Jean-Michel Sénard

Effects of yohimbine on plasma catecholamine levels in orthostatic hypotension related to Parkinson disease or multiple system atrophy.

Different pathophysiological mechanisms may underly orthostatic hypotension (OH) observed in neurological degenerative disorders. The present study investigates the responses to the pharmacological activation of sympathetic pathways induced by yohimbine (0.2 mg/kg orally) through measurements of plasma catecholamine levels in parkinsonian patients with (n = 9) or without OH (n = 11), in patients with multiple system atrophy (MSA) plus OH (n = 9), and in controls (n = 6). Basal norepinephrine plasma levels in parkinsonian patients with OH (71 +/- 11 pg/ml) were significantly lower (p < 0.05) than in parkinsonian patients without OH (280 +/- 25 pg/ml) or in controls (259 +/- 48 pg/ml). In patients with MSA plus OH, basal catecholamine plasma levels were in the normal range (344 +/- 54 pg/ml). Yohimbine significantly increased norepinephrine (p < 0.05) but not epinephrine plasma levels in all groups. However, the increment obtained in parkinsonian patients with OH (+53 +/- 18 pg/ml) remained significantly lower (p < 0.05) than in parkinsonian patients without OH or in controls (+638 +/- 140 and +457 +/- 103 pg/ml, respectively) as well as in MSA plus OH (+633 +/- 142 pg/ml). Yohimbine failed to modify the blood pressure and heart rate at the dose used. The results suggest that the yohimbine test is useful to elucidate the site of the dysfunction of the efferent sympathetic pathways in these two conditions. In Parkinson disease with OH, the lesion is both central and postganglionnic, whereas in MSA it is only centrally located.

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 Parkinsons 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 Parkinsons disease are not accompanied by major changes in autonomic cardiovascular function and (b) dopaminergic drugs blunted the sympathetic response to standing up.

Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects.

Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short‐term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan.

Factors related to orthostatic hypotension in Parkinson's disease.

INTRODUCTIONnOrthostatic hypotension (OH), a frequent feature of Parkinsons disease (PD) can contribute to falls and is usually related to the disease itself and/or to drugs.nnnOBJECTIVESnTo explore factors related to OH and to assess the concordance between abnormal blood pressure (BP) fall after standing and the presence of orthostatic symptoms.nnnMETHODSnNon-demented, non-operated idiopathic PD out-patients were questioned about the presence of orthostatic symptoms. Afterward, BP was measured 5-min after lying down and for 3-min after standing up. OH was defined as systolic and/or diastolic BP fall ≥ 20 and/or 10 mmHg after standing. Patients were further evaluated by the Unified PD Rating Scale (UPDRS) and their medications were recorded.nnnRESULTSn103 patients were included in this study (mean age = 66 ± 1 years, mean disease duration = 9 ± 1 years; mean UPDRS II+III in ON-state = 37 ± 2 points). Forty-one subjects (40%) reported the presence of orthostatic symptoms during the previous week and 38 (37%) had OH according to manometric definition. Independent factors related to OH, as assessed by logistic regression were age >68 years (OR, 95% CI=3.61, 1.31-9.95), polypharmacy (defined as intake of >5 medications, OR = 3.59, 1.33-9.69), amantadine (7.45, 1.91-29.07) or diuretics (5.48, 1.10-54.76), whereas the consumption of entacapone was protective (0.20, 0.05-0.76). The agreement between abnormal BP fall and presence of orthostatic symptoms was poor (kappa = 0.12 ± 0.1, p = 0.23).nnnCONCLUSIONnOH was significantly related to older age, polypharmacy and amantadine or diuretics intake, while entacapone exposure appeared to reduce the risk of OH. Low concordance between OH and orthostatic symptoms was observed.

New Directions in the Drug Treatment of Parkinson’s Disease

SummaryParkinson’s disease, a clinical syndrome with 4 cardinal features (bradykinesia, resting tremor, increased muscular rigidity and impaired postural balance), is mainly caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although levodopa remains the ‘gold standard’ in the treatment of the disease, several emerging strategies are currently being developed. The first concerns new symptomatic drugs that either potentiate the effects of levodopa (e.g. slow-release preparations of levodopa, catechol-O-methyltransferase inhibitors and new dopamine agonists) or target clinical symptoms resistant to dopaminergic drugs (e.g. glutamate antagonists). The second strategy is to find drugs that are able to prevent or delay the neuronal death observed in Parkinson’s disease. Several neuroprotective drugs are now in development in experimental research, but clinical trials in this area are still lacking. The development of these new drugs also depends on the validation of new clinical methodologies.

Dosage-dependent regulation of cell proliferation and adhesion through dual β2-adrenergic receptor/cAMP signals

The role of β‐adrenergic receptors (β‐ARs) remains controversial in normal and tumor breast. Herein we explore the cAMP signaling involved in β ‐AR‐dependent control of proliferation and adhesion of nontumor human breast cell line MCF‐10A. Low concentrations of a β‐agonist, isoproterenol (ISO), promote cell adhesion (87.5% cells remaining adherent to the plastic dishes following specific detachment vs. 35.0% in control, P<0.001), while increasing concentrations further engages an additional 36% inhibition of Erk1/2 phosphorylation (p‐Erk1/2)‐dependent cell proliferation (P<0.01). Isoproterenol dose response on cell adhesion was fitted to a 2‐site curve (EC50(1): 16.5±11.5 fM, EC50(2): 4.08 ±3.09 nM), while ISO significantly inhibited p‐Erk1/2 according to a 1‐site model (EC50: 0.25 ±0.13 nM). Using β‐AR‐selective agonist/antagonists and cAMP analogs/inhibitors, we identified a dosage‐dependent signaling in which low ISO concentrations target a β2‐AR population localized in raft microdomains and stimulate a Gs/cAMP/Epac/ adhesion‐signaling module, while higher concentrations engage a concomitant activation of another β2‐AR population outside rafts and inhibit the proliferation by a Gs/cAMP/PKA‐dependent signaling module. Our data provide a new molecular basis for the dose‐dependent switch of β‐AR signaling. This study also sheds light on a new cAMP pathway core mechanism with a single receptor triggering dual cAMP signaling controlled by PKA or Epac but with different cellular outputs.—Bruzzone, A., Saulière, A., Finana, F., Sénard, J.‐M., Lüthy, I., Galés, C. Dosage‐dependent regulation of cell proliferation and adhesion through dual β2‐adrenergic receptor/cAMP signals. FASEB J. 28, 1342–1354 (2014). www.fasebj.org

Levosimedan improves hemodynamics functions without sympathetic activation in severe heart failure patients: direct evidence from sympathetic neural recording.

Abstract Levosimendan is a new inodilatory agent with calcium sensitizing activity. A major concern regarding the use of inotropic agent in heart failure is their effect on the sympathetic tone. This effect could explain increase in short term mortality with other inotropes. We aimed to assess the effect of levosimendan on sympathetic tone measured directly by microneurogra-phy. In a group of acute decompensated heart failure patients, we assessed cardiac performance by digital plethysmography measurement. Sympathetic tone was assessed through recording of muscle sympathetic nerve activity (MSNA) by micro-neurography. Recording were done blindly, for each patient after dobutamine perfusion was stopped (baseline) and 48 h after levosimendan infusion. Clinical, biological and morphological data were collected. We compared cardiac parameters and MSNA before and after administration of levosimendan. 13 patients were recruited (48 ± 3.6 years). Systolic blood pressure and rate pressure product (mmHg × Beat/min) decreased significantly after levosimendan infusion (P< 0.05). Cardiac output and stroke volume were significantly increased after levosimendan infusion (P< 0.05). A significant decrease of MSNA activity is observed after levosimendan infusion (P< 0.01). Levosimendan induced improvement of cardiac performance, associated with a decreased in MSNA. This study show for the first time that levosimendan has no direct detrimental effect on the sympathetic nervous system.

G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning

Biased agonism at G protein coupled receptors emerges as an opportunity for development of drugs with enhanced benefit/risk balance making biased ligand identification a priority. However, ligand biased signature, classically inferred from ligand activity across multiple pathways, displays high variability in recombinant systems. Functional assays usually necessity receptor/effector overexpression that should be controlled among assays to allow comparison but this calibration currently fails. Herein, we demonstrate that Gα expression level dictates the biased profiling of agonists and, to a lesser extent of β-blockers, in a Gα isoform- and receptor-specific way, depending on specific G protein activity in different membrane territories. These results have major therapeutic implications since they suggest that the ligand bias phenotype is not necessarily maintained in pathological cell background characterized by fluctuations in G protein expression. Thus, we recommend implementation of G protein stoichiometry as a new parameter in biased ligand screening programs.

Lacrimation in Parkinson's disease

The present study compares lacrimal secretion in control subjects and patients with Parkinsons disease with use of Schirmers test. Tear secretion was decreased in Parkinsons disease. The reduction was more marked in stages III-IV than in stages I-II. The results are discussed in relationship with autonomic dysfunction in Parkinsons disease.

Delineating biased ligand efficacy at 7TM receptors from an experimental perspective.

During the last 10 years, the concept of biased agonism also called functional selectivity swamped the pharmacology of 7 transmembrane receptors and paved the way for developing signaling pathway-selective drugs with increased efficacy and less adverse effects. Initially thought to select the activation of only a subset of the signaling pathways by the reference agonist, bias ligands revealed higher complexity as they have been shown to stabilize variable receptor conformations that associate with distinct signaling events from the reference. Today, one major challenge relies on the in vitro determination of the bias and classification of these ligands, as a prerequisite for future in vivo and clinical translation. In this review, current experimental considerations for the bias evaluation related to choice of the cellular model, of the signaling pathway as well as of the assays are presented and discussed.