[Knowledge, practices and expectations in the management of overactive bladder in general practice and gynecology in France]. / Connaissances, pratiques et attentes pour la prise en charge de l'hyperactivité vésicale en France.

INTRODUCTION: Overactive bladder (OAB) is a clinical syndrome characterized by urgency to urinate, with or without urinary incontinence, often associated with nycturia and pollakiuria. The aim of this practice survey is to identify diagnostic modalities and treatment circuits according to the patient's clinical profile and to practitioner's specialty. MATERIAL AND METHODS: A cross-sectional survey was conducted among 262 physicians practicing in France: 181 general practitioners (GPs) and 81 gynecologists. RESULTS: Urinary disorders were more easily addressed with patients by gynecologists than GPs. Behavioral therapy was the most widely used therapeutic measure, however half of the patients abandoned it. In oldest women and men of all ages, drugs were commonly prescribed, nevertheless only 4 out of 10 patients continued the treatment beyond 6months, according to the physicians. Incontinence was the symptom for which patients were in most need of relief. GPs and gynecologists expressed a need for training, practical tools and recommendations related to OAB. CONCLUSION: Patients and doctors are reluctant to talk about urinary disorders. Non-urologist physicians such as GPs and gynecologists, as health professionals best placed to detect and diagnose OAB, are in demand for training, practical tools and recommendations. LEVEL OF EVIDENCE: 3.

Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias.

BACKGROUND AND PURPOSE: Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I(Nap)) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I(Nap) and in integrative models of I(Nap)-induced arrhythmias. EXPERIMENTAL APPROACH: Sodium current was investigated using patch clamp technique on wild-type and DeltaKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat. KEY RESULTS: We demonstrated that F 15845 is a potent blocker of I(Nap) acting from the extracellular side of the channel. Blockade of I(Nap) was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I(Nap) activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I(Nap) is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias. CONCLUSIONS AND IMPLICATIONS: F 15845, a novel anti-anginal drug targeting I(Nap), demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias.

F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models.

BACKGROUND AND PURPOSE: Activation of the persistent sodium current in ischaemic myocardium results in calcium overload which is toxic for the cardiomyocyte. Thus, the activity of 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate (F 15845), a new selective persistent sodium current blocker, in protecting against the effects of cardiac ischaemia was examined, in both in vitro and in vivo models. EXPERIMENTAL APPROACH: Electrophysiological studies using patch-clamp and conventional microlelectrode techniques, isolated perfused hearts and models of angina in anaesthetized animals were used to assess the protection afforded by F 15845 against ischaemia-induced changes. KEY RESULTS: F 15845 reduced the persistent sodium current activated by veratridine (IC(50) 1.58 x 10(-6) mol.L(-1)). F 15845 blocked voltage-gated human cardiac sodium channels in a novel, voltage-dependent manner, selectively affecting steady-state inactivation. F 15845 did not affect action potential shape and basal function of guinea pig isolated perfused hearts but did reduce ischaemia-induced diastolic contracture in this model (IC(50) 0.64 x 10(-6) mol.L(-1)). In rabbits, F 15845 given i.v. (ED(50) 0.05 mg.kg(-1)) or orally (ED(50) 0.13 mg.kg(-1)) dose-dependently and powerfully inhibited regional myocardial ischaemia-induced ST segment elevation in the absence of haemodynamic effects, implying direct cardiac activity. In dogs, F 15845 dose-dependently inhibited epicardial ST segment changes (70 +/- 8% at 0.63 mg.kg(-1)) in an experimental angina model of demand ischaemia, again without haemodynamic effects, confirming a direct anti-anginal activity. CONCLUSIONS AND IMPLICATIONS: F 15845 is a selective, potent blocker of the persistent sodium current, generated by the human Na(v)1.5 channel isoforms, and prevents cardiac angina in animal models.

Characterization of nifedipine-resistant calcium current in neonatal rat ventricular cardiomyocytes.

Calcium current was recorded from ventricular cardiomyocytes of rats at various stages of postnatal development using the whole cell patch-clamp technique. In cultured 3-day-old neonatal cells, the current carried by Ca(2+) or Ba(2+) (5 mM) was not completely inhibited by 2 microM nifedipine. A residual current was activated in the same voltage range as the L-type, nifedipine-sensitive Ca(2+) current, but its steady-state inactivation was negatively shifted by 16 mV. This nifedipine-resistant calcium current was not further inhibited by other organic calcium current antagonists such as PN200-110, verapamil, and diltiazem nor by nickel, omega-conotoxin, or tetrodotoxin. It was completely blocked by cadmium and increased by isoproterenol and forskolin. This current was >20% of total calcium current in ventricular myocytes freshly isolated from neonatal rats, and it decreased during postnatal maturation, disappearing at the adult stage. This suggests that this current could be caused by an isoform of the L-type calcium channel expressed in a way that reflects the developmental stage of the rat heart.

Effects of adrenergic stimulation on postnatal development and calcium current in newborn rat cardiomyocytes in primary culture.

With a primary culture of ventricular cardiomyocytes from newborn rats as an in vitro model, the long-term effects of norepinephrine (NE) on hypertrophic postnatal development and the I/V properties of L-type calcium currents were investigated with the whole-cell configuration of patch-clamp technique. These effects of NE also were tested in the presence of propranolol (P). Compared with mean values obtained in control conditions, the measurement of cell membrane capacitance (Cm) as an index of cell growth demonstrated that Cm was increased by 12, 35, and 42% after 1, 3, and 6 days, respectively, of treatment with 2 microM NE. Similar increases were observed when propranolol (2 microM) was added to the NE treatment, suggesting that growth potentiation could be attributed to the alpha-adrenergic effect of NE. Under control conditions, the L-type calcium current (ICa-L) density did not alter with the age of the culture. However, in the presence of NE, ICa-L density increased significantly compared with control conditions at the same stage of culture and was also significantly increased after 3 and 6 days of NE treatment when compared with ICa-L density after 1 day of NE treatment. Similar results were obtained in the presence of propranolol. These results show that the growth and functional properties of neonatal cardiomyocytes in primary culture can be regulated by catecholamines and demonstrate that these regulatory effects were achieved through activation of alpha-adrenoceptors.

Mechanisms of Na+-Ca2+ exchange inhibition by amphiphiles in cardiac myocytes: importance of transbilayer movement.

The membrane lipid environment and lipid signaling pathways are potentially involved in the modulation of the activity of the cardiac Na(+)-Ca(2+) exchanger (NCX). In the present study biophysical mechanisms of interactions of amphiphiles with the NCX and the functional consequences were examined. For this purpose, intracellular Ca(2+) concentration jumps were generated by laser-flash photolysis of caged Ca(2+) in guinea-pig ventricular myocytes and Na(+)-Ca(2+) exchange currents ( I(Na/Ca)) were recorded in the whole-cell configuration of the patch-clamp technique. The inhibitory effect of amphiphiles increased with the length of the aliphatic chain between C(7) and C(10) and was more potent with cationic or anionic head groups than with uncharged head groups. Long-chain cationic amines (C(12)) exhibited a cut-off in their efficacy in I(Na/Ca) inhibition. Analysis of the time-course, comparison with the Ni(2+)-induced I(Na/Ca) block and confocal laser scanning microscopy experiments with fluorescent lipid analogs (C(6)- and C(12)-NBD-labeled analogs) suggested that amphiphiles need to be incorporated into the membrane. Furthermore, NCX block appears to require transbilayer movement of the amphiphile to the inner leaflet ("flip"). We conclude that both, hydrophobic and electrostatic interactions between the lipids and the NCX may be important factors for the modulation by lipids and could be relevant in cardiac diseases where the lipid metabolism is altered.

Alpha-adrenoceptor stimulation induces hypertrophy and increases L-type calcium current density in neonatal rat ventricular cardiomyocytes in culture.

Effects of chronic alpha-adrenoceptor stimulation on hypertrophy and L-type calcium current (I(Ca-L) ) were investigated in neonatal rat ventricular cardiomyocytes in culture using whole-cell patch-clamp technique and measurement of protein- and RNA-to-DNA ratios. Chronic exposure to norepinephrine (2 microM) plus propranolol (2 microM) of cardiomyocytes during 1 and 3 days in culture increased cell membrane capacitance, protein- and RNA-to DNA ratios and was accompanied by an increase in I(Ca-L) density. These effects were not observed in the presence of prazosin (2 microM) suggesting that they could be due to alpha(1) -adrenoceptor stimulation. They were also prevented by cycloheximide (5 microM) and actinomycin D (1 microM). These effects were not observed in 1 and 3 day-cultured cells pre-treated for only 1 hour with norepinephrine. They were potentiated when calcium concentration was increased in the culture medium and, in contrast they were abolished in the presence of the L-type calcium current inhibitor, nifedipine (2 microM). The present study demonstrates that hypertrophy induced by long-term stimulation of alpha(1) -adrenoceptors is accompanied by an increase in the expression of functional calcium channels in neonatal rat cardiomyocytes. These results reveal the existence of a novel alpha(1) -mediated positive regulation of L-type calcium current different from that due to acute stimulation of alpha(1) -adrenoceptors in neonatal ventricular cardiomyocytes.