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Biomedical subjects

J M Senard

Publications and source records attributed to J M Senard.

At least 109 records · Page 6Linked to original sources
PubMed1990

Adrenergic supersensitivity in parkinsonians with orthostatic hypotension.

The adrenergic status was studied through evaluation of platelet alpha 2-adrenoceptor number [( 3H]yohimbine binding sites), plasma catecholamine levels and blood pressure response to noradrenaline infusion in three groups of subjects (1) Parkinsonians with orthostatic hypotension; (2) Parkinsonians without orthostatic hypotension; and (3) control subjects. In Parkinsonians with orthostatic hypotension, systolic and diastolic blood pressures significantly (P less than 0.05) decreased from 144 +/- 9 and 76 +/- 6 mmHg in the lying position to 95 +/- 12 and 60 +/- 7 mmHg after 5 min standing. In these patients, noradrenaline plasma levels were significantly low (62 +/- 11 pg ml-1, (P less than 0.05) when compared with controls (219 +/- 13 pg ml-1) whereas no difference was noticed in Parkinsonians without orthostatic hypotension (195 +/- 14 pg ml-1). The noradrenaline dose required for a 25 mmHg increase in systolic blood pressure was significantly (P less than 0.01) lower in Parkinsonians with orthostatic hypotension (0.19 +/- 0.03 microgram kg-1) when compared with Parkinsonians without orthostatic hypotension (0.86 +/- 0.11 microgram kg-1) or with controls (0.68 +/- 0.1 microgram kg-1). Platelet alpha 2-adrenoceptor number was higher in Parkinsonians with orthostatic hypotension (313 +/- 52 fmol mg-1 protein) than in Parkinsonians without orthostatic hypotension (168 +/- 9 fmol mg-1 protein) or in controls (175 +/- 4 fmol mg-1 protein) with no change in Kd. This study demonstrates that in patients with Parkinson's disease, orthostatic hypotension is associated with an increase in both vascular sensitivity to noradrenaline and platelet alpha 2-adrenoceptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Reserpine induces vascular alpha 2-adrenergic supersensitivity and platelet alpha 2-adrenoceptor up-regulation in dog.

1. The aim of the present study was to investigate the influence of catecholamine levels on the regulation of alpha 2-adrenoceptor sensitivity in dogs. 2. Blood pressure and heart rate values at rest, plasma catecholamine levels, platelet and adipocyte alpha 2-adrenoceptors as well as the alpha 2-mediated cardiovascular responses to clonidine (10 micrograms kg-1 i.v., after alpha 1-, beta-adrenoceptor plus muscarinic blockade) or noradrenaline (0.5, 1, 2 and 4 micrograms kg-1 i.v. after alpha 1- and beta-adrenoceptor blockade) were measured before and after reserpine treatment (0.1 mg kg-1 day-1 s.c. over 15 days). 3. Reserpine induced a significant decrease in resting systolic and diastolic blood pressures (213 +/- 2/87 +/- 6 mmHg before vs 158 +/- 5/59 +/- 3 mmHg after treatment) as well as in heart rate (91 +/- 2 beats min-1 before vs 76 +/- 3 beats min-1 after treatment). 4. A 5 min tilt test performed under chloralose anesthesia, failed to modify blood pressure before treatment whereas it induced a significant fall in the same animals after the 15 day treatment. Plasma levels of noradrenaline significantly decreased (262 +/- 58 vs 66 +/- 31 pg ml-1) whereas plasma adrenaline levels were unchanged. 5. The alpha 2-mediated pressor responses to noradrenaline were significantly increased after reserpine. Clonidine induced a marked pressor effect (+72 and +45% in systolic and diastolic blood pressures respectively) after reserpine treatment. This effect was suppressed by administration of RX-821002, a new specific alpha 2-adrenoceptor antagonist. 6. Reserpine treatment significantly increased platelet alpha 2-adrenoceptor number (identified with [3H]- yohimbine or [3H]-RX821002) with no change in Kd values. alpha 2-Adrenoceptor number remained unchanged in adipocytes (identified with [3H]-RX821002). 7. These results show that a 15 day treatment with reserpine induces a vascular alpha 2-adrenergic supersensitivity and an up-regulation in platelet alpha 2-adrenoceptors. In contrast, this phenomenon does not involve all the tissues since adipocyte alpha 2-adrenoceptors escape the effect of reserpine. We suggest that the levels of plasma noradrenaline play an important role in the regulation of the platelet and vascular alpha 2-adrenoceptors. In contrast, adipocyte alpha 2-adrenoceptors are not affected by changes in plasma noradrenaline levels.

Adipose Tissue↗
PubMed1990

Identification of human platelet alpha 2-adrenoceptors with a new antagonist [3H]-RX821002, a 2-methoxy derivative of idazoxan.

1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1990

Decreased high affinity state in platelet alpha 2-adrenoceptors from diabetic patients with orthostatic hypotension.

Plasma catecholamine levels, total platelet alpha 2-adrenoceptor number and affinity state (using [3H]yohimbine binding) were investigated in insulin-dependent diabetic patients with (n = 12) or without (n = 10) orthostatic hypotension due to autonomic neuropathy as well as in normal control subjects (n = 6). Mean resting basal catecholamine values were similar in the three groups. One-minute standing elicited an increase in norepinephrine plasma level (but not in epinephrine plasma levels) in control group but not in diabetic patients (with or without orthostatic hypotension). The maximal number of platelet alpha 2-adrenoceptors (and KD) calculated by [3H]yohimbine saturation experiments was similar in the three groups. The percentage of platelet alpha 2-adrenoceptors in high affinity state (inhibition experiments of [3H]yohimbine by UK14,304, a specific alpha 2-adrenergic full agonist) was significantly lower in diabetic patients with orthostatic hypotension (29.2 +/- 5.3%) than in the other two groups. No significant difference was found between the control group (60.0 +/- 2.0%) and diabetic patients without orthostatic hypotension (64.3 +/- 3.1%). Since platelet alpha 2-adrenoceptors are thought to be a suitable index of vascular alpha-adrenoceptors, the decrease in platelet alpha 2-adrenoceptors in high affinity state could explain the occurrence of orthostatic hypotension in insulin-dependent diabetic patients. Multiple pathophysiological mechanisms underly orthostatic hypotension in insulin-dependent diabetic patients and include anomalies both in the sympathetic nervous system and in alpha 2-adrenoceptor coupling.

Adrenergic alpha-Agonists↗
PubMed1990

Blood pressure and plasma catecholamines in never-treated parkinsonian patients: effect of a selective D1 agonist (CY 208-243).

We found blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), and epinephrine (E) levels in the lying and the standing positions to be similar in never-treated parkinsonian patients (stages 1 and 2) and age-matched controls. CY 208-243, a new centrally active D1 agonist, significantly decreased BP, HR, and NE (but not E) values in the lying position; it elicited orthostatic hypotension and blunted the rise in NE elicited by standing up. These results indicate that the early stages of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and suggest the involvement of central D1-receptors in the control of sympathetic tone.

Antiparkinson Agents↗
PubMed1990

[Platelet alpha 2 adrenergic receptors, plasma catecholamines and orthostatic hypotension in insulin-dependent diabetic patients].

Plasma catecholamine levels, total platelet alpha 2-adrenoceptor number and affinity state (using [3H]-yohimbine binding) have been investigated in insulin-dependent diabetic patients with (n = 12) or without (n = 10) orthostatic hypotension as well as in normal control subjects (n = 6). Mean resting basal catecholamine values were similar in the three groups. One min standing elicited an increase in norepinephrine plasma level (but not in epinephrine plasma levels) in control group but not in diabetic patients (with or without orthostatic hypotension). The maximal number of platelet alpha 2-adrenoceptors (and Kd) calculated by [3H]-yohimbine saturation experiments was similar in the three groups. The percentage of platelet alpha 2-adrenoceptors in high affinity state determined by inhibition experiments of [3H]-yohimbine binding by UK14,304 (a specific alpha 2-adrenergic full agonist) was significantly lower in diabetic patients with orthostatic hypotension (29.2 +/- 5.3%) than in the other two groups. No significant difference was found between the control group (60.0 +/- 2.0%) and diabetic patients without orthostatic hypotension (64.3 +/- 3.1%). These results indicate that orthostatic hypotension in insulin-dependent diabetic patients is marked by a lack of noradrenaline increase in standing position and by a decrease in platelet alpha 2-adrenoceptors in high affinity state. Thus we suggest that orthostatic hypotension of diabetes mellitus is the result of sympathetic nerves injuries and of abnormalities in alpha 2-adrenoceptors coupling.

Autonomic Nervous System Diseases↗
PubMed1989

[Neurogenic arterial hypertension in humans].

The purpose of this study was to investigate baroreflex activity in hypertensive patients with orthostatic hypotension (OH) due to sinoaortic baroreceptor denervation. The study concerned 3 patients (pts), 58-63 years, mean age 60.6 +/- 2 with both arterial hypertension (paroxysms recorded at 250/130 mmHg) and OH. They received radiation therapy to the entire cervical area for neoplasm, 9.6 +/- 2.8 years ago and had a carotid murmur without significant stenosis. Every pt had a severe and symptomatic OH: blood pressure (BP) and heart rate (HR) were respectively 163 +/- 17/105 +/- 7, 82 +/- 5 b/mn in lying position and 82 +/- 16/53 +/- 9 mmHg, 99 +/- 1 b/mm in standing position. The standing-induced increase in HR was lower (delta HR = + 17.3 b/mn) than expected; atropine (0.02 mg/kg) infusion and cold pressor test were ineffective; the massage of sinocarotid receptors induced a slight decrease in HR (delta HR = - 8 b/mn) and BP was not modified by Valsalva's maneuver. Infusion of norepinephrine (0.016 mg/mn) performed in one pt, increased BP without effect on HR. Platelet alpha 2-adrenoreceptors (alpha 2AR) evaluated by (3H) Yohimbine binding showed a significant increase in alpha 2AR number (Bmax), without any significant change in affinity (KD) when compared with normotensive and essential hypertensive pts: (table; see text) This study described an unusual etiology of a paroxysmal hypertension with orthostatic hypotension, demonstrated the impairment of baroreflex activity and suggested the potential interest of platelet alpha 2 adrenoceptors measurement to evaluate sympathetic tone in these patients.

Blood Pressure↗
PubMed1989

[Alpha 2-adrenergic receptors and arterial pressure].

The aim of this work was to investigate the influence of blood pressure levels on human platelet alpha 2-adrenergic receptivity. The study was carried out on 12 mild essential hypertensive patients and 7 normotensive parkinsonians with orthostatic hypotension. Alpha 2-adrenoceptors number and affinity were determined by 3H-yohimbine binding, plasma catecholamines were measured by HPLC and adrenaline-induced platelet aggregation by turbidimetry. Results obtained were compared with those of two groups of 12 normotensive control subjects. In hypertensive patients, both platelet alpha 2-adrenoceptors (139 +/- 6 vs 176 +/- 18 fmol/mg protein) and velocity of adrenaline-induced platelet aggregation were decreased whereas plasma adrenaline and noradrenaline remained unchanged. In patients with orthostatic hypotension, there was an increased number of platelet alpha 2-adrenoceptors (313 +/- 52 vs 168 +/- 8 fmol/mg protein) associated with a significant decrease in plasma noradrenaline (62 +/- 11 vs 190 +/- 25 pg/ml). In none of the two groups of patients there was any change in receptor affinity for 3H-yohimbine. These results indicate that human platelet alpha 2-adrenoceptors levels are related to blood pressure values. Moreover, up-regulation in orthostatic hypotension and lack of down-regulation in essential hypertension suggest that only sustained abnormal plasma noradrenaline levels could allow the development of alpha 2-adrenoceptors regulatory mechanisms. These variations can represent tentative compensatory mechanisms for normalization of blood pressure levels.

Aged↗
PubMed1989

Interactions of full and partial agonists with HT29 cell alpha 2-adrenoceptor: comparative study of [3H]UK-14,304 and [3H]clonidine binding.

The HT29 cell line expresses alpha 2-adrenoceptors that are negatively coupled to the adenylate cyclase system and is, in this respect, a valuable model for in vitro study of alpha 2-adrenergic receptivity in a tissue from human origin. In these cancerous cells, UK-14,304 is a full agonist of the alpha 2-adrenergic-mediated inhibition of the vasoactive intestinal peptide-induced cyclic AMP accumulation, whereas clonidine acts only as a partial agonist. In the present report, we used [3H]UK-14,304 as radioligand and compared its binding characteristics with those of [3H]clonidine in order to better understand the difference between full and partial agonism on the basis of agonist/receptor interactions. [3H]UK-14,304 labeled with high affinity (KD = 0.39 +/- 0.05 nM) a single class of sites having the pharmacological specificity of an alpha 2-adrenoceptor. Comparison of [3H]UK-14,304, [3H]clonidine, and [3H]yohimbine Bmax proved that both 3H-agonists labeled the same number of sites (172 +/- 14 versus 179 +/- 21 fmol/mg of protein), whereas the 3H-antagonist recognized more sites (246 +/- 22 fmol/mg of protein). Inhibition of [3H]yohimbine by the two agonists was consistent with the existence of an heterogeneous population of receptors and analysis of the data according a two-site inhibition model showed 1) that the KiL/KiH ratio was higher for UK-14,304 than for clonidine and 2) that the percentages of high affinity state receptor recognized by both agonists were identical (56 +/- 4% with UK-14,304 and 59 +/- 5% with clonidine). Kinetics of [3H]UK-14,304 and [3H]clonidine binding indicated more complex agonist-receptor interactions than equilibrium data did. Association as well as dissociation of both radioligands appeared to be biphasic, suggesting a relative heterogeneity of 3H-agonist binding sites. Kinetic behavior of [3H]UK-14,304 only differed from that of [3H]clonidine by a much slower dissociation rate and by its ability to induce the formation of a tightly bound component, which corresponded to the formation of a very stable full agonist/receptor/Gi complex. Effects of guanosine-5'-(imido)-triphosphate and GTP on [3H]UK-14,304 and [3H]clonidine binding also proved that the agonists were not similarly sensitive to guanine nucleotides.

Adrenergic alpha-Agonists↗
PubMed1988

Two weeks of treatment with deprenyl (selegiline) does not prolong L-dopa effect in parkinsonian patients: a double-blind cross-over placebo-controlled trial.

We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefit in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.

Aged↗
PubMed1986

Mesulergine (CU 32-085) in the treatment of Parkinson's disease.

The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.

Adult↗
PubMedDate not supplied

Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study.

A prospective survey was performed to characterize the prevalence of sleep attacks and to evaluate precipitating factors in a group of 236 patients with idiopathic Parkinson's disease. Sleep attacks were reported by 72 patients (30.5%). Multivariate analysis showed a marked association between the occurrence of sudden sleep episodes and first autonomic failure, followed by treatment with ropinirole and bromocriptine. The present work underlines the major contributing role of autonomic failure followed by dopamine agonists in the occurrence of such an event. Because a relationship between sleep attacks and not only ropinirole but also bromocriptine treatment was described, the present work suggests that sleep attacks are a common side effect of all dopamine agonists.

Aged↗
PubMedDate not supplied

Fluoxetine-induced pressor response in freely moving rats: a role for vasopressin and sympathetic tone.

The present study was performed in order to assess, in freely moving rats, the cardiovascular effects of central administration of fluoxetine, a serotonin reuptake inhibitor. Two kinds of experiments were performed: 1) acute central administration of fluoxetine. and 2) chronic intraperitoneal administration of fluoxetine plus selegiline, a monoamine oxidase B inhibitor. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 microg) induced an increase in blood pressure. This fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate. At the dose of 10 microg i.c.v., fluoxetine significantly increased mean blood pressure by 16 +/- 4 mmHg. This pressor response was reduced by an intravenous (i.v.) pretreatment with the alpha1-adrenoceptor antagonist, prazosin (500 microg kg(-1)) (+ 7 +/- 4 mmHg, P <0.05) or with the V1A-vasopressin receptor antagonist (20 microg kg(-1)) (+5 +/- 3 mmHg, P < 0.05). The pressor response was completely abolished by a concomitant pretreatment with prazosin plus the V1A-vasopressin receptor antagonist. Pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg kg(-1) i.v.), or the 5-HT2 receptor antagonist, ketanserine (5 mg kg(-1) i.v.), did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 microg i.c.v.), vasopressin plasma levels were significantly higher (39 +/- 5 pg mL(-1) than in rats receiving 10 microL i.c.v. saline (14 +/- 4 pg mL(-1)). A 30 day intraperitoneal (i.p.) administration of fluoxetine in association with selegiline induced an increase in noradrenaline plasma levels and locomotor activity without any significant change in blood pressure and heart rate. These data suggest that, the pressor response elicited by central acute administration of fluoxetine is mediated by both an increase in sympathetic tone and vasopressin release. This observation could suggest the putative interest of alpha1-adrenoceptor and or V1A-vasopressin receptor antagonists in the treatment of "Serotonin Syndrome".

Analysis of Variance↗
PubMedDate not supplied

L-Dopa-induced sedation: a double-blind cross-over controlled study versus triazolam and placebo in healthy volunteers.

Incidental case reports suggest that some parkinsonian patients treated with dopaminergic drugs complain of drowsiness but few controlled data are available. We compared the sedative effects of L-Dopa (200 mg + 50 mg benserazide, PO), triazolam (0.125 mg) and placebo in a randomized double-blind cross-over design in 22 healthy volunteers pretreated with domperidone (60 mg/day). Drowsiness was assessed using a visual analog scale (VAS), a computerized choice reaction time test (CRT) and an electro-oculogram (EOG). L-Dopa and triazolam induced significant drowsiness, compared to placebo, on VAS, CRT and some EOG parameters. After this first evaluation session, all subjects were chronically treated for 11 days with 600 mg/d of L-Dopa. Drowsiness induced by L-Dopa, triazolam or placebo was then tested again on three consecutive days to assess putative dopaminergic tolerance. After chronic L-Dopa treatment, triazolam-induced sedation remained unchanged while L-Dopa sedative effects were no longer significant except on the VAS, preventing the conclusion that tolerance occurred. These data suggest that an acute dose of L-Dopa induces sedation in L-Dopa-naive subjects. This sedative effect must be considered in clinical practice and when studying the effects of L-Dopa on motor or neuropsychological performance, especially in acute tests.

Adult↗
PubMedDate not supplied

A study of salivary secretion in Parkinson's disease.

Hypersialorrhea is frequently reported in patients with idiopathic Parkinson's Disease (PD). Excessive production of saliva, swallowing difficulties, or both could explain this complaint. Dopamine (DA) has been shown to modulate salivary secretion in a number of vertebrate and invertebrate species. The present study was performed to compare the unstimulated salivary flow in 83 patients with PD (8 untreated and 75 treated with levodopa + DA agonist) and in 65 age- and sex-matched control subjects. The Mann-Whitney U-test showed a significantly lower salivary flow in treated patients with PD (535 +/- 42 mg/2 min) (p < 0.002) and de novo patients (447 +/- 141) (p < 0.03) compared to controls (834 +/- 68 mg/2 min) with no relation with age or sex. Finally, the present study of reduced salivary flow in PD suggests that complaints of hypersialorrhea are not caused by a salivary defect, but could be explained by difficulties in swallowing. The decrease in salivary flow could be explained by autonomic dysfunction in PD.

Adult↗