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Biomedical subjects

Jean-Michel Senard

Publications and source records attributed to Jean-Michel Senard.

At least 19 recordsLinked to original sources
PubMed2007

In vivo pharmacodynamic interactions between two drugs used in orthostatic hypotension--midodrine and dihydroergotamine.

A combination of midodrine and dihydroergotamine (DHE) is frequently used clinically in patients suffering from severe orthostatic hypotension (OH). Whereas midodrine acts as a selective, peripheral alpha1-receptor agonist, DHE displays complex pharmacology and can behave as an alpha-adrenergic receptor agonist or antagonist. Surprisingly, the consequences of such a combination on blood pressure have never been investigated. The present study was performed in order to evaluate the pressor effects induced by the administration of both midodrine and DHE in old conscious dogs (n = 6) in experimental condition reproducing autonomic failure-related baroreflex dysfunction (atropine 0.1 mg/kg). For this purpose, we first studied the relative potency and intrinsic activity of each agonist and noradrenaline (NA) for the alpha1-adrenergic receptor. The orders of potency obtained in our study were 0.35, 11 and 400 microg/kg for NA, DHE and midodrine, and intrinsic activity: NA > midodrine > DHE. These results strongly suggest that DHE really acts in vivo as an alpha1-adrenoceptor partial agonist. Afterwards, the pressor effects of coadministration of midodrine (0.4 mg/kg) and DHE (15 microg/kg) were investigated: in one setting, midodrine was first administered, followed by DHE; in another, DHE was first administered, followed by midodrine. Our results show that in conscious dogs, the combination of midodrine and DHE leads to near-complete abolition of the pressor effect induced by the first administered drug. This in vivo proof of such antagonistic effects on blood pressure could explain clinical observations of worsening of OH in humans administered midodrine plus DHE. Although in vivo results obtained in conscious healthy dogs need to be experimentally and clinically confirmed in humans suffering from OH, these results strongly suggest that a midodrine-DHE combined treatment should be avoided in clinical practice.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2006

ApoO, a novel apolipoprotein, is an original glycoprotein up-regulated by diabetes in human heart.

Obesity is an independent risk factor for cardiac failure. Obesity promotes excessive deposition of fat in adipose and nonadipose tissues. Intramyocardial lipid overload is a relatively common finding in nonischemic heart failure, especially in obese and diabetic patients, and promotes lipoapoptosis that contributes to the alteration of cardiac function. Lipoprotein production has been proposed as a heart-protective mechanism through the unloading of surplus cellular lipids. We previously analyzed the heart transcriptome in a dog nutritional model of obesity, and we identified a new apolipoprotein, regulated by obesity in heart, which is the subject of this study. We detected this new protein in the following lipoproteins: high density lipoprotein, low density lipoprotein, and very low density lipoprotein. We designated it apolipoprotein O. Apolipoprotein O is a 198-amino acid protein that contains a 23-amino acidlong signal peptide. The apolipoprotein O gene is expressed in a set of human tissues. Confocal immunofluorescence microscopy colocalized apolipoprotein O and perilipins, a cellular marker of the lipid droplet. Chondroitinase ABC deglycosylation analysis or cell incubation with p-nitrophenyl-beta-d-xyloside indicated that apolipoprotein O belongs to the proteoglycan family. Naringenin or CP-346086 treatments indicated that apolipoprotein O secretion requires microsomal triglyceride transfer protein activity. Apolipoprotein O gene expression is up-regulated in the human diabetic heart. Apolipoprotein O promoted cholesterol efflux from macrophage cells. To our knowledge, apolipoprotein O is the first chondroitin sulfate chain containing apolipoprotein. Apolipoprotein O may be involved in myocardium-protective mechanisms against lipid accumulation, or it may have specific properties mediated by its unique glycosylation pattern.

3T3 Cells↗
PubMed2006

Dopamine beta-hydroxylase deficiency.

Dopamine beta-hydroxylase (DbetaH) deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DbetaH deficiency is unknown. Only a limited number of cases with this disease have been reported. DbetaH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DbetaH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS). Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

Autonomic Nervous System↗
PubMed2006

Cerebral autoregulation is preserved in multiple system atrophy: A transcranial Doppler study.

Patients with multiple system atrophy (MSA) present large changes in blood pressure (BP) due to autonomic disturbances. We analyzed how this change may influence dynamic cerebral autoregulation (DCA). Simultaneous recordings of arterial BP (Finapres) and middle cerebral artery (MCA) blood flow velocity (BFV) (transcranial Doppler) were performed in 10 patients with MSA (61 +/- 12 yr of age) and 12 healthy volunteers (61 +/- 11 yr of age): cerebral BFV response to oscillations in mean BP was studied in the supine position by cross-spectral analysis of mean BP and mean MCA BFV. The DCA was also studied during the decrease in BP the first seconds when standing up from a sitting position by the assessment of the cerebrovascular resistance index (CR; mean BP/mean MCA BFV ratio). The MCA BFV/BP cross-spectral analysis showed a phase for the mid-frequency band (0.07-0.2 Hz) significantly larger in MSA, suggesting more active autoregulation in response to larger changes in BP. Changes in CR reflecting the rate of autoregulation, when standing did not differ between the two groups. These data suggest that dynamic cerebral autoregulation is preserved in MSA.

Aged↗
PubMed2006

Blood pressure disorders during Parkinson's disease: epidemiology, pathophysiology and management.

Blood pressure disorders are highly prevalent in the course of Parkinson's disease (PD). They relate to autonomic failure and are frequently associated with orthostatic hypotension, postprandial hypotension and supine hypertension. Supine hypertension, which may concern up to 50% of patients with PD and autonomic failure, is driven by residual sympathetic activity and changes in sensitivity of vascular adrenergic receptors. It can also be induced or worsened by antihypotensive drugs. Even if little data is available, a set of arguments suggests that supine hypertension sometimes requires treatment. This review will focus on recent data on the pathophysiology and the management of supine hypertension in the context of its association with orthostatic hypotension.

Antihypertensive Agents↗
PubMed2005

Adverse drug reactions related to drugs used in orthostatic hypotension: a prospective and systematic pharmacovigilance study in France.

OBJECTIVE: The aim of the present study was to investigate and characterise adverse drug reactions (ADRs) to drugs used in France for orthostatic hypotension (OH). METHODS: In this prospective and systematic study, 121 consecutive out-patients suffering from primary (Parkinson's disease, pure autonomic failure, multiple system atrophy, Lewy bodies disease) or secondary (diabetic and non-diabetic peripheral neuropathies) autonomic failure with symptomatic OH requiring pharmacological treatment with at least one drug marketed in France for OH were included together with six patients with refractory neurocardiogenic syncope. RESULTS: Of the patients, 85 received a monotherapy-mainly with midodrine (49.4%)-and 42 received various combinations, the association of midodrine and fludrocortisone being the most frequent (66.6%). Of all the 127 patients, 88 suffered from a total of 141 ADRs (1.60 per patient) with no statistical difference in ADR frequency between monotherapy and drug combinations (P>0.05). Among ADRs, 24 (17.0%) were considered as "serious" and 16 (11.3%) were considered as "unexpected", most of them observed with heptaminol. CONCLUSIONS: This study shows a high frequency of ADRs (especially serious and unexpected ADRs) with antihypotensive drugs. It strongly suggests the need for a better evaluation of the safety profile of antihypotensive drugs and improvement in summary of product characteristics.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

The vasoactive peptide adrenomedullin is secreted by adipocytes and inhibits lipolysis through NO-mediated beta-adrenergic agonist oxidation.

Adipocytes are known to secrete a number of adipokines, but many adipocyte secretions and their functional importance remain to be characterized. This work shows that human white adipocytes and 3T3-F442A-derived adipocytes produce adrenomedullin (AM) and that AM acts in an autocrine/paracrine way on lipid metabolism by extracellular inactivation of isoproterenol, a beta-adrenergic agonist. AM is described as a counter-regulatory factor involved in the control of cardiovascular homeostasis. This peptide is believed to protect the heart from several complications implicated in obesity-linked cardiomorbidity, such as arterial hypertension, cardiac fibrosis, and decreased sinusal variability. The exact source of circulating AM remains a matter of debate, although endothelial and vascular smooth muscle cells seem to be important sites of production. We show that human adipose cells and 3T3-F442A-derived adipocytes express AM receptors and secrete AM. The function of this feature was investigated in 3T3-F442A cell line at the level of lipolysis regulation. AM inhibited beta-adrenergic-stimulated lipolysis by a nitric oxide (NO)-dependent mechanism, inducing a significant decrease in pD2 value for isoproterenol (8.6 +/- 0.2 vs. 9.8 +/- 0.1, P<0.001). This effect is cGMP-independent since it occurred in the presence of the NO-sensitive guanylate cyclase inhibitor ODQ. It is apparently mediated by a novel extracellular mechanism. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated that AM-produced NO oxidized isoproterenol to generate its aminochrome, namely isoprenochrome. Isoprenochrome amounts were increased 3.62 +/- 1.13-fold in cell culture media (P<0.05). We describe for the first time that AM down-regulates lipolysis in adipocytes through the chemical modification of a beta-agonist.

Adipocytes↗
PubMed2005

Heat-related morbidity in patients with orthostatic hypotension and primary autonomic failure.

We investigated the effects of high-external-temperature exposure on neurogenic orthostatic hypotension (OH). Thirty-one patients with autonomic failure (AF) and pharmacologically treated OH related to probable multiple-system atrophy (n=7), Parkinson's disease (n=10), pure autonomic failure (n=7), and diffuse Lewy body disease (n=7) and 26 parkinsonians without AF were included. Prevalence and severity of clinical events were studied during the August 2003 heat wave and the 2004 summer. The prevalence of OH-related events was significantly higher in 2003 [45.1 vs. 11.5%; P=0.0052; OR=6.31 (1.35--33.53)] and 2004 [42.3 vs. 12.0%; P=0.014; OR=5.40 (1.28--22.68)] in AF than in controls. The mean severity score for clinical events was significantly higher in AF than in controls during 2003 heat wave (1.2+/-1.4 vs. 0.2+/-0.5) but similar in summer 2004 (0.7+/-1.0 vs. 0.1+/-0.3). Severe events (unusual home care, assistance, or hospitalization) were only observed in AF patients. A nonstatistically significant higher prevalence of clinical events was observed in AF patients prescribed fludrocortisone (66.7%) by comparison to heptaminol (42.9%), midodrine (45.5%), or midodrine plus fludrocortisone (28.6%). This study shows that AF patients have a poor clinical outcome when exposed to high temperatures and that heat exposure is a risk factor for OH worsening.

Aged↗
PubMed2004

Uncomplicated human obesity is associated with a specific cardiac transcriptome: involvement of the Wnt pathway.

A dramatic increase in obesity prevalence and cardiovascular morbidity is expected for the coming years. However, with relevance to the heart, little is known about the specific contribution of obesity on associated morbidity. Consequently, global analysis of gene regulations in human heart was undertaken to monitor molecular regulations related to obesity or to obesity-related hypertension. Transcriptome analysis using cDNA arrays was performed in right appendage biopsies from obese patients (n=5), from patients with arterial hypertension with (n=5) or without obesity (n=5), and from 5 leans. All biopsies came from patients that had cardiac surgery and coronary bypass. Statistical analysis of the data revealed 2686 differentially expressed genes out of 11,500 when compared with lean tissues. Differential expression was verified by real-time PCR in 84% of 50 randomly chosen genes. Among genes encountered, 397 were specifically regulated in obese, 1,299 in non-obese hypertensive, and 355 in obese hypertensive patients, respectively, whereas an additional set of 153 genes was differentially expressed in all these situations. Ontology analysis, hierarchical clustering, and molecular pathway analysis indicated that the heart molecular picture of obesity differs clearly from that observed for obesity-related hypertension or arterial hypertension. Clearly, the Wnt pathway known to be involved in cardiac hypertrophy mechanisms, showed opposite regulation in obese heart compared with hypertensive heart and potentially prevented the development of cardiac remodeling in obese patients. All over, this work shows that uncomplicated obesity has a strong impact on cardiac gene expression, which could be considered as precursor signs for future cardiac disease and also demonstrates that obesity-related hypertension generates a heart-molecular-distinct phenotype that cannot be predicted by a simple sum of the impact of obesity and arterial hypertension on gene expression.

Cardiomegaly↗
PubMed2004

Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs.

In the present study, we investigated, using custom dog cDNA arrays, the time course of transcriptional changes in the left ventricle of dogs fed a normal diet or a high-fat diet (HFD) for 9-24 wk. Array hybridizations were performed with complex probes representing mRNAs expressed in left ventricles from obese hypertensive and lean control dogs. We identified 63 differentially expressed genes, and expression of 17 of 20 randomly chosen genes was confirmed by real-time PCR. Transcripts were categorized into groups involved in metabolism, cell signaling, tissue remodeling, ionic regulation, cell proliferation, and protein synthesis. Hierarchical clustering indicated that the pattern of coregulated genes depends on duration of the HFD, suggesting that HFD-induced obesity hypertension is associated with continuous cardiac transcriptome adaptation despite stability of both body weight and blood pressure. GenMAPP analysis of the data pointed out the crucial importance of the ventricle TGF-beta pathway. Our results suggest that this system may be involved in molecular remodeling during HFD and in changes observed in the transcription profile, reflecting functional and morphological abnormalities that arise during prolonged HFD. These results also suggest some novel regulatory pathways for cardiac adaptation to obesity.

Animals↗
PubMed2004

Intestinal obstruction associated with oral midodrine.

We report a case of severe ileus possibly related to midodrine. To our knowledge, this case report is the first one suggesting an inhibitory effect of midodrine on intestinal motility. The potential pharmacological mechanisms leading to this adverse drug reaction are discussed below.

Adrenergic alpha-Agonists↗
PubMed2004

Pharmacology of orthostatic hypotension in Parkinson's disease: from pathophysiology to management.

Orthostatic hypotension is highly prevalent in the elderly, and affects up to 20% of patients with Parkinson's disease. Pharmacological approaches help to demonstrate that Parkinson's disease is a primary autonomic failure with involvement of the peripheral autonomic nervous system as shown by decreased [(123)I] meta-iodobenzylguanidine cardiac uptake and preserved growth hormone response to clonidine. No specific clinical trial has evaluated efficacy of antihypotensive drugs in Parkinson's disease. End point of treatment should be a reduction in postural symptoms. Midodrine (Proamatin), Roberts Pharmaceutical), a vasoconstrictor and fludrocortisone (Florinef), Bristol-Myers Squibb), a volume expander are first choice drugs. No data are available on their effects on orthostatic hypotension-related morbidity. The usefulness of other drugs remains to be demonstrated. This review will highlight the importance of nonpharmacological measures in the management of orthostatic hypotension in Parkinson's disease.

Antiparkinson Agents↗
PubMed2003

[Blood pressure disorders during idiopathic Parkinson's disease].

SEVERAL EXPLANATIONS FOR THE HIGH PREVALENCE: In Parkinson's disease, the prevalence of symptomatic orthostatic hypotension (OH) concerns more than 20% of the patients. At least 2 factors explain this high prevalence. Dopamine-mimetic drugs may induce or enhance the occurrence of OH. Parkinson's disease is a cause of primary autonomic failure with involvement of the peripheral nervous system. CHARACTERISTIC HISTOLOGICAL AND PHARMACOLOGICAL ELEMENTS: Histology indicates that Lewy bodies exist in the sympathetic glands. Pharmacology reveals cardiac sympathetic denervation. These histological and pharmacological characteristics clearly differentiate autonomic failure of Parkinson's disease from multiple system atrophy (Shy-Drager's syndrome). If autonomic abnormalities appear to be present since the early stages of the disease, the early onset, within the first year, of symptomatic OH in the course of a parkinsonian syndrome can be considered as an exclusion criterion for idiopathic Parkinson's disease. REGARDING TREATMENT: No specific clinical trials have assessed the efficacy of antihypotensive drugs in the treatment of OH in Parkinson's disease. The management of this symptom requires education of the patient and the development of non-pharmacological measures. Drug therapy should be reserved for symptomatic patients who do not improve with the preceding methods. Among the drugs available, domperidone, although widely used, has no proven effect on OH like the cardiovascular analeptics. The alpha1-adrenergic agonists (midodrine) or mineralocorticosteroids (fludrocortisone) are the most frequently used drugs.

Adrenergic alpha-Agonists↗
PubMed2003

Cardiac transcriptome analysis in obesity-related hypertension.

Obesity is associated with volumetric arterial hypertension and with early increase in heart rate and decreased heart rate variability. The consequences of obesity-related hypertension on heart gene regulation are poorly known and were investigated in a model of obesity-related hypertension induced by high fat diet in dogs. When compared with control animals (n=6), a 9-week high fat diet (n=6) provoked significant weight gain and increased blood pressure load and heart rate but failed to significantly change left ventricular mass assessed by echocardiography. Subtractive hybridization of dog heart cDNA libraries were used to generate sublibraries containing differentially expressed cDNAs that were in turn spotted onto membranes to create custom microarrays. Hybridizations of these microarrays with complex probes representing mRNAs expressed in right atria and left ventricles from obese hypertensive and control dogs were performed. Thirty-eight differentially expressed genes were identified; altered expression was confirmed by Northern blot analysis in 15. In addition, real-time quantitative polymerase chain reaction confirmed differential expression for 80% of the randomly chosen tested genes. Once identified, transcripts were categorized into groups involved in metabolism, cell signaling, ionic regulation, cell proliferation, protein synthesis, and tissue remodeling. In addition, we found a set of 11 cDNAs encoding proteins with unknown functions. This study clearly shows that obesity-related hypertension, lasting for only 9 weeks, causes marked changes in gene expression in right atrium as well as the left ventricle that may contribute to early functional changes in heart function and to long-term structural changes such as left ventricular hypertrophy and remodeling.

Animals↗
PubMed2003

Clinical and economic analysis of spa therapy in Parkinson's disease.

The effectiveness of spa therapy in the management of patients with Parkinson's disease (PD) has never been evaluated. This is assessed in this pilot study. A prospective, randomized, cross-over, controlled study was conducted in 31 PD patients who underwent a 20-week spa period, including spa therapy for 3 weeks, and a 20-week non-spa period. Effectiveness was assessed using quality of life scales (PDQ-39 and SF-36), motor scale (UPDRS) and psychological questionnaire (GHQ-28), at baseline and at 4 (T4) and at 20 weeks (T20). Direct medical costs (radiological and laboratory tests, physician fees, drug therapy, and ancillary care) were recorded over each 20-week period. At T4, spa therapy improved significantly several dimensions of PDQ-39 and SF-36, part IV of the UPDRS, and GHQ-28. At T20, no difference in any parameter was found. The mean direct medical cost over 20 weeks (euro;1,328 +/- 167; pound 776 +/- 97 per patient) in the spa period was slightly but significantly reduced in comparison with that of the non-spa period (euro;1380 +/- 523; pound 807 +/- 306 per patient). This cost-effectiveness analysis suggests that spa therapy is more effective and less expensive than conventional treatment alone and could be beneficial in the management of PD.

Balneology↗
PubMed2003

Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson's disease.

[(123)I]Metaiodobenzylguanidine ([(123)I]MIBG) cardiac scintigraphy could be helpful to differentiate Parkinson's disease (PD) from multiple system atrophy (MSA), demonstrating that, in PD with autonomic failure but not in MSA, there is a myocardial postganglionic sympathetic dysfunction. To investigate whether this method is more sensitive than standard autonomic testing to detect early involvement of sympathetic cardiac efferent, we analyse MIBG myocardial uptake in 8 PD patients with normal autonomic testing (nondysautonomia PD group, NDPD) in comparison with 10 PD patients with abnormal autonomic testing (dysautonomia PD group, DPD) and 10 MSA patients. Global MIBG uptake was assessed using the ratio of [(123)I]MIBG uptake in the heart to the upper mediastinum (H/M) on planar scintigraphic data. Regional MIBG uptake was determined on two single photon emission tomography scans in regions of the left ventricle. The mean H/M ratios were significantly different among the three groups (P < 0.0001). H/M ratios of both NDPD and DPD patients groups (H/M = 1.83 +/- 0.50 and 1.24 +/- 0.40, respectively) were significantly lower than in MSA patients (H/M = 2.52 +/- 0.60). However, in NDPD patients, H/M was significantly higher than in DPD patients. When compared to MSA patients, NDPD patients showed a regional reduction in MIBG uptake in all left ventricle regions markedly in the apex and the inferior wall. Our results suggest that MIBG myocardial scintigraphy (analysis of both H/M ratio and regional MIBG uptake) may be more sensitive than standard autonomic testing for the early detection of silent autonomic dysfunction in PD.

3-Iodobenzylguanidine↗
PubMed2003

Blood pressure and heart rate variability in patients with essential hyperhidrosis.

INTRODUCTION: Essential hyperhidrosis (EH) is often considered to be related to an increased activity of sympathetic nervous system (SNS). However, there is a lack of studies comparing autonomic nervous system (ANS) activity in controls and in EH patients. The aim of the present study was to simultaneously investigate in patients with severe EH, blood pressure, heart rate variability and plasma catecholamine levels in comparison with controls. METHODS: 19 EH patients and 20 controls with normal ANS function assessed by clinical testing were included. Blood pressure (BP) and heart rate (HR) were measured using a Finapres beat-to-beat monitor. BP and HR variabilities (Fast Fourier transformation) and plasma catecholamine levels (HPLC) were obtained at rest and during a 15 min 70 degrees head-up tilt test. RESULTS: At rest, a significantly higher relative energy of low frequency band (LF) of systolic BP was observed in EH in comparison with controls contrasting with the lack of difference in BP, HR, plasma catecholamine levels and in other spectral parameters. During tilt, all changes were comparable in EH and in control subjects excepting relative energy of LF of SBP which remained unchanged when compared to the resting condition in EH group. CONCLUSIONS: In EH, SNS is not over-reactive even if resting overactivity cannot be excluded.

Adolescent↗