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Biomedical subjects

P Bousquet

Publications and source records attributed to P Bousquet.

At least 19 recordsLinked to original sources
PubMed1996

Polyclonal anti-idiotypic antibodies to idazoxan and their interaction with human brain imidazoline binding sites.

Polyclonal antibodies were raised in rabbits against purified polyclonal anti-idazoxan antibodies. The anti-idiotypic antibodies thus obtained, proved able to inhibit [3H]idazoxan specific binding to anti-idazoxan antibodies. Applied to human nucleus reticularis lateralis membrane preparations, these antibodies (20 micrograms) inhibited about 50 and 70% of the imidazoline specific binding of [3H]idazoxan and [3H]clonidine, respectively. Furthermore, they specifically immunoprecipitated 50% of [3H]idazoxan binding activity of imidazoline binding sites solubilized from the same tissue. [3H]Rauwolscine binding to alpha 2-adrenoceptors in rat cortex was not significantly affected by these antibodies. The antibodies labeled a 43 kDa protein in Western blots of partially purified imidazoline binding sites from human brain. In conclusion, these anti-idiotypic antibodies recognize imidazoline binding sites from human brain and allow the detection of a 43 kDa binding protein associated with or representing the imidazoline receptor expressed in human brain.

Adrenergic alpha-Agonists↗
PubMed1996

MK-801 and memantine inhibit a centrally induced increase in myocardial oxygen demand in rabbits.

Electrical stimulation of the paraventricular nucleus of the hypothalamus in the anaesthetized rabbit induces an increase in indexes of myocardial oxygen demand. This increase in myocardial oxygen demand is due to the activation of sympathetic pathways which include glutamatergic relays. In this model, systemic injection of dizolcipine (MK-801) and memantine inhibited these responses. Because these drugs have only one pharmacological property in common i.e. blockade of the NMDA receptor channel complex, these results fit with our previous results concerning the possible involvement of NMDA receptors in the central control of sympathetic activation. Memantine appears to be an interesting prototype for centrally acting cardioprotective drugs devoid of serious side effects.

Animals↗
PubMed1996

Inhibition of centrally induced ventricular arrhythmias by rilmenidine and idazoxan in rabbits.

In a model of ventricular arrhythmias of central origin, we investigated the effects of rilmenidine, an oxazoline with antihypertensive properties, and idazoxan, an imidazoline that is an antagonist of the hypotensive effects of rilmenidine. Bicuculline, a GABAA receptor antagonist, was administered intracisternally (i.c.) to produce arrhythmias in pentobarbitone anaesthetised rabbits; 10 micrograms/kg bicuculline i.c. induced polymorphic ventricular ectopic beats and ventricular tachycardia while blood pressure increased by about 50-60% and sinusal heart rate decreased by about 20%. Rilmenidine, either administered intravenously (0.01, 0.1, 1 mg/kg i.v.) or i.c. (3, 10, 30 micrograms/kg) dose-dependently prevented the occurrence of bicuculline-induced arrhythmias while, because of a lower base-line, the blood pressure values reached were less as compared to controls. Idazoxan administered i.v. (3, 10 mg/kg) had a similar action. Idazoxan i.c. (15 micrograms/kg) had no significant antiarrhythmic effect but antagonized in part the haemodynamic and antiarrhythmic effects of rilmenidine (1 mg/kg i.v.; 30 micrograms/kg i.c.). It is suggested that the antiarrhythmic effects observed with rilmenidine are mainly mediated by blunting the bicuculline-induced increase in the sympathetic nervous output to the heart and the vascular beds. These effects of rilmenidine are likely to originate both from the central and peripheral nervous system. The antiarrhythmic effects of idazoxan i.v. might be related to a blocking action on alpha 2-adrenoceptors at the level of the coronary arteries and other vascular beds.

Adrenergic alpha-Antagonists↗
PubMed1996

Comparative effects of idazoxan, prazosin, and yohimbine on coronary ligation-induced arrhythmias in spontaneously hypertensive rats.

We investigated whether certain drugs with alpha-adrenergic antagonist activity display anti-arrhythmic effects in hypertensive animals subjected to acute coronary artery ligation. The left anterior descending coronary artery (LAD) was ligated in open-chest pentobarbital-anesthetized spontaneously hypertensive rats (SHR); arrhythmias were subsequently recorded for 30 min. Drugs were administered intravenously, (i.v.) 5 min before ligation. The effects of yohimbine and idazoxan were compared with those of prazosin. Prazosin (100 mu g/kg) increased the occurrence of ventricular tachycardia (VT). In contrast, yohimbine 1.6 mg/kg decreased both the occurrence and the duration of VT and the occurrence and the duration of ventricular fibrillation, (VF). The results obtained with idazoxan 1 mg/kg were similar to those with yohimbine. The ECG alterations induced by coronary artery ligation in rats treated with yohimbine and idazoxan were more pronounced than in controls and in rats treated with prazosin, suggesting that the antiarrhythmic effects observed were not mediated by antiischemic activity. The protective effects against ligation-induced arrhythmias were preceded by a hypotensive effect and a decrease in the rate-pressure product in yohimbine-treated but not in idazoxan-treated animals. In rats treated with prazosin, more arrhythmic events were observed, although hemodynamics were similar to those in rats treated with yohimbine. Our results suggest that the yohimbine-induced antiarrhythmic action is not due to an alteration of conduction or repolarization rates. In this model, yohimbine and idazoxan appear to protect against ligation-induced arrhythmias. These data suggest that drugs with alpha-adrenergic properties might influence the nervous drive to the heart in SHR with cardiac ischemia. However, further investigations are needed to ascertain whether the alpha-adrenoceptor blockade participates in this effect.

Adrenergic alpha-Antagonists↗
PubMed1996

GABAergic and glutaminergic modulation of centrally evoked arrhythmias in rats.

A standard electrical stimulus applied to the posterior hypothalamus evoked cardiac arrhythmogenic responses in the spontaneously hypertensive rat. Isolated premature ventricular beats or doublets and nonsustained ventricular tachycardic salvos were observed. This effect was associated with a large rise in blood pressure (79 +/- 3 mm Hg). The same stimulus in normotensive Wistar-Kyoto rats produced no significant cardiac arrhythmias, and the rise in blood pressure was smaller (36 +/- 2 mm Hg). We investigated the influence of baclofen, a GABAB receptor agonist, and two N-methyl-D-aspartate receptor antagonists on the arrhythmogenic response to hypothalamic stimulation. Intravenous baclofen (3 mg/kg) had no effect in the normotensive Wistar-Kyoto rats, but in the spontaneously hypertensive rats it enhanced the adjusted mean value of the number of extrasystoles from 0.5 +/- 0.5 to 18 +/- 1 (P < .001). This value was also increased (from 3 +/- 1 to 17 +/- 1, P < .001) by an intracisternal injection of baclofen (1 micrograms/kg). This facilitatory effect of baclofen was prevented by treatment with atenolol (0.5 mg/kg). Two glutamate receptor antagonists, ketamine (7.5 mg/kg IV) and kynurenic acid (200 micrograms/kg intracerebroventricularly), prevented both the arrhythmogenic response to the hypothalamic stimulation and its facilitation by baclofen. The study confirms that hypothalamic stimulation facilitates the development of arrhythmias through a sympathetic drive and that these arrhythmias are easier to induce in spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. Both the central GABAergic and the glutamatergic systems are implicated in the development of these ventricular arrhythmias, since baclofen could disinhibit the glutamatergic central pathway. These results could account for the ability of the spontaneously hypertensive rats to develop ventricular arrhythmias of central origin.

Animals↗
PubMed1995

Evidence for a spinal origin of the effect of baclofen on the myocardial oxygen demand indexes.

In a previous study in anaesthetized rabbits we observed that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) elicited substantial rises in the maximum rate of change of left ventricular pressure (dP/dtmax) and in myocardial oxygen demand indexes (rate-pressure product and triple product), similar to the changes observed during stress or physical effort. Baclofen, a selective GABA(B) receptor agonist, injected intravenously prevented these responses. In the present study, we show that low doses of baclofen (0.1, 0.3 and 1 microgram/kg), injected intrathecally (i.t.) at the T9 level, reduced the myocardial oxygen demand during PVN stimulation. After 0.3 microgram/kg baclofen i.t., the peak value of the triple product during stimulation was 140 +/- 20 compared with 193 +/- 20 before treatment. An i.t. injection (500 micrograms/kg), of saclofen a selective GABA(B) receptor antagonist, did not modify the resting haemodynamics significantly but attenuated the inhibitory effects of baclofen (3 mg/kg i.v.). These results suggest that the main site of the effects of baclofen is located within the spinal cord and that GABA(B) receptors probably mediate these effects by modulating the central control of cardiac function. In conclusion, baclofen might be a useful tool to prevent the centrally evoked increases of myocardial oxygen demand.

Animals↗
PubMed1995

Dupuytren's disease, carpal tunnel syndrome, trigger finger, and diabetes mellitus.

A comparative prospective study of 120 adult diabetics (60 insulin dependent, 60 non-insulin dependent) and 120 non-diabetic adults as controls showed significantly higher incidence of Dupuytren's disease, limited joint motion, carpal tunnel syndrome, and flexor tenosynovitis in the diabetic population. Of the diabetic patients one third had a mild non-progressive form of Dupuytren's disease, which commonly involved the long and ring rays. Limited joint motion was noted in a third of diabetics, and carpal tunnel syndrome was observed in 15-25%, and flexor tenosynovitis in about a fifth. Limited joint motion co-existed with Dupuytren's disease in 57% of insulin-dependent diabetics. Diabetic polyneuropathy was found in two thirds of insulin-dependent diabetics and in one third of non-insulin dependent diabetics. All these hand changes were more marked in insulin-dependent diabetics and they showed a positive correlation with increasing age of the patient, duration of the diabetes, and the presence of a microangiopathy.

Adult↗
PubMed1995

Inhibition of the centrally induced increases in myocardial oxygen demand in rabbits by chronic treatment with baclofen, a selective GABAB agonist.

1. A previous study from our group demonstrated that neurones of the paraventricular nucleus of the hypothalamus (PVN) are selectively involved in the central control of the cardiac function. Moreover, in that study, it was shown that baclofen, a selective GABAB receptor agonist, is capable of modulating the increases in myocardial contractility and oxygen demand evoked by electrical or pharmacological stimulation of the PVN. Nevertheless, the acute administration of this compound was frequently accompanied by a cardiodepressant effect. 2. In the present study, the effects of a long term treatment (14 days) with baclofen (3 or 10 mg kg-1, i.p.) have been examined on the excitatory haemodynamic responses evoked by central pharmacological stimulation in anaesthetized rabbits. 3. The i.c.v. injection of L-glutamate (3 mg kg-1) induced marked increases in dP/dtmax (32%), mean arterial pressure (39%) and on two indices of myocardial oxygen consumption: the rate-pressure product (34%) and the triple product (78%). 4. Baclofen blunted the positive inotropic response and the increases in myocardial oxygen consumption induced by L-glutamate in a dose-related manner. The higher dose of baclofen (10 mg kg-1, i.p.), reduced by more than 50% these excitatory effects of L-glutamate without eliciting any significant negative effect on basal haemodynamics. The same doses of baclofen were not able to blunt the hypertensive response induced by central stimulation. 5. These results confirm and extend our previous findings suggesting that it is possible to discriminate the central control of vasomotor tone from that of cardiac function and also that baclofen can modulate the latter. It is concluded that when given chronically, baclofen modulates the increases in myocardial oxygen demand induced by activation of the central nervous system in doses which do not depress the resting cardiac function.

Animals↗
PubMed1995

[Supra-tentorial low-grade astrocytomas in adults. Prognostic factors and therapeutic indications. Apropos of a series of 141 patients].

An abundant literature provides informations upon the prognosis of supratentorial low grade (grade II) astrocytomas, but the series are quite heterogeneous in terms of clinical material, neuropathological evaluation and statistical methods of analysis. So, outcome, prognostic factors and therapeutical indications are poorly defined. A retrospective study of 141 adults patients suffering ordinary low grade astrocytoma diagnosed in our unit between 1978 and 1988 was conducted. A follow up of 5 years or more, since neuropathological diagnosis, was mandatory for inclusion. Endpoint of statistical analysis was duration of survival. Results were expressed after uni and multivariates analysis. Clinical and morphological features of our series were comparable to those previously reported in the literature. Median survival time was 52 months. Considering age at diagnosis, survival curve analysis showed highly significant differences (p < 0.0001) and established three prognostic classes of age (before 50, between 50 and 60, and after 60 years of age). Comparisons of survival curves showed significant statistical differences (p < 0.0001) according to pretreatment functional status. Analysis of a clinical condition using a functional scale is more powerful, from a statistical point of view, than an individual analysis of each constituting parameters. In this series a good correlation was found between functional status and age at diagnosis. Neurological deficit was more correlated to age than to tumor location. Multivariate analysis, using the Cox model, defined some parameters acting independently on duration of survival: fronto-parietal location (p < 0.0001), pretherapeutical functional status (p < 0.001), age at diagnosis (p = 0.001), deepseated or multicentric tumor, mass effect (p < 0.01), frontal location (p < 0.02), total surgical removal (p < 0.05). Non significant parameters were: radiotherapy, time before diagnosis, age of onset, sex, contrast enhancement on CT scan. Our results are in agreement with previously reported data confirmed literature data concerning prognostic factors characteristics of the host (age), characteristics of the tumor (location) and expressing the influence of the tumor on the host (functional status). Our series documented prognostic clinical forms of these tumors (function of age, of performance status, and of tumor location). Our results confirm the relative inefficacy of therapeutic weapons, considering the population as a whole, on duration of survival. Based on our results and on recently published data, a decision tree analysis was proposed for management of grade II astrocytomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Imidazoline receptors: from basic concepts to recent developments.

The existence is now fully demonstrated of binding sites specifically recognizing the imidazoline structure or similar chemical structures, both in the brain and in certain peripheral tissues, including the kidney, some of which participate in the control of blood pressure. These binding sites are different from alpha 2-adrenoceptors, both functionally and biochemically. The fact that at least medullary binding sites are associated with a precise function, i.e., modulation of sympathetic activity of central origin and therefore the regulation of vasomotor tone, indicates that they are true receptors. These imidazoline receptors of the ventrolateral region of the medulla play an important role in the mechanism of the hypotensive action of substances such as clonidine or rilmenidinc. Confirmation of dual pharmacological mechanisms involved in the hypotensive and sedative effects, respectively, of these drugs has justified attribution of the hypotensive effect to involvement of imidazoline receptors in the region of the medulla mentioned and the sedative effect to activation of classic alpha 2-adrenoceptors of the locus ceruleus. This distinction between to mechanisms opens up a novel approach to the development of new centrally acting antihypertensive substances free of the troublesome adverse effects of the first generation. Many questions remain unanswered, including the precise nature of the endogenous ligand(s) of imidazoline receptors, the structure of the receptor and its mechanisms of coupling to second messenger, the possible existence of variants of these receptors, their mode of interaction with alpha-adrenoceptors, and identification of true subtypes of these imidazoline receptors.

Animals↗
PubMed1994

Heterogeneity of imidazoline binding sites revealed by a cirazoline derivative.

The affinity of AMPI (2-[3-aminophenoxy]methyl imidazoline) for [3H]clonidine and [3H]idazoxan imidazoline binding sites was determined in various rabbit and human tissues. Although cirazoline showed a high affinity (nM range) in all the tested tissues, its derivative, AMPI, had a high affinity (nM range) in rabbit brain and kidney but a low affinity (microM range) in the human brain. These differences in affinities were very similar to those obtained with amiloride. The same results were obtained when considering [3H]clonidine or [3H]idazoxan specific imidazoline binding sites.

Animals↗
PubMed1994

Role of imidazoline receptors in cardiovascular regulation.

The involvement of nonadrenergic imidazoline specific receptors in the central control of the vasomotor tone and in the mechanism of action of drugs bearing an imidazoline structure, or analogs, is now well documented. Imidazoline-specific binding sites were found in many tissues and species. Moreover, until now, it is only in the brainstem that such binding sites are associated with a function: the hypotensive effect of imidazoline-like drugs. Rilmenidine, which is an oxazoline structurally related to the reference imidazolines, exerts a central hypotensive effect of central origin involving imidazoline receptors. The selectivity of rilmenidine for the imidazoline receptors compared to alpha 2-adrenergic receptors could explain the low incidence of sedative side effects observed with this antihypertensive drug. A specific anti-imidazoline radioimmunoassay allowed us to detect the presence of an immunoreactive imidazoline-like substance in human sera. High levels of this immunoreactive substance are associated with high blood pressure in 20-30% of the hypertensive patients. This observation indicates that high levels of this immunoreactive substance in the serum can be associated with some kinds of primary hypertension. The cause-and-effect relation between these 2 phenomena has not yet been determined. This substance is in process of purification; it could be a candidate to be an endogenous ligand of the imidazoline receptors.

Animals↗
PubMed1994

Isolation of a human cerebral imidazoline-specific binding protein.

The first isolation of a human brain specific imidazoline binding protein is described. This protein was obtained using affinity chromatography and was revealed with the aid of an anti-idiotypic antibody specific for imidazoline binding sites. The protein (43 kDa) differs from other imidazoline binding proteins previously isolated from peripheral tissues, in particular by being also sensitive to clonidine.

Antibodies, Anti-Idiotypic↗