopamine prodrug, L-dopa, could suppress streptozotocin-induced diabetic glomerular hyperfiltration, and thus prevent further evolution of the diabetic nephropathy. Male Wistar rats treated with streptozotocin (60 mg/kg, intravenously) rapidly developed hyperglycemia which was stabilized (congruent to 4 g/L) by a daily insulin injection. Within two weeks, a significant increase in glomerular filtration rate (GFR) and a rise in the filtration fraction were observed as described in the early stage of diabetic nephropathy. Increase in both GFR and in the filtration fraction were normalized by treating the rats with L-dopa (10 mg/kg, subcutaneously, twice a day for one week). The effects of L-dopa were linked to endorenal DA synthesis and to DA-1 receptor stimulation since both carbidopa and SCH 23390 suppressed them.

Animals↗
PubMed1990

[Prevention by L-dopa of early renal consequences of diabetes induced by streptozocin in rats].

The early renal effects associated with streptozotocin-induced diabetes in rats (glomerular hyperfiltration and increase in filtration fraction) are similar to modifications reported in the early stage of human diabetic nephropathy. We examined the reversibility of these early renal diabetic effects by dopamine, which might correct glomerular hyperfiltration thanks to its preferential vasodilatory action on glomerular efferent arterioles. A dopamine prodrug, L-dopa was used to increase endorenal dopamine synthesis. Studies were carried out on streptozotocin-treated (60 mg/kg, i.v.) Wistar rats, supplemented with NPH insulin (2 to 3 U/day) such as to stabilize hyperglycemia at 22 mmol/l. One week after diabetes induction, animals were treated during a week either with L-dopa (10 mg/kg, s.c. twice daily) or L-dopa plus a dopa-decarboxylase inhibitor, carbidopa (10 mg/kg, s.c. 30 min before each L-dopa injection) or L-dopa plus a selective D1 receptor antagonist, SCH 23390 (100 micrograms/kg, s.c., with each L-dopa injection). Control diabetic animals received the solvent of L-dopa and control non-diabetic animals received the solvent of streptozotocin. After one week of L-dopa or other treatment, the renal functions of the rats were investigated (polyfructosan and PAH clearances) under inactin anaesthesia. As expected, streptozotocin induced glomerular hyperfiltration (1.3 +/- 0.07, n = 14, versus 0.93 +/- 0.05 ml/min.g kidney weight in non-diabetic controls, p less than 0.001) and an increase in filtration fraction (52.4 +/- 5.1 versus 32.1 +/- 1.7%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

New 1,4-dihydropyridine derivatives combining calcium antagonism and alpha-adrenolytic properties.

A series of twelve 1,4-dihydropyridine derivatives incorporating an alpha-adrenergic moiety in one of the ester chains was synthesized. The compounds were evaluated for their calcium antagonist activities by the inhibition of [3H]nitrendipine binding and, in vitro, on pig coronary artery. Their alpha 1- and alpha 2-adrenolytic effects were assessed from their inhibition of [3H]prazosin and [3H]yohimbine binding and, in vitro, on rat aorta and guinea pig vas deferens. Compounds 6 and 9-11 displayed strong calcium antagonist activities, identical with that of nicardipine. The moderate alpha-adrenolytic properties observed were attributed to the presence of alpha-adrenergic moieties. The four chiral derivatives 6a (R,R), 6b (S,S), 6c (S,R), and 6d (R,S) with an N-methyl-N-(benzodioxanylmethyl)amino group on the ester chain were prepared and tested as done previously. Some structure-activity relationships are discussed.

Animals↗
PubMed1989

Beta-adrenoceptor binding potencies of new aliphatic and alicyclic oxime ethers and their relevance to intraocular pressure control.

The selectivity and binding potency of a series of alkyliminoxypropanolamines characterized by the lack of an aromatic nucleus are studied using a new non-selective radioligand, (-)-(125I)-Iodocyanopindolol. The relationship between the effectiveness in lowering the intraocular pressure (IOP) in experimental hypertensive rabbit eyes and their capacity to bind to ciliary processes beta 2-adrenoceptors is discussed. The inhibition constant (Ki) and beta 2/beta 1 ratios indicate a beta 2-selectivity for the tested drugs. Cyclopropyl, dicyclopropyl, cyclopentyl and cyclohexyl derivatives displayed a potent binding to ciliary processes beta 2-adrenoceptors and lowered the IOP about -18%. These compounds induced a lowering in IOP equal to that produced by timolol and appear to be effective and safe beta-adrenergic antagonists in open-angle glaucoma therapy. Decreasing the size of the alkyl group of the oxime, removing the oxime function or modifying the beta-hydroxyl group from the side chain led to a significant decrease in beta 2-adrenoceptor binding and induced weak hypotensive ocular activity. Since the tested alkyliminoxypropanolamine series has very similar physicochemical characteristics and therefore, ruled out the differences in their ability to reach, through the cornea, the targeted ciliary processes, it was demonstrated that contrary to generally held views, the action of the new beta-antagonist series on IOP is related to their ability to antagonize ocular beta 2-adrenoceptors.

Animals↗
PubMed1988

Effects of amiloride and its analogues on [3H]batrachotoxinin-A 20-alpha benzoate binding, [3H]tetracaine binding and 22Na influx.

The ability of amiloride and its analogues to inhibit [3H]batrachotoxinin-A 20-alpha benzoate [( 3H]BTX-B) and [3H]tetracaine binding to rat synaptosomes and to a rat heart membrane preparation was tested. Their ability to inhibit 22Na influx was determined with rat synaptosomes. 5-N-substituted analogues were generally more potent in inhibiting [3H]BTX-B and [3H]tetracaine binding than compounds substituted on the guanidine group. However, the inhibition was not competitive. Amiloride and some of its analogues were as active or more active in inhibiting [3H]tetracaine binding than they were in inhibiting [3H]BTX-B binding. 22Na influx was inhibited with the same relative potencies as [3H]BTX-B binding and a good correlation was found between the two inhibitions. These results show an effect of amiloride and its analogues on the voltage-sensitive Na+ channels, which could partly explain the inotropic effects of these drugs.

Amiloride↗
PubMed1988

Inhibitory effects of some cyclohexylaralkylamines related to perhexiline on sodium influx, binding of [3H]batrachotoxinin A 20-alpha-benzoate and [3H]nitrendipine and on guinea pig left atria contractions.

The antagonist activities of some cyclohexylaralkylamines derived from perhexiline on the fast Na+ channel and slow Ca2+ channel in rat brain and rat heart were examined and compared to the antagonist activities of nifedipine, verapamil, prenylamine and perhexiline. Prenylamine, perhexiline and the cyclohexylaralkylamine derivatives inhibited the [3H]batrachotoxinin A 20-alpha-benzoate binding more than the [3H]nitrendipine binding in rat brain. The nature of the interaction of the cyclohexylaralkylamines with the binding of [3H]batrachotoxinin and [3H]nitrendipine was non-competitive. The synaptosomal 22Na uptake induced by protoveratrine B, a Na+ channel agonist, was also inhibited. Prenylamine, perhexiline and perhexiline derivatives were more potent on the fast Na+ channel than on the Ca2+ channel in contrast to nifedipine and verapamil. The inhibition of Na+ and Ca2+ channels was also shown in guinea pig left atria. Perhexiline, prenylamine and the perhexiline derivatives inhibited the protoveratrine B-induced contraction more than they inhibited that induced by CaCl2, in contrast with nifedipine and verapamil. Our results showed that prenylamine, perhexiline and its related cyclohexylaralkylamines inhibited the fast Na+ channel far more than the slow Ca2+ channel in rat brain, rat heart and guinea pig atria.

Animals↗
PubMed1988

Soft drug derivatives related to perhexiline. Part I: In vitro studies.

A series of cyclohexylaralkylamines derived from perhexiline was synthesized according to the "soft drug" concept. An amide function was introduced as a labile centre to give non-toxic moieties in vivo after the "soft drugs" had attained their therapeutic aims. Compounds were evaluated for their alpha-adrenolytic, calcium antagonist and vasodilator activities in vitro. Some of them, 2, 3, 7 and 15 on rat aorta had alpha-adrenolytic effects comparable to that of perhexiline. Most of them were about 10 times more active calcium antagonists on depolarized pig coronary artery than perhexiline. All derivatives produced concentration-related coronary dilation in the perfused guinea pig heart. Compound 2 was equipotent to perhexiline. The decrease in coronary resistance might, at least partly, be attributable to the alpha-blocking properties of the molecules. In conclusion, the introduction of an amide function into the perhexiline skeleton does not markedly alter the in vitro pharmacological properties.

Adrenergic alpha-Antagonists↗
PubMed1988

Soft drug derivatives related to perhexiline. Part II: In vivo studies.

A series of cyclohexylaralkylamines derived from perhexiline and synthesized according to the "soft drug" concept were evaluated for haemodynamic effects and myocardial oxygen consumption in vivo. In anaesthetized rabbits, the most active compounds, 2, 5, and 11 decreased arterial blood pressure, to a greater extent dp/dtmax and, to a lesser extent heart rate. The decrease in cardiac work and the decrease in cardiac output varied concomitantly. The cardiac effort index decreased in all cases to a greater degree than with perhexiline. In anaesthetized open-chest dogs, the potential antianginal properties of compounds 2, 5 and 11 were due to a decrease in cardiac work via a decrease in cardiac output and myocardial oxygen consumption. None of these compounds reduced arterial blood pressure. Compounds 2 and 5 decreased myocardial oxygen consumption more than perhexiline. Compound 5 was the most promising molecule of this series both as regards cardiac work and myocardial oxygen consumption, being active at a lower dose than perhexiline and having a long active span. These studies suggest that compounds 2, 5 and 11 might be beneficial to patients with angina pectoris.

Animals↗
PubMed1987

Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-alpha-benzoate and 3H-tetracaine.

The effects of antianginal drugs, especially arylalkylamines and structurally related derivatives, on 3H-batrachotoxinin-A 20-alpha-benzoate (3H-BTX-B) binding and on 3H-tetracaine binding were studied on rat synaptosomal and heart membrane preparations. The effect of the same drugs on the Na+ influx induced by protoveratrine B was studied on the rat synaptosomal preparation. Antianginal drugs tested inhibited 3H-BTX-B binding in rat synaptosomes, arylalkylamine derivatives being the most potent: IC50 values were 27 nM for flunarizine, 32 nM for prenylamine, 79 nM for cinnarizine. Similarly, these drugs were the most potent when tested in cardiac membrane preparations. All the drugs tested were very weak inhibitors of 3H-tetracaine binding (IC50 ranging from 0.01 mM to more than 1 mM) except for guanabenz, which was more potent (IC50:0.3 microM on the synaptosomal preparation). The various drugs tested inhibited the 22Na+ influx induced by protoveratrine B, with IC50 values ranging from 15 microM (prenylamine) to 110 microM (verapamil), with the exception of nifedipine which had an IC50 of more than 0.1 mM. The inhibition of 22Na+ influx correlated well with the inhibition of 3H-BTX-B binding. These findings suggest that some antianginal drugs, especially the arylalkylamines may have, in addition to their calcium antagonist activity, direct effects on sodium channels.

Angina Pectoris↗
PubMed1987

A novel positive inotropic series. 1st communication: in vitro studies of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolone derivatives.

A series of 3-, 4-, 5-, 6-, 7- and 8-pyridyl-2(1H)-quinolones and related compounds were evaluated for positive inotropic and vasodilatory activities in vitro. Most of them produced dose-related increases in myocardial contractility on guinea pig isolated atria and perfused heart. In guinea pig atria, the 6-pyridyl molecules were more active than the 5-pyridyl ones; the mean ED50 of compounds 14, 32 and 33 was 4.0 x 10(-7) mol/l i.e. 33 times that of sulmazole; that of compounds 6 and 7 was 2.0 x 10(-5) mol/l. The potencies of the 5- and the 6-pyridyl series also differed by 2 log units on perfused guinea pig heart. The 5- and 6-pyridyl series induced relaxation in precontracted pig coronary artery and coronary vasodilation on perfused guinea pig heart. Compounds 14, 32 and 33 also showed alpha-adrenolytic properties, which were by 0.7 log unit lower than that of phentolamine. These results indicate that this novel cardiotonic series exert positive inotropic and coronary vasodilatory effects.

Animals↗
PubMed1987

A novel positive inotropic series. 2nd communication: in vivo studies of 5- and 6-pyridyl-2(1H)-quinolone derivatives.

In the anaesthetized rabbits and dogs, the 6-pyridyl compounds 14, 32 and 33 (0.1-3 mg/kg) and the 5-pyridyl compounds 6 and 7 (1-10 mg/kg), administered i.v., produced dose-related increases in cardiac contractile force lasting more than 30 min. They also produced relatively minor and shorter-lasting increases in heart rate. Only the 6-pyridyl series decreased blood pressure. The effects were not blocked by propranolol. In the normal haemodynamic states, myocardial oxygen consumption did not increase. When the haemodynamic characteristics of heart failure were produced by propranolol in anaesthetized rabbits and dogs, compounds 14, 32 and 33 reversed these effects, increasing in particular cardiac output. These studies suggest that compounds of the 6-pyridyl series might be beneficial in patients with congestive heart failure.

Anesthesia↗
PubMed1986

Delayed up-regulation of alpha-adrenoceptor populations in particular regions of the rat brain after stimulation of the nucleus locus coeruleus.

We previously showed that electrical stimulation of the nucleus locus coeruleus resulted 4 weeks later in greatly improved performance in the acquisition and extinction of a food-reinforced operant task. To ascertain whether adrenergic receptors of particular brain regions were involved in this long term behavioral modification, we studied the characteristics of alpha 1, and alpha 2 and beta-binding sites after stimulation of the locus coeruleus. In the first experiment these characteristics were studied, 4 weeks after treatment, in cortex, hippocampus, hypothalamus and the brainstem. Neither the number, nor the affinity of beta-receptors ([125I]iodocyanopindolol binding sites) was modified in any brain region. A significant increase in the number of alpha 1-receptors ([3H]prazosin binding sites) was observed in the cortex (62%). The number of alpha 2-receptors, ([3H]yohimbine binding sites), was significantly increased in cortex (99%), hippocampus (33%) and hypothalamus (113%). No significant alteration of the alpha 1, alpha 2 and beta-adrenoceptors was observed in the brainstem. To investigate the time course of these adrenoceptor changes, the characteristics of alpha 1, alpha 2 and beta-adrenoceptors were studied 2 weeks after stimulation using the same ligands and in the same brain regions. The only significant modifications observed were an increase of the alpha 2-adrenoceptors in the cortex (19.4%) and in the hypothalamus (54%). Furthermore, in both experiments, the increase in the number of alpha 1 and alpha 2-receptors was associated with a significant decrease in affinity. These results are discussed in relation to our previous behavioral and pharmacological findings.

Animals↗
PubMed1986

Anti-anginal arylalkylamines and sodium channels: [3H]-batrachotoxinin-A 20-alpha-benzoate and [3H]-tetracaine binding.

[3H]-batrachotoxinin-A 20-alpha-benzoate ([3H]-BTX-B) and [3H]-tetracaine are useful ligands for the study of sodium channels. Inhibition of their binding by various anti-anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation. Diphenylalkylamines and structurally related drugs inhibited [3H]-BTX-B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]-tetracaine binding. These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.

Angina Pectoris↗