[Pharmacological management of anxiety in patients suffering from schizophrenia]. / Prise en charge médicamenteuse de l'anxiété chez le patient souffrant de schizophrénie.

INTRODUCTION: Anxiety is a major and frequent symptom of schizophrenia, which is associated with an increased risk of relapse, impaired functioning, lower quality of life and increased incidence of suicide attempts. Despite its clinical relevance, anxiety in schizophrenia remains poorly understood. In the prodromic phase, anxiety indicates a progression towards psychotic decompensation. After a first episode, it is an indicator of relapse. LITERATURE FINDINGS: Two approaches have been used to investigate anxiety in schizophrenia: (i) categorical approach (comorbidity of schizophrenia and anxiety disorders) and (ii) dimensional approach (anxiety as a major symptom of the "dysphoric" dimension). Clinical categorical studies reported an increased frequency of comorbidity between schizophrenia and obsessive-compulsive disorder, panic disorder, social phobia, post-traumatic stress disorder, generalized anxiety disorder, agoraphobia, and specific phobia. The dimensional approach proposes that five different factors contribute to the structure of the Positive and Negative Syndrome Scale (PANSS), with anxiety as a major symptom of the "dysphoria" dimension. Concerning diagnosis, it is unclear whether psychotic and neurotic anxiety differs in nature or intensity. Nevertheless, both are frequently opposed. DISCUSSION: Psychotic anxiety is intense, profound and hermetic. In contrast to neurotic anxiety, it is associated with psychomotor disturbances, such as agitation and sideration. There is no specific tool to evaluate anxiety in schizophrenia. The dimensional approach usually runs an evaluation using items or factors extracted from the most widely-used scales, i.e. PANSS or Brief Psychiatric Rating Scale (BPRS) or from anxiety scales developed in non-schizophrenic populations, such as the Hamilton Anxiety Scale (HAMA). Recently, we developed a specific scale for hetero-evaluation (Échelle Anxiété Schizophrénie [EAS scale]). The EAS scale was recently validated and the study of its sensitivity is ongoing. THERAPEUTICAL ISSUES: Several studies have examined the effects of antipsychotics on the anxious/depressive cluster extracted from the PANSS, and some other studies have specifically evaluated the effect of antipsychotics on depressive symptoms using the Montgomery and Asberg Depression Rating Scale (MADRS) and Calgary Depression Scale for Schizophrenia (CDSS), but to our knowledge, no study has reported the effect of antipsychotics or other treatment on anxiety when using a schizophrenia-specific scale. There are no specific guideline treatments for anxiety in schizophrenia. Among phenothiazines, cyamemazine is frequently prescribed in France, because of its potent anxiolytic activity and good neurological tolerance. Some authors have suggested a specific treatment with benzodiazepines. However, benzodiazepines should be used with caution, due to undesirable actions such as dependence, rebound and potentiation of certain lateral effects.

Inhibition of the Na+/K+ cotransport system by cyclic AMP and intracellular Ca2+ in human red cells.

Human erythrocytes are able to incorporate cyclic AMP (cAMP) in amounts larger than those required to saturate cAMP-dependent protein kinase. In contrast to previous observations in avian red blood cells in which cAMP stimulates the Na+/K+ cotransport system, we demonstrate that cAMP inhibits this system in human erythrocytes. The cotransport inhibition is enhanced by addition of phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine to the incubation medium. The cAMP concentration giving half-maximal cotransport inhibition showed a wide variation among different individuals (from 0.1 to 5 mM external cAMP concentration). In contrast to cAMP, cyclic GMP showed little effect on the cotransport system. Ca2+ introduced into the cell interior was an inhibitor of the Na+/K+ cotransport system. These results suggest that in human cells in which endogeneous levels of cAMP and Ca2+ are modulated by hormones, the Na+/K+ cotransport system may be under hormonal regulation.

A kinetic analysis of Na-Li countertransport in human red blood cells.

We examined the kinetic properties of the interactions between inner and outer cation sites of the Na-Li countertransport system in human red blood cells. Li-stimulated Na efflux [V(Na)] was measured as a function of external Li [(Li)o] and internal Na [(Na)i] contents. At each (Li)o, a Hanes plot of (Na)i/V(Na) vs. (Na)i allowed us to calculate the apparent dissociation constant for internal Na (KiNa) and the maximal rate of Na efflux [Vmax(Na)]. In erythrocytes from 10 different subjects, the Vmax(Na)/KiNa ratios were independent of the external Li concentrations. In other experiments, Na-stimulated Li efflux [V(Li)] was measured as a function of external Na and internal Li contents. In three subjects studied, the Vmax(Li)/KiLi ratios were independent of the external Na concentrations. The data strongly suggest that the countertransport mechanism is consecutive ("ping-pong").

Endogenous sodium-potassium-chloride cotransport inhibitor in congestive heart failure.

OBJECTIVES: This study sought to evaluate the relation, if any, between fluid overload in congestive heart failure (CHF) and a newly discovered endogenous natriuretic factor acting like loop diuretic drugs: cotransport inhibitory factor (CIF). BACKGROUND: The humoral mechanisms regulating volume overload in CHF are not fully understood. Therefore, we investigated whether there is a role for CIF in this pathologic condition. METHODS: Plasma and urinary CIF levels were investigated in 23 patients with chronic CHF and compared with changes in plasma atrial natriuretic peptide (ANP). Twelve patients without CHF served as control subjects. RESULTS: CHF was associated with a highly significant threefold increase in both plasma CIF levels (mean +/- SD 7.10 +/- 3.01 vs. 2.28 +/- 0.92 U/ml, p < 0.0001) and urinary CIF excretion (7,849 +/- 3,600 vs. 2,351 +/- 1,297 U/day, p < 0.0001) with respect to patients without CHF. CIF increased as a function of impairment in left ventricular ejection fraction (r = -0.703, p < 0.0001) and the severity of clinical status. Plasma ANP was also increased in patients with CHF, although to a lesser extent (68%, p = 0.0501) than plasma CIF, and was also significantly correlated with left ventricular ejection fraction (r = -0.552, p = 0.0004). CONCLUSIONS: Plasma and urinary CIF activities were strongly and very significantly increased in chronic CHF. In addition to ANP, this long-term natriuretic agent may be of potential importance in reducing fluid overload in CHF.

Kinetic aspects of red blood cell sodium transport systems in essential hypertension.

A kinetic study of the interaction of internal sodium with four different erythrocyte sodium transport pathways (ouabain-sensitive Na+-K+ pump, bumetanide-sensitive Na+-K+ cotransport system, Na+-Li+ countertransport, and Na+leak) has facilitated the distinction of the following subgroups of patients with essential hypertension: 1) Leak (+), exhibiting increased passive sodium permeability; 2) Co (-), showing low apparent affinity of the Na+-K+ cotransport system for internal sodium; 3) Counter (+), characterized by increased maximal rates of Na+-Li+ countertransport; and 4) Pump (-), characterized by an abnormally low apparent affinity of the Na+-K+ pump for internal sodium. We present here a new and simple sodium-loading method that allows a simultaneous kinetic study of the above abnormalities. The use of this kinetic assay may improve estimation of the frequencies, clinical features, and other properties of each subgroup of hypertensive patients in different populations.

Abnormal erythrocyte cation transport in primary hypertension. Clinical and experimental studies.

Several abnormalities concerning sodium (Na+) transport in erythrocytes of essential hypertensive patients have been recently observed. An abnormal extrusion of an erythrocyte Na+ load was described in our laboratory. This defect appeared to be specific for essential hypertension since it was absent in the secondary forms of the disease. The present investigation was performed on 194 Caucasian subjects with essential hypertension or born of hypertensive parents, 86 normotensive controls, and 14 families (78 subjects) studied over two to three generations. The distribution pattern of the erythrocyte defect is compatible with the expression of a single gene transmitted according to an autosomic and dominant mode. To confirm the genetic association between the red blood cell abnormality and primary hypertension, genetically hypertensive rats were investigated in parallel to our clinical studies. A reduction in the net Na+ extrusion from red blood cells was found in two varieties of genetic hypertension (SHR and H-prone-Na+-sensitive Sabra rats). The abnormality could be detected before the development of a significant hypertension. When these various rat sub-strains were acutely or chronically loaded with Na+ (either intraperitoneally or orally), a significant increase in erythrocyte Na+ content was observed only in those substrains having a genetic propensity to develop hypertension. This finding, which appears to be a consequence of the reduction in net Na+ efflux, is of interest for several reasons. It confirms the existence of a close association between a genetic predisposition to develop high blood pressure and cell Na+ retention in the presence of an excess Na+ intake. It draws attention to the possible role of intracellular Na+ in the pathogenesis of primary hypertension. Of more practical importance, the abnormal Na+ handling in erythrocytes may be a genetic marker of primary hypertension.

Interaction of internal Na+ and external K+ with the erythrocyte Na+, K+ cotransport system in essential hypertension.

External K+ inhibits the maximal rate of outward Na+, K+ cotransport in human red cells with no effect on the apparent affinity for internal Na+. The K+ concentration giving half-maximal inhibition (KIK) varied from 16 to 30 mM in 24 normotensive control subjects. Six of the 38 hypertensive patients showed a KIK above the upper limit of this normal range. Only three hypertensive patients showed a KIK below normal range. The internal Na+ content giving half-maximal stimulation of outward Na+, K+ cotransport (KSNa) was measured in the hypertensive patients (a normal range of KSNa = 9 to 16 mmol/liter cells was previously established in 50 normotensive control subjects). Eighteen hypertensive patients showed an abnormally high KSNa, as previously described in hypertensive patients whose Na+, K+ cotransport system had a low affinity for internal Na+ (Co -). Comparison of KSNa with KIK showed that all six hypertensive patients with high KIK and all three hypertensive patients with low KIK were Co - hypertensive.

Salidiuretic action by genistein in the isolated, perfused rat kidney.

The urinary isoflavonoid genistein inhibits membrane Na-K-Cl cotransporters at similar concentrations as furosemide, but the significance of this action is unknown. Genistein was therefore investigated in rats for its potential salidiuretic actions. In the isolated, perfused rat kidney, genistein induced a maximal salidiuretic action similar to that of furosemide but was 3 to 5 times less potent than furosemide in terms of active doses (natriuresis EC50, 237+/-92 versus 56+/-20 micromol/L for genistein and furosemide, respectively). Genistein and furosemide had no additive salidiuretic actions. Genistein had no significant effect on glomerular filtration rate but was able to significantly reduce renal vascular resistance with respect to vehicle isolated perfused kidney. Indomethacin (10 micromol/L), a blocker of prostaglandin biosynthesis, reduced salidiuresis and renal vasorelaxation by genistein. Subcutaneous genistein (15 mg/kg) induced a statistically significant increase in diuresis and natriuresis with respect to vehicle during the first 6 hours of administration in rats. In conclusion, genistein compares well with furosemide in vitro for its salidiuretic profile and potency in the isolated perfused rat kidney and is also natriuretic by the subcutaneous route in the rat. Further studies are required to investigate potential natriuretic and perhaps hypotensive actions of dietary genistein.

The erythrocyte Na,K,Cl cotransporter and its circulating inhibitor in Dahl salt-sensitive rats.

BACKGROUND: Abnormal Na,K,Cl cotransport is thought to be a pathogenic factor in Dahl salt-sensitive rat models, but the only direct evidence for this is an increased cotransport activity found in erythrocytes from salt-loaded Dahl salt-sensitive rats. OBJECTIVE: To re-examine erythrocyte cotransport fluxes and a circulating cotransport inhibitory factor (CIF) in inbred Dahl rats maintained on a low (0.2%) salt diet. Cotransport fluxes were investigated both under basal conditions and after stimulation by cell shrinking. METHODS: Blood was drawn from 12 male Dahl salt-sensitive and 12 Dahl salt-resistant rats of the inbred John Rapp strain. Erythrocyte Na,K,Cl cotransport activity was equated to the bumetanide-sensitive fluxes of sodium, rubidium or lithium. Plasma CIF activity was tested in human erythrocytes. RESULTS: In Dahl salt-sensitive rats: (1) plasma CIF activity (5.7+/-0.4 units/ml) was modestly higher than in Dahl salt-resistant rats (2.97+/-0.12 units/ml, P < 0.0001), but much lower than that previously found in salt-loaded Dahl salt-sensitive rats (16.1 units/ml), and (2) erythrocytes exhibited a similar bumetanide-sensitive sodium efflux (rate constant 0.056+/-0.008 h(-1)) as in Dahl salt-resistant rats (0.047+/-0.007 h(-1)). Following hypertonic shock, the bumetanide-sensitive rubidium influx reacted more to cell shrinkage in Dahl salt-sensitive than in Dahl salt-resistant erythrocytes (cell volume decrease required to stimulate bumetanide-sensitive rubidium influx by 4000 micromol/l cells per h=-4.04+/-0.36 versus -5.89+/-0.44 fl, respectively; P< 0.01). CONCLUSIONS: When fed a low-salt diet, Dahl salt-sensitive rats present slightly increased plasma CIF levels and normal erythrocyte cotransport fluxes under basal conditions, but an increased response to a hypertonic shock. Therefore, if there is any primary cotransport abnormality in Dahl salt-sensitive rats, it appears to be restricted to the renal Na,K,Cl cotransporter BSC1 isoform. Alternatively, any such change may be the consequence of abnormal regulation by osmolarity-dependent mechanisms.

Blood pressure and erythrocyte Na+ transport systems in a French urban male population.

This paper reports an investigation of blood pressure (taken as a continuous variable) as a function of: erythrocyte Na+ content; Na+,K+ pump; Na+,K+ cotransport and Na+,Li+ countertransport fluxes, and passive cation permeabilities in fresh erythrocytes from 129 French males who were living in an urban area and were not under treatment for any medical condition (after allowing for the effects of age, body mass index, alcohol and tobacco consumption). In contrast with previous findings in a North American population, we were unable to confirm that blood pressure was correlated with erythrocyte Na+ content and Na+,K+-AT-Pase activity. Conversely, the only transport parameter correlated (negatively) with blood pressure was outward Na+,K+ cotransport [r = -0.20, P less than 0.05 and r = -0.19, P less than 0.05, for systolic (SAP) and diastolic arterial pressure (DAP), respectively; n = 114]. When allowing for age, body mass index and alcohol consumption, the correlation coefficient between the Na+,K+ cotransport system and blood pressure increased from -0.20 to -0.28 (P less than 0.01) for SAP and from -0.19 to -0.28 (P less than 0.01) for DAP (n = 105). We conclude that the correlations between blood pressure and erythrocyte Na+ transport function could differ between North American and French (or Mediterranean) populations. In any case, a decreased pump or outward Na+,K+ cotransport activity may lead hypertensive subjects to a similar increase in cell Na+ (and Ca2+) content in the vascular wall.

Renal and vascular actions of equol in the rat.

BACKGROUND: The urinary isoflavonoid equol inhibits membrane Na-K-Cl cotransporters at similar concentrations to those at which furosemide inhibits them, but the significance of this action is not known. OBJECTIVE: To investigate the potential salidiuretic and vascular actions of equol in the rat. METHODS: Renal functioning was assessed in vitro in the isolated perfused kidney and in vivo in conscious rats. The vascular contractility of isolated aorta was assessed. RESULTS: In the isolated perfused kidney equol was concentrated 50- to 70-fold in the urinary fluid, it was 3-4 times less potent than furosemide at increasing diuresis, natriuresis and kaliuresis (the difference was due to its higher protein-binding affinity), and it induced a modest but significant increase in glomerular filtration rate. In vivo, orally administered equol was a modest natriuretic agent, about 8-fold less potent than orally administered furosemide (in molar terms). In isolated aortic rings precontracted by administration of phenylephrine, administration of equol relaxed the contracted aorta at 10-fold lower concentrations (concentration for half-maximal activity 58.9 +/- 16 micromol/l, n = 3) than did furosemide (concentration for half-maximal activity 633 +/- 145 micromol/l, n = 3). CONCLUSIONS: Equol is a modest natriuretic and vasorelaxant agent in the rat. Further studies are required in order to investigate the potential natriuretic and perhaps hypotensive actions of dietary equol precursors (daidzein).

Erythrocyte cation transport systems and plasma lipids in a general male population.

The relationships between five erythrocyte cation transport systems (Na(+)-K+ pump, Na(+)-K+ cotransport, Na(+)-Li+ countertransport and Na+ and K+ passive permeabilities) and plasma lipids (total plasma cholesterol, high-density lipoprotein cholesterol and triglycerides) were investigated in 129 male adult subjects with no known history of hypertension. Na+ and K+ erythrocyte contents were also considered for their possible relationships with plasma lipids. Na(+)-K+ cotransport and passive Na+ permeability were both significantly correlated with plasma triglycerides. Conversely, no significant correlation was found between erythrocyte cation transport systems or erythrocyte cation contents and total cholesterol. These findings suggest that plasma lipids can modulate erythrocyte ion transport activity in the general population.

Fenspiride and membrane transduction signals in rat alveolar macrophages.

Fenspiride inhibits the calcium signal evoked by the inflammatory peptide formyl-Met-Leu-Phe (fMLP) in peritoneal macrophages, but at concentrations (approximately 1 mM) far above the therapeutic range (approximately 1 microM). Here, in rat alveolar macrophages, high fenspiride concentrations (1 mM) were required to inhibit the calcium signals evoked by the calcium agonist Bay K8644 or by ionomycin. Moreover, fenspiride (1 mM) was a poor inhibitor of the cell membrane depolarization induced by gramicidine D. By contrast, fenspiride blocked Na+-H+ antiport activation by (i) fMLP with an IC50 = 3.1 +/- 1.9 nM and (ii) PMA (phorbol 12-myristate 13-acetate) with an IC50 = 9.2 +/- 3.1 nM. Finally, protein kinase C (PKC) activity of macrophage homogenate was not significantly modified by 10 or 100 microM fenspiride (at 100 microM: 2.57 +/- 1.60 vs. 2.80 +/- 1.71 pmol/10(6) cells/min). In conclusion, fenspiride inhibits fMLP- and PMA-induced pH signals in rat alveolar macrophages, probably by acting distally on the PKC transduction signal. This pH antagonistic action may be relevant for the antiinflammatory mechanism of fenspiride and requires further investigation.

Stimulation of K+ fluxes by diuretic drugs in human red cells.

Two different families of diuretic drugs--(i) (aryloxy)acetic acid diuretics (ethacrynic acid, tienilic acid and (--)-indacrinone) and (ii) furopyridines [(+/-)-BN 50157 and (+/-)-cycletanide]--stimulate K+ movements across human red cell membranes. The kinetic properties of this effect (K+-specificity, saturability, optical isomerism, antagonism by structural analogues, etc.) strongly suggest that it is mediated by a K+-transport system with a specific binding site for some diuretic drugs. The stimulated K+ fluxes are resistant to ouabain, bumetanide and quinine, thus suggesting that they are not mediated by the Na+,K+-pump, Na+,K+-cotransport or by the Ca2+-dependent K+-permeability ('Gardos effect'). The replacement of Cl- by NO3- ions can either decrease, increase or have no effect on the stimulated K+ fluxes, depending on the diuretic drug. Although not conclusive, these observations suggest that the K+ fluxes are not mediated by stimulation of a chloride-dependent K+ carrier. The study of structural analogues showed that the intensity of the stimulation of K+ fluxes is strongly correlated with the magnitude of the natriuretic effect. Curiously, some antiallergic furopyridines are able to inhibit K+ fluxes.

Influence of membrane sodium transport upon the relation between blood lead and blood pressure in a general male population.

Five red blood cell cation transport systems (RBCTS), together with blood lead level and blood pressure, were measured in 129 male adult subjects who were not occupationally exposed to lead or subsequent to a course of treatment for hypertension. Blood lead was positively related with systolic blood pressure, and to a lesser degree with diastolic blood pressure. Blood lead was found significantly negatively related to one of the RBCTS, Na+,K+ cotransport, and in addition, Na+,K+ cotransport appeared negatively related to blood pressure. Final results showed that blood lead no longer accounts for an increase in systolic blood pressure when Na+,K+ cotransport was taken into account; the same trend was observed with diastolic blood pressure. These findings suggest that a blood lead-related Na+,K+ cotransport impairment could explain the blood pressure increase observed to parallel the blood lead increase.

Disturbances of transmembranous sodium transport systems induced by ethanol in human erythrocytes. An approach to the pressor effect of alcohol.

Several epidemiological and clinical studies have established a clear association between alcohol consumption and hypertension. The mechanism of the pressor effect of ethanol is not well understood. We studied the in vitro effects of increasing amounts of ethanol on different Na+ transport systems from human erythrocytes. Ethanol at concentrations higher than 32 mmol/L stimulated ouabain-sensitive Na+ efflux, the Na+ efflux depending on the Na+:Li+ countertransport and Na+ leak. At the same concentrations, ethanol inhibited bumetanide-sensitive Na+ efflux. We conclude that, with the exception of Na+-K+ pump, alcohol-induced alterations and those observed in erythrocytes from essential hypertensives may overlap. Therefore, alcohol consumption could potentiate those genetic abnormalities of Na+ transport and contribute to the pathogenesis of essential hypertension.

[Na+, K+, Cl-]-cotransport function and dysfunction in different forms of primary hypertension.

We investigated the effect of an increase in cell Na+ content on outward and inward unidirectional fluxes catalyzed by the [Na+, K+, Cl-]-cotransport system in human erythrocytes (incubated in Li-Rb media). Erythrocytes with low Na+ content exhibited an uncoupled K+ efflux. The increase in cell Na+ content resulted in a more marked stimulation of outward Na+, K+ than of inward Li+, Rb+ cotransport fluxes (with stoichiometries not very different from one-to-one). These results suggest that in human erythrocytes and in nonepithelial cells with small but outwardly directed electrochemical Cl- gradients, the [Na+, K+, Cl-]-cotransport system may behave as a "second pump" by using the extra energy supplied by an additional net [K+, Cl-] efflux. The [Na+, K+, Cl-]-cotransport system (of vascular cells and/or noradrenergic endings) may play two different roles in primary hypertension: (a) "defective second pump" in some essential hypertensive patients with decreased cotransport affinity for internal Na+ and (b) "compensatory second pump" in other forms of primary hypertension where abnormalities in the Na+, K+ pump or in other ion transport systems may predispose the cell to a defective extrusion of excess cell Na+ content.

Opposite effects of cell growth factors and cicletanine sulfate on the sodium-independent [Cl-/HCO3-] exchange in cultured vascular smooth muscle.

Cicletanine sulfate was tested on bicarbonate-dependent pHi changes in cultured vascular smooth muscle (A10 line). Cicletanine sulfate exhibited double reactivity with regard to the cell alkalinization induced by bicarbonate uptake. The analysis of 11 concentration-response curves revealed a high reactivity component (IC50 approximately 3.5 x 10(-8) mol/L) and a weak reactivity component (IC50 approximately 4 x 10(-4) ml/L). Regarding the cell acidification induced by bicarbonate extrusion, cicletanine sulfate exhibited a single high reactivity component (IC50 = 5.9 +/- 2.9 x 10(-7) mol/l; mean +/- SD, n = 7). The high and weak reactivity sites were both sensitive to DIDS. Analysis of the data strongly suggested that the highly reactive site corresponds to a sodium-independent (Cl-/HCO3-] exchanger, which catalyzes net bicarbonate efflux, and the weak-reactivity site corresponds to the inwardly directed sodium-dependent [Cl-/HCO3-] exchanger. Three cell growth factors--epidermal growth factor, arginine-vasopressin, and insulin--were able to stimulate the sodium-independent [Cl-/HCO3-] exchanger in A10 cells. Finally, cicletanine sulfate (30 mumol/L) partially inhibited serum-dependent A10 cell growth. In conclusion, cicletanine sulfate and cell growth factors exert opposite effects (inhibition and stimulation, respectively) on the sodium-independent [Cl-/HCO3-] exchanger in cultured vascular smooth muscle. The effect of cicletanine sulfate on the sodium-independent [Cl-/HCO3-] exchanger may account for the ability of cicletanine to favorably alter vascular pathology in spontaneously hypertensive rat (SHR) models.

Inhibition by (-)-cicletanine of the vascular reactivity to angiotensin II and vasopressin in isolated rat vessels.

In pithed rats, the levorotatory (-)-enantiomer of cicletanine reduces the pressor responses to angiotensin II (AII) and also, to a lesser extent, those to arginine-vasopressin (AVP). Here we have attempted to characterize further these inhibitory effects by studies of isolated perfused rat kidney and mesenteric vascular beds. In the isolated rat kidney, (-)-cicletanine behaves as a noncompetitive antagonist of AII- and AVP-receptor stimulation, with Ki values of 9.6 and 208 micromol/L respectively. In the isolated mesenteric vascular bed, (-)-cicletanine antagonized both AII dependent contractions with an inhibitory concentration (IC50) of 54.0 +/- 20.5 micromol/L (n = 6), and AVP dependent contractions with an IC50 of 31.6 +/- 5.0 micromol/L (n = 8). In conclusion, (-)-cicletanine antagonizes AII more effectively in rat kidney than in mesenteric vascular beds. Moreover, in rat kidney vascular beds (-)-cicletanine is more potent in blocking the pressor responses to AII than in blocking those to AVP. A selective blockade of AII induced contractions in kidney vascular beds can be one factor explaining both the greater antagonistic potency of (-)-cicletanine against AII compared with AVP in pithed rats, and the renal protective properties of cicletanine in both hypertensive and aged rats.

5-HT3- and 5-HT2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity.

RATIONALE: Cyamemazine is a neuroleptic compound which possesses anxiolytic properties in humans. On the other hand, 5-HT3- and 5-HT2C-receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types. OBJECTIVE: The present study was undertaken to establish whether cyamemazine antagonizes 5-HT3- and/or 5-HT2C-mediated responses, and whether it compares with reference compounds. METHODS: Cyamemazine was tested for its ability to antagonize: (i) 5-HT3-dependent contraction of the isolated guinea-pig ileum and bradycardic responses in the rat and (ii) 5-HT2C-dependent phospholipase C (PLC) stimulation in rat brain membranes. RESULTS: In isolated guinea-pig ileum, cyamemazine potently and competitively antagonized 5-HT-dependent contractions (pA2 = 7.52 +/- 0.08; n = 5). In this test, cyamemazine was 5-7 times more potent (pIC50 = 6.75 +/- 0.13) than tropisetron (pIC50 = 6.02 +/- 0.04). In rats, cyamemazine i.v. antagonized 5-HT-dependent bradycardic responses with ID50% = 3.2 +/- 1.5 mg/kg (n = 4). Finally, in rat brain membranes cyamemazine antagonized 5-HT2C-dependent PLC stimulation with Ki = 424 nM (mianserin exhibits a Ki = 113 nM). CONCLUSIONS: Cyamemazine behaves as an antagonist at both 5-HT3- and 5-HT2C-receptors, which compares well with reference compounds. These 5-HT3- and 5-HT2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders.