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Biomedical subjects

J M Senard

Publications and source records attributed to J M Senard.

At least 91 records · Page 5Linked to original sources
PubMed1993

Characterization and distribution of alpha 2-adrenergic receptors in the human intestinal mucosa.

The subtype and the expression of the alpha 2-adrenergic receptor were investigated in the normal mucosa from human intestine by means of radioligand binding, RNase mapping, and measurement of adenylate cyclase activity. The study of the binding of the alpha 2-adrenergic antagonist, [3H]RX821002, to epithelial cell membranes indicated the existence of a single class of noninteracting sites displaying a high affinity for the radioligand (Kd = 1.1 +/- 0.5 nM). The rank order of potency of antagonists to inhibit [3H]RX821002 binding (RX821002 > yohimbine = rauwolscine > phentolamine approximately idazoxan >> chlorpromazine > prazosin) suggested that the receptor is of the alpha 2A subtype. A conclusion which is confirmed by the fact that only alpha 2C10 transcripts were found in the human intestine mucosa. Competition curves with (-)-norepinephrine demonstrated that 60% of the receptor population exhibited high affinity for agonists. This high-affinity state was abolished by the addition of GTP plus Na+ or by prior treatment of the membranes with pertussis toxin indicating it corresponded to G protein-coupled receptors. [32P]ADP-ribosylation and immunoblotting experiments identified two pertussis toxin-sensitive G proteins corresponding to Gi2 and Gi3. The study of the distribution of the receptor indicated that (a) the proximal colon is the intestine segment exhibiting the highest receptor density and (b) the receptor is predominantly expressed in crypts and is preferentially located in the basolateral membrane of the polarized cell. The distribution of the receptor along the crypt-surface axis of the colon mucosa can be correlated with a higher level of alpha 2C10-specific mRNA and a higher efficiency of UK14304 to inhibit adenylate cyclase in crypt cells.

Adenosine Diphosphate Ribose↗
PubMed1993

Current status of dopamine agonists in Parkinson's disease management.

The occurrence of late side effects of long term levodopa therapy (fluctuations in motor performance, abnormal movements, and symptoms unresponsive to dihydroxyphenylalanine) led to the search for novel anti-Parkinsonian drugs. Dopamine agonists are one of the newer families of anti-Parkinsonian agents, and they include ergot derivatives and apomorphine, which can be used in the different stages of Parkinson's disease. Ergot derivatives (bromocriptine, lisuride, pergolide) are believed to act independently of the dying cells of the substantia nigra, acting instead directly on postsynaptic dopamine receptors in the striatum. They are usually used in combination with levodopa when late side effects occur, especially 'wearing-off' or decreased efficacy of levodopa. They can also be prescribed earlier in combination with levodopa in de novo Parkinsonian patients, and in this setting are thought to delay the occurrence of late adverse motor effects. In some patients, monotherapy with relatively high doses of ergot derivatives can be used as initial treatment. However, their efficacy often decreases after 1 to 3 years, thus justifying a late combination with levodopa. Apomorphine is a non-ergot derivative dopamine agonist, which is used subcutaneously for the treatment of severe 'off' refractory periods, in combination with other dopaminergic drugs without changing the patient's routine drug regimen.

Apomorphine↗
PubMed1993

[Ambulatory monitoring of blood pressure in orthostatic hypotension of Parkinson disease].

Ambulatory recordings of blood pressure (BP) and heart rate were performed using a Spacelabs device during day and night periods in parkinsonian patients with (n = 19) or without (n = 19) orthostatic hypotension. In patients with orthostatic hypotension, the average blood pressure during the night (systolic BP: 137 +/- 5 mmHg; diastolic BP: 80 +/- 3 mmHg) was higher (p < 0.05) than during the diurnal period (systolic BP: 121 +/- 3 mmHg; diastolic BP: 76 +/- 2 mmHg). In parkinsonian patients without orthostatic hypotension, a physiological decrease in BP was recorded during the nocturnal period. In patients with orthostatic hypotension, BP variability was higher (p < 0.05) during the day (systolic BP: 14.6 +/- 1.3%, diastolic BP: 16.5 +/- 1.0%) than during the night (systolic BP: 9.1 +/- 0.8%, diastolic BP: 10.8 +/- 1.1%). The blood pressure load (% of BP values above 140/90 mmHg) during the night was significantly higher (p < 0.05) than during the day for both systolic (41.2 +/- 8.1 vs 19.6 +/- 4.7%) and diastolic BP (24.9 +/- 6.9 vs 16.3 +/- 4.9%). A normal decrease in heart rate was found in both groups during the night. A fall of at least 25 mmHg in systolic BP after meals occurred in 10 patients with orthostatic hypotension and in 1 without orthostatic hypotension. These results indicate that orthostatic hypotension in Parkinson's disease is associated with specific modifications of ambulatory blood pressure including loss of circadian rhythm of BP, increased diurnal BP variability and often post-prandial hypotension.

Aged↗
PubMed1993

[Beta-adrenergic receptivity and left ventricular hypertrophy caused by pressure overload in man].

The effect of left ventricular chronic pressure overload on right atrial (RA) and left ventricular (LV) myocardial beta-adrenoceptor (beta-AR) density and subtypes ([I125] cyanopindolol binding), adenylate cyclase activity (AC) and ADP-pertussis toxin ribosylated proteins was investigated in 13 patients with aortic stenosis (AO) and compared with the results obtained in 10 patients with mitral stenosis (MI) taken as controls. None of the patients included had any impairement of systolic function or increased plasma catecholamine levels. The total number of beta-AR in RA (62 +/- 6 vs 77 +/- 12 fmoles/mg prot) and LV (39 +/- 7 vs 32 +/- 2 fmoles/mg prot) was similar in AO and in MI. The percentage of beta 1-AR was significantly lower in LV from AO (35 +/- 11 vs 73 +/- 5% in MI) but identical in RA (79 +/- 5 vs 73 +/- 8%). The basal activity of AC was similar in membranes from patients with AO (19 +/- 4 and 22 +/- 5 pmol.mg-1 prot in RA and LV) and in controls (21 +/- 6 and 27 +/- 3 pmol.mg-1 prot in RA and LV). Isoprenaline-induced stimulation of AC was significantly lower in LV membranes from patients with AO (7 +/- 6 vs 45 +/- 6% in MI) but remained identical in RA membranes (51 +/- 18 vs 36 +/- 18% in MI). The quantification of ADP-pertussis toxin ribosylated proteins indicated a lower substrate concentration in myocardial membranes from patients with AO when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Lack of yohimbine effect on ambulatory blood pressure recording: a double-blind cross-over trial in parkinsonians with orthostatic hypotension.

Yohimbine is an alpha 2-adrenergic antagonist which has been proposed for the treatment of orthostatic hypotension (OH). We investigated in a double-blind placebo-controlled crossover trial the effects of yohimbine (2 mg tid) on blood pressure (BP) and heart rate (HR) using ambulatory monitoring of blood pressure (AMBP) in 17 patients (69 +/- 5 years) with Parkinson's disease (PD) suffering from non drug-induced OH. At the end of each sequence of 4 weeks, mean systolic (SBP) and diastolic (DBP) BP and HR (+/- SD), BP variability (coefficient of variation of the mean) and nychtemeral rhythm were calculated for day-time (09:00-19:00 h) and night-time (23:00-06:00 h). OH related to PD was characterized by: i) loss of the nychtemeral rhythm of BP (night/day ratio: 1.18 +/- 0.14) but not of HR (night/day ratio: 0.87 +/- 0.04), ii) high variability of BP during day-time and iii) post-prandial hypotension (12 out of 17 patients). There was no significant difference in AMBP parameters between baseline, yohimbine and placebo periods. This study shows that AMBP is a simple and reproducible method to assess the effects of drugs used in the management of OH on BP parameters (mean values and variability) and that yohimbine is not effective to correct OH of PD. Future studies must investigate other more selective alpha 2-adrenergic antagonists.

Aged↗
PubMed1992

Parkinson's disease and weight loss: a study with anthropometric and nutritional assessment.

In order to investigate a putative weight loss in patients with Parkinson's disease, an anthropometric and biochemical study was undertaken. We compared body weight and indexes of fat [body mass index (BMI), tricipital skinfold] and lean [midarm muscle area (MMA), calf circumference] mass in men and women suffering from idiopathic Parkinson's disease with normal controls. We found that women suffering from Parkinson's disease exhibited a significant weight loss (-8.5%) and decreased calf circumference when compared with controls. A decrease (-4.3%) in total body weight was also found in men with Parkinson's disease but the difference did not reach the level of significance. Protein biochemical markers of nutritional status (albumin, prealbumin, retinol binding protein, transferrin) were normal in Parkinson's disease patients. The present study demonstrates the occurrence of weight loss in a large population of patients with Parkinson's disease. The putative mechanisms involved in the weight loss are discussed.

Aged↗
PubMed1992

Ambulatory blood pressure in patients with Parkinson's disease without and with orthostatic hypotension.

Non-invasive ambulatory recordings of blood pressure and heart rate were performed using a Spacelabs device during day and night periods in patients with Parkinson's disease with (n = 19) or without orthostatic hypotension (n = 19). In patients with orthostatic hypotension, the average systolic and diastolic blood pressure during the night (137 +/- 5/80 +/- 3 mmHg) was higher (p less than 0.05) than during the day period (121 +/- 3/76 +/- 2 mmHg). In patients without orthostatic hypotension, a decrease in blood pressure was recorded during the nocturnal period. In patients with orthostatic hypotension, the blood pressure variability was higher (p less than 0.05) during the day (systolic: 14.6 +/- 1.3%; diastolic: 16.5 +/- 1.0%) than during the night (systolic: 9.1 +/- 0.8%; diastolic: 10.8 +/- 1.1%). The blood pressure load (percentage of values above 140/90 mmHg) during the night was significantly higher than during the day for both systolic (41.2 +/- 8.1 vs. 19.6 +/- 4.7%) and diastolic blood pressure (24.9 +/- 6.9 vs. 16.3 +/- 4.9%). There was a decrease in heart rate in both groups during the night. A fall of 25 mmHg or more in systolic blood pressure after meals occurred in ten patients with orthostatic hypotension and in one patient without orthostatic hypotension. These results indicate that orthostatic hypotension in Parkinson's disease is associated with specific modifications of ambulatory blood pressure including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability and post-prandial hypotension.

Aged↗
PubMed1992

[Calcium channel blockers and prevention of migraine].

Calcium antagonists have been proposed for the prophylactic treatment of migraine because of their putative vasodilating antispasmodic effect and of their action against the cellular consequences of brain hypoxia. Published reports of controlled double-blind studies of calcium antagonists for the prophylactic treatment of migraine are reviewed herein. The effectiveness of verapamil, diltiazem, and nifedipine in this indication cannot be considered as firmly demonstrated, when problems with trial design and the amount of available data are taken into account. Nimodipine failed to demonstrate significant effectiveness in migraine with or without an aura. In contrast, the ability of a diphenylpiperazine, flunarizine, to decrease the incidence of migraine attacks in patients with common or classical migraine has been firmly demonstrated, although there is less evidence of this agent's effectiveness on the duration and severity of attacks. The percentage of patients who respond to flunarizine seems comparable to the percentages of propranolol or pizotifen responders. However, flunarizine is associated with unpleasant (weight gain) or severe (extrapyramidal or depressive symptoms) adverse effects which limit its place to that of a second-line drug. Lastly, the analysis of these studies failed to disclose a correlation between calcium movements across the cell membrane and effectiveness for the prevention of migraine attacks. Flunarizine's effect in migraine probably involves monoamine mechanisms which bear no relation to calcium.

Adrenergic beta-Antagonists↗
PubMed1991

Pharmacological evidence of alpha 1- and alpha 2-adrenergic supersensitivity in orthostatic hypotension due to spinal cord injury: a case report.

Sympathetic efferent pathways and alpha-adrenergic receptivity were investigated in one patient with spinal cord transection (D1 level) and orthostatic hypotension. The lack of increase in catecholamine plasma levels during orthostasis and the paradoxical pressor effect of clonidine (2 micrograms/kg orally) suggested complete interruption of efferent sympathetic pathways. The pressor response to exogenous noradrenaline was significantly higher in the patient than in 6 normal controls (0.09 vs 0.72 micrograms.kg-1), indicating supersensitivity of vascular alpha-adrenoceptors. The platelet alpha 2-adrenergic receptor number, measured with [3H]yohimbine, was 507 in the patient vs 178 fmol.mg-1 protein in controls. The increase in systolic blood pressure induced by 10 mg midodrine, a specific alpha 1-agonist, was significantly higher in the patient (delta = 56 mm Hg) than in controls (delta = 15 mm Hg). The results indicate that in the patient there was alpha-adrenergic supersensitivity both of alpha 1- and alpha 2-adrenoceptors. This led to successfully oral treatment of the orthostatic hypotension with clonidine 150 micrograms bd and midodrine 10 mg bd.

Blood Pressure↗
PubMed1991

Effects of levodopa and bromocriptine on blood pressure and plasma catecholamines in parkinsonians.

Blood pressure (BP), heart rate (HR), plasma noradrenaline (NA), and adrenaline (A) levels in the lying and standing position were compared in patients with Parkinson's disease (PD) and control subjects. Three groups of PD patients (stage 2 and 3) were investigated: six patients deprived of antiparkinsonian drugs from 48 h, seven levodopa + benserazide-treated patients, and seven bromocriptine-treated patients. BP, HR, NA, and A were similar at rest and in the standing position in controls and in PD patients deprived of antiparkinsonian drugs from 48 h. Chronic treatment with levodopa (+ benserazide) failed to modify BP, HR, NA, and A. Bromocriptine decreased BP, HR, and NA (but not A) at rest. In PD patients treated with levodopa (+ benserazide) or bromocriptine alone, the rise in NA (but not A) elicited by standing up was reduced. These results indicate that (a) stages 2 to 3 of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and (b) dopaminergic drugs blunted the sympathetic response to standing up.

Aged↗
PubMed1991

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).

Administration, Sublingual↗
PubMed1991

Absence of arterial hypertension despite chronic plasma noradrenaline elevation: evidence for down-regulation of alpha-adrenoceptors. A case report.

A 44 year old-healthy female presented chronic and stable high levels of plasma noradrenaline (NA) without any major change in adrenaline. The diagnosis of phaeochromocytoma was discarded. These increased levels of NA offered an unique opportunity to investigate under in vivo conditions a putative regulation of alpha-adrenoceptors by this endogenous catecholamine. Infusion rates of exogenous NA up to 0.74 micrograms/kg per min were unable to induce any change in blood pressure (or heart rate) in the subject, In contrast, in normotensive controls, an increase in blood pressure (+ 15 mm Hg) was observed with 0.39 micrograms/kg per min. The magnitude of yohimbine-induced increase in plasma NA was similar in the subject and in the controls. Platelet alpha 2-adrenoceptors evaluated by specific [3H]-yohimbine binding showed a significantly lower level in the subject when compared to controls. The results show that a sustained increase in plasma NA is able to induce down-regulation of alpha-adrenoceptors. This down-regulation can explain the lack of arterial hypertension despite the increased sympathetic tone.

Adult↗
PubMed1991

Effect of a 7-day treatment with idazoxan and its 2-methoxy derivative RX 821002 [correction of RX 821001] on alpha 2-adrenoceptors and non-adrenoceptor idazoxan binding sites in rabbits.

1. The present study investigates the influence of a 7-day treatment with 2 mg kg-1, s.c., twice daily of RX 821002 (an alpha 2-adrenoceptor antagonist which binds only to alpha 2-adrenoceptors) or idazoxan (alpha 2-antagonist which binds to alpha 2-adrenoceptors and also to non-adrenoceptor idazoxan binding sites: NAIBS) on alpha 2-adrenoceptor (labelled with [3H]-RX 821002) and NAIBS (labelled with [3H]-idazoxan) number in three tissues (adipocytes, colocytes and platelets) in the rabbit. 2. Acute administration of RX 821002 or idazoxan increased plasma non-esterified fatty acids (NEFA) and catecholamine levels with no change in plasma glucose levels. 3. The 7-day treatment with RX 821002 or idazoxan failed to influence food intake, total body weight or perirenal adipose tissue weight. 4. RX 821002 and idazoxan increased the number of [3H]-RX 821002 binding sites in adipose tissue with no change in colocytes or platelets. 5. RX 821002 and idazoxan failed to modify [3H]-idazoxan binding sites on adipocytes and colocytes. No significant [3H]-idazoxan binding was detected on rabbit platelets. 6. The results show that a 7-day treatment with alpha 2-antagonists induces an up-regulation in adipocyte alpha 2-adrenoceptors. In contrast, this phenomenon does not involve all the tissues since colocytes and platelets escape the effects of alpha 2-antagonists. The data suggest a differential regulation of alpha 2-adrenoceptors according to their location. 7. The fact that NAIBS did not vary suggests that alpha 2-adrenoceptors and NAIBS are two different entities. Finally, since RX 821002 and idazoxan exert similar effects after either acute or chronic treatment, it is suggested that NAIBS are not involved in the control of catecholamine release or in NEFA or glucose metabolism.

Adipose Tissue↗
PubMed1990

Identification of alpha 2-adrenoceptors and non-adrenergic idazoxan binding sites in rabbit colon epithelial cells.

alpha 2-Adrenoceptors are possibly involved in the regulation of the hydroelectrolytic flux across the digestive mucosa. As no data are available concerning the existence of these receptors in colon epithelial cells, we aimed to investigate the existence of alpha 2-adrenoceptors in this tissue using tritiated antagonists. [3H]Yohimbine and [3H]rauwolscine were not usable to label colonic alpha 2-adrenoceptors because of their very high level of non-specific binding. In contrast, the methoxy derivative of idazoxan, [3H]RX821002, appeared a convenient radioligand for the purpose. [3H]RX821002 bound with high affinity (KD = 6.2 +/- 0.8 nM) to a single population of non-interacting sites (Bmax = 193 +/- 17 fmol/mg protein). The rank order of potency of catecholamine enantiomers and adrenergic drugs to inhibit [3H]RX821002 binding demonstrated that the labelled sites are alpha 2-adrenoceptors and that 53% of the receptors are in a high-affinity state sensitive to GTP + NaCl. [3H]Idazoxan also bound to colocyte membranes, but inhibition by (-)-adrenaline and various imidazoline compounds indicated that this radioligands labels alpha 2-adrenoceptors and non-adrenergic sites. When experiments were performed under binding conditions impeding the interaction of [3H]idazoxan with the alpha 2-adrenoceptors (i.e. in presence of 10(-4) M (-)-adrenaline), the Bmax of non-adrenergic idazoxan binding sites was 97 +/- 8 fmol/mg protein and the KD was 3.5 +/- 0.5 nM. The sites were pharmacologically characterized with various imidazoline and non-imidazoline drugs. In order to study the putative relationship between alpha 2-adrenoceptors and non-adrenergic idazoxan binding sites, the expression of both kinds of sites was investigated along the crypt-to-surface axis. Crypt cells had a higher number of alpha 2-adrenoceptors than surface cells, whereas the number of non-adrenergic idazoxan binding sites remained constant. The results show that (i) alpha 2-adrenoceptors coexist with non-adrenergic idazoxan binding sites in rabbit colocytes; (ii) the number of alpha 2-adrenoceptors is higher in crypt cells than in surface cells and (iii) alpha 2-adrenoceptors and non-adrenergic binding sites are different and unrelated.

Adrenergic alpha-Antagonists↗