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Francesc Artigas - One of the best experts on this subject based on the ideXlab platform.

  • Pindolol augmentation enhances response outcomes in first depressive episodes
    European Neuropsychopharmacology, 2009
    Co-Authors: Maria J Portella, Javier De Diegoadelino, Dolors Puigdemont, Rosario Perezegea, Enric Alvarez, Francesc Artigas, Victor Perez
    Abstract:

    Effectiveness of Pindolol addition to SSRIs is still a matter of debate. Recently, Geretsegger et al. [Geretsegger, C., Bitterlich, W., Stelzig, R., Stuppaeck, C., Bondy, B. and Aichhorn, W. (2008) Paroxetine with Pindolol augmentation: a double-blind, randomized, placebo-controlled study in depressed in-patients. Eur. Neuropsychopharmacol. 18, 141-146.] have found that never-medicated depressed patients showed a significant sustained response with Paroxetine + Pindolol treatment. Also, patients with a first depressive episode displayed a trend for higher sustained response rates with Pindolol co-administration. Re-analysing the data of a previous clinical trial of Fluoxetine + Pindolol [Perez, V., Gilaberte, I., Faries, D., Alvarez, E. and Artigas, F. (1997). Randomised, double-blind, placebo-controlled trial of Pindolol in combination with Fluoxetine antidepressant treatment. Lancet 349, 1594-1597.], we have found that first depressive episodes are associated with a significant higher percentage of sustained responses when administering Fluoxetine + Pindolol (70.3%) compared to Fluoxetine + Placebo (44%). Moreover, based on a survival analysis, among the patients with a first depressive episode, those who received Fluoxetine + Pindolol achieved a sustained response significantly earlier (19 days) than those on Fluoxetine + Placebo (35 days). Interestingly, none of these effects were observed in the subsample of recurrent patients. The results suggest that Pindolol augmentation accelerates and enhances the action of SSRI at the beginning of the illness.

  • Pindolol augmentation of antidepressant response
    Current Drug Targets, 2006
    Co-Authors: Francesc Artigas, Albert Adell, Pau Celada
    Abstract:

    Pindolol, a partial s-adrenoceptor/5-HT 1A receptor antagonist was first used to accelerate the onset of action of antidepressant drugs in 1994. Since then, it has been used in more than a dozen controlled trials to examine whether it can reduce the lag to clinical improvement, and/or improve the clinical response in treatment-resistant patients. A recent metaanalysis concluded that Pindolol accelerates the antidepressant response but does not increase the effectiveness of SSRIs in unresponsive patients. Several studies have examined the pharmacology of Pindolol to clarify the neurobiological basis of its clinical action. Pindolol was initially used due to its ability to block 5-HT1A receptor-mediated responses and to enhance the neurochemical effects of SSRIs. In transfected cells, however, Pindolol is a weak (20-25%) partial agonist at 5-HT1A receptors and, as such, its actions greatly depend on the system used. In line with this, other reports have also shown that Pindolol can reduce serotonergic cell firing when given alone. Positron emission tomography (PET) scan studies have shown that Pindolol displays a preferential occupancy of pre- vs. postsynaptic 5-HT1A receptors, although the overall occupancy is lower than desirable, which suggests that higher doses (e.g., 15 mg/day) may be more effective than the currently used 7.5 mg daily dosage. However, given the complex pharmacology of Pindolol, it is hoped that new developments in this field can proceed through the use of a) selective and silent 5-HT1A receptor antagonists in combination with SSRIs, or b) dual action agents (SSRI + 5-HT1A receptor blockers).

  • how does Pindolol improve antidepressant action
    Trends in Pharmacological Sciences, 2001
    Co-Authors: Francesc Artigas, Pau Celada, Marc Laruelle, Albert Adell
    Abstract:

    Since 1994, the beta-adrenoceptor and 5-HT(1A/1B) receptor ligand Pindolol has been used to accelerate or enhance the clinical effects of antidepressant drugs, such as the selective 5-HT reuptake inhibitors (SSRIs), that act primarily on 5-HT-containing neurones. Pindolol was initially thought to act by preventing the inhibition of 5-HT release, elicited by SSRIs and other 5-HT-acting drugs, as a result of its ability to antagonize the action of 5-HT at midbrain raphe 5-HT(1A) autoreceptors that control the activity of ascending 5-HT-mediated pathways. However, the partial agonist properties of Pindolol at 5-HT(1A) receptors and beta-adrenoceptors suggest that other explanations for its action are also possible. In this article, recent controversial data on the mechanism of action of Pindolol, which are crucial for the development of more rapid and efficient antidepressant therapies, will be discussed.

  • augmentation of fluoxetine s antidepressant action by Pindolol analysis of clinical pharmacokinetic and methodologic factors
    Journal of Clinical Psychopharmacology, 2001
    Co-Authors: Victor L Perez, Dolors Puigdemont, Enric Alvarez, Inmaculada Gilaberte, Francesc Artigas
    Abstract:

    In a controlled trial, the beta-adrenoceptor/5-hydroxytryptamine-1A (5-HT1A) receptor antagonist Pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (> or = 50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus Pindolol (N = 55) and 29 days for fluoxetine plus placebo (N = 56) (p = 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of Pindolol remained stable between 3 days (first blood sampling) and 6 weeks. Mean values were approximately 26 nM, a concentration higher than the Ki of (-)Pindolol for human 5-HT1A autoreceptors (11 nM). Plasma fluoxetine and norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p = 0.043), but there was no significant relationship to the clinical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained response between both groups would have also been detected (1) in a 2-week trial, (2) without a placebo lead-in phase, and (3) with less frequent visits. However, the use of "response" instead of "sustained response" as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p = 0.08 instead of p = 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data of all sustained responders (N = 27) in the fluoxetine-plus-placebo group with the first 27 responders in the fluoxetine-plus-Pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively; p = 0.0002). This indicates that the faster response in the fluoxetine-plus-Pindolol group is not a result of the greater proportion of responders.

  • a double blind randomized placebo controlled trial of Pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors
    Archives of General Psychiatry, 1999
    Co-Authors: Victor Perez, Dolors Puigdemont, Joaquim Soler, Enrique Alvarez, Francesc Artigas
    Abstract:

    Background Pindolol has been reported to hasten the antidepressant action of selective serotonin reuptake inhibitors in open-label and placebo-controlled trials. Pilot studies also suggested that Pindolol could augment the antidepressant response in unresponsive patients. We investigated whether the addition of Pindolol can induce a rapid response in treatment-resistant patients. Methods After a single-blind lead-in placebo phase of 5 days to exclude placebo responders, 80 outpatients with major depression who did not respond to a minimum of 6 weeks of treatment with clomipramine hydrochloride, 150 mg/d; fluoxetine hydrochloride, 40 mg/d; fluvoxamine maleate, 200 mg/d; or paroxetine hydrochloride, 40 mg/d, were randomly assigned to additionally receive placebo (3 times daily) or Pindolol (2.5 mg 3 times daily) for 10 days. The median number of ineffective treatments in the current episode was 2 (range, 1-4). Hamilton Rating Scale for Depression and Montgomery-Asberg Scale for Depression scores were used as primary measures of efficacy. Results At end point, the Hamilton and Montgomery-Asberg scores and change from baseline in Hamilton score were not significantly different in patients taking placebo or Pindolol. The response rate was equal in both groups (12.5%). No differences in the clinical outcome were found when the various pretreatment subgroups were considered. At end point, the plasma concentration of Pindolol was 9.9±5.1 ng/mL (mean±SD; n=40). Conclusions Although Pindolol can accelerate the antidepressant action of selective serotonin reuptake inhibitors in previously untreated patients, it does not elicit a rapid clinical response in treatment-resistant patients within a 10-day period.

Michael Maes - One of the best experts on this subject based on the ideXlab platform.

  • Pindolol and mianserin augment the antidepressant activity of fluoxetine in hospitalized major depressed patients including those with treatment resistance
    Journal of Clinical Psychopharmacology, 1999
    Co-Authors: Michael Maes, Isabelle Libbrecht, Fran Van Hunsel, Dirk Campens, Herbert Y Meltzer
    Abstract:

    The aims of this study were to examine whether Pindolol, a serotonin (5-hydroxytryptamine [5-HT])-1A receptor antagonist, and mianserin, a 5-HT2A/C and alpha2-adrenoceptor (alpha2-AR) antagonist, may augment the clinical efficacy of fluoxetine, a selective serotonin reuptake inhibitor, and shorten the latency of onset of antidepressive activity in the treatment of major and treatment-resistant depression (TRD). Ten days after admission to the hospital, 31 major depressed patients were randomly assigned using a double-blind, controlled design to receive fluoxetine 20 mg daily, fluoxetine 20 mg daily plus Pindolol 7.5 mg daily, or fluoxetine 20 mg plus mianserin 30 mg daily for 5 weeks. The 17-item Hamilton Rating Scale for Depression (HAM-D) score was the primary outcome measure. Analysis of efficacy was conducted according to the intent-to-treat analysis principle considering the change from baseline to endpoint. It was found that fluoxetine plus Pindolol and fluoxetine plus mianserin were significantly more effective than fluoxetine alone. Using an outcome measure of 50% reduction in the HAM-D, a 60% response rate was found in patients treated with either fluoxetine plus Pindolol or fluoxetine plus mianserin compared with a 9% response rate in patients treated with fluoxetine alone. The HAM-D score 1 week after starting fluoxetine plus mianserin decreased more than 4 points and was significantly greater than that obtained by fluoxetine alone. The results suggest that Pindolol and mianserin augment the efficacy of fluoxetine in the treatment of TRD and that mianserin, but not Pindolol, may significantly shorten the latency of onset of antidepressive action when combined with fluoxetine.

  • Efficacy of treatment with trazodone in combination with Pindolol or fluoxetine in major depression
    Journal of affective disorders, 1996
    Co-Authors: Michael Maes, Eric Vandoolaeghe, Roger Desnyder
    Abstract:

    Fluoxetine, a selective serotonin (5-HT) reuptake inhibitor (SSRI), and trazodone, a heterocyclic antidepressant, are effective in the treatment of major depression and treatment resistant depression (TRD). Chronic treatment with both drugs causes increases in extracellular 5-HT through 5-HT reuptake inhibition and desensitization of inhibitory 5-HT1A autoreceptors. It has been shown that Pindolol, a serotonin (5-HT)1A-receptor antagonist, may shorten the latency of onset of SSRIs in depression. The aim of the present study was to examine whether Pindolol may increase the efficacy of a subtherapeutical dosage of trazodone in the treatment of major depression and TRD, defined according to the Thase and Rush criteria (1995). Thirty-three major depressed inpatients of whom 26 with TRD participated in this study. Ten days after hospitalization, treatment with trazodone 100 mg/day was started. After 1 week trazodone treatment, patients were randomized-using a double blind placebo controlled design-to receive trazodone 100 mg/day+placebo; trazodone 100 mg/day+Pindolol 7.5 mg/day: or trazodone 100 mg/day+fluoxetine 20 mg/day and treated during 4 weeks. The 17-item Hamilton Depression Rating Scale (HDRS) was used as outcome measure. It was found that trazodone+Pindolol was as effective as trazodone+fluoxetine in the treatment of major depression and TRD and significantly more effective than trazodone+placebo. Using an outcome measure of 50% reduction in the HDRS, we found that 72.5% of the depressed patients treated with trazodone+Pindolol and 75% of depressed patients treated with trazodone+fluoxetine showed a clinically significant response compared with 20.0% of trazodone+placebo-treated patients.

  • effect of Pindolol on hormone secretion and body temperature partial agonist effects
    Journal of Neural Transmission, 1996
    Co-Authors: Herbert Y Meltzer, Michael Maes
    Abstract:

    Pindolol has been shown to be a partial agonist at 5-HT1a receptors in preclinical studies. It has also been reported to inhibit the effects of other 5-HT1a partial agonists such as ipsapirone and buspirone on hormone secretion and body temperature in man, indicating its antagonist action at 5-HT1a receptors in man. To determine if Pindolol has 5-HT1a agonist as well as antagonist effects in man, Pindolol, 30 mg, p.o. and placebo, were given single blind in random order to 23 normal men with indwelling venous catheters and its effects on hormone secretion and body temperature noted. Pindolol significantly increased basal plasma cortisol concentrations, whereas it decreased plasma prolactin (PRL) concentrations and body temperature. The increase in plasma cortisol due to Pindolol suggests a 5-HT1a agonist action and is consistent with a 5-HT1a partial agonist mechanism in man whereas the PRL effects are consistent with an antagonist action at 5-HT1a receptors. The effects of Pindolol on plasma cortisol concentration and body temperature were significantly negatively correlated. Furthermore, these results indicate significant differences in the 5-HT1a-dependent regulation of PRL and the hypothalamo-pituitary-adrenal (HPA) axis and body temperature, and suggest that human basal PRL secretion is tonically stimulated by a 5-HT1a mechanism whereas the HPA axis and body temperature are not. Since rodent studies suggest differences in 5-HT1a receptor sensitivity between males and females, the results reported here need to be replicated in females. These differences in the effect of Pindolol are discussed in terms of receptor reserve theory.

  • Pindolol pretreatment blocks stimulation by meta chlorophenylpiperazine of prolactin but not cortisol secretion in normal men
    Psychiatry Research-neuroimaging, 1995
    Co-Authors: Herbert Y Meltzer, Michael Maes
    Abstract:

    Previous reports from this laboratory have shown that Pindolol, a partial serotonin1A receptor agonist, inhibited prolactin, but not cortisol secretion induced by administration of the serotonin (5-HT) precursor L-5-hydroxytryptophan or the direct-acting 5-HT2A/5HT2C receptor agonist MK-212. The findings suggest additive or interactive effects of 5-HT1A and 5-HT2A/5-HT2C receptors in modulating 5-HT-related prolactin, but not cortisol, responsivity. To examine further the role of 5-HT1A and 5-HT2A/5-HT2C receptors in prolactin and cortisol secretion in healthy men, the effects of meta-chlorophenylpiperazine (mCPP), a potent 5-HT receptor agonist, on the above hormones were studied in eight healthy men with and without Pindolol pretreatment. It has previously been demonstrated that ketanserin, a 5-HT2A antagonist, and ritanserin, a 5-HT2A/5-HT2C antagonist, block the prolactin and attenuate the hypothalamic-pituitary-adrenal axis responses to mCPP in man or rodents. Administration of mCPP induced a significant increase in plasma concentrations of prolactin and cortisol. The mCPP-induced prolactin concentrations were significantly blocked by pretreatment with Pindolol, whereas mCPP-stimulated cortisol levels were not diminished by Pindolol pretreatment. Thus, mCPP-induced prolactin secretion appears to require the availability of both 5-HT2C and 5-HT1A receptor activation, since blockade of either of these receptors may diminish the mCPP-induced prolactin response. Cortisol secretion stimulated by mCPP may occur following 5-HT2C receptor stimulation in the presence of 5-HT1A receptor blockade.

P J Cowen - One of the best experts on this subject based on the ideXlab platform.

  • preferential 5 ht1a autoreceptor occupancy by Pindolol is attenuated in depressed patients effect of treatment or an endophenotype of depression
    Neuropsychopharmacology, 2004
    Co-Authors: Eugenii A Rabiner, Zubin Bhagwagar, Roger N Gunn, P J Cowen, Paul M Grasby
    Abstract:

    Using positron emission tomography and the selective 5-HT1A receptor radioligand [11C]WAY100635, we previously demonstrated a preferential occupancy of 5-HT1A autoreceptors, compared to postsynaptic receptors by Pindolol in healthy volunteers. We have speculated that preferential occupancy may be clinically important for the purported actions of Pindolol in accelerating the antidepressant effects of selective serotonin re-uptake inhibitors (SSRIs). In this study, we have examined the preferential occupancy by Pindolol of 5-HT1A autoreceptors, following three different Pindolol regimes (10 mg single dose, 2.5 mg t.i.d., and 5 mg t.i.d., in 15 depressed patients on SSRIs. In addition, seven healthy volunteers were examined following a single 10 mg dose of Pindolol. We found a preferential occupancy of 22.6+/-7.7% following a single dose of 10 mg of Pindolol, in the healthy volunteers, which was attenuated in depressed patients on the same dose of Pindolol to 2.9+/-10.8% (Student's t=3.94, df=12, p=0.002). In addition, we found a significant negative correlation between the degree of preferential occupancy and the severity of depression as assessed by the Hamilton depression rating score (HAM-D), Spearman's rho=-0.728, N=14, p=0.003, in the depressed sample. A possible mechanism underlying preferential occupancy and the attenuation of this phenomenon in depressed patients on SSRIs may include changes in the proportion of high affinity 5-HT1A sites in the autoreceptor region of the midbrain raphe. Speculatively, the degree of preferential occupancy may serve as a surrogate marker for depression, or the pharmacological effects of antidepressants.

  • Pindolol augmentation of selective serotonin reuptake inhibitors pet evidence that the dose used in clinical trials is too low
    American Journal of Psychiatry, 2001
    Co-Authors: Eugenii A Rabiner, Zubin Bhagwagar, Roger N Gunn, P J Cowen, Peter A Sargent, Christopher J Bench, Paul M Grasby
    Abstract:

    OBJECTIVE: Positron emission tomography (PET) was used to examine whether the dose of Pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT1A) autoreceptor in depressed patients receiving medication. METHOD: The authors examined eight depressed patients on one of two regimes of Pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635. RESULTS: The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT1A autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy. CONCLUSIONS: The dose of Pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of Pindolol’s efficacy will necessitate doses higher than those used in present clinical trials.

  • electrophysiological and neurochemical evidence that Pindolol has agonist properties at the 5 ht1a autoreceptor in vivo
    British Journal of Pharmacology, 1998
    Co-Authors: E M Clifford, P J Cowen, Sarah E Gartside, Valerie Umbers, Mihaly Hajos, T Sharp
    Abstract:

    It has been hypothesized that 5-HT1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the β-adrenoceptor/5-HT1 ligand, Pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of Pindolol at the 5-HT1A autoreceptor by measuring its effect on 5-HT neuronal activity and release in the anaesthetized rat. Pindolol inhibited the electrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose-related (0.2–1.0 mg kg−1, i.v.), and was reversed by the 5-HT1A receptor antagonist, WAY 100635 (0.1 mg kg−1, i.v.), in 6/7 cases tested. Pindolol also inhibited 5-HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of Pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). In microdialysis experiments, Pindolol caused a dose-related (0.8 and 4 mg kg−1, i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 μM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg−1, i.v.), Pindolol (4 mg kg−1, i.v.) did not decrease, but rather increased 5-HT levels. We conclude that, under the experimental conditions used in this study, Pindolol displays agonist effects at the 5-HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of Pindolol in depression which are based on the rationale that the drug is an effective 5-HT1A autoreceptor antagonist.

  • effect of Pindolol on the prolactin response to d fenfluramine
    Psychopharmacology, 1995
    Co-Authors: S B G Park, P J Cowen
    Abstract:

    We studied the effect of the 5-HT1A receptor antagonist, Pindolol, on the prolactin (PRL) response to the 5-HT releasing agent,d-fenfluramine (d-FEN), in ten healthy male volunteers. Pindolol pretreatment lowered baseline PRL levels but, when this effect was taken into account, did not significantly attenuate the PRL response tod-FEN. Within the limitations that attend the use of Pindolol as a 5-HT1A receptor antagonist, the data suggest that although 5-HT1A receptors may play a role in the tonic release of PRL, they are not involved in the release of PRL produced byd-FEN. We propose that the PRL response tod-FEN may involve selective activation of postsynaptic 5-HT2 receptors.

  • effect of Pindolol on endocrine and temperature responses to buspirone in healthy volunteers
    Psychopharmacology, 1992
    Co-Authors: Ian M Anderson, P J Cowen
    Abstract:

    Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, Pindolol (80 mg over 3 days). Following Pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of Pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.

Millan Mark - One of the best experts on this subject based on the ideXlab platform.

  • modulation of dialysate levels of dopamine noradrenaline and serotonin 5 ht in the frontal cortex of freely moving rats by Pindolol alone and in association with 5 ht reuptake inhibitors comparative roles of β adrenergic 5 ht1a and 5 ht1b receptors
    Neuropsychopharmacology, 1999
    Co-Authors: Alain P Gobert, Millan Mark
    Abstract:

    (-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and β1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential β1-AR antagonist, betaxolol, and the preferential β2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-Pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-Pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-Pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of β1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA—though not of NAD. In contrast to (-)-Pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT—but not DA or NAD levels—elicited by fluoxetine. In conclusion, (-)-Pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at β1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-Pindolol upon the actions of antidepressant agents.

  • agonist and antagonist actions of Pindolol at recombinant human serotonin1a 5 ht1a receptors
    Neuropsychopharmacology, 1998
    Co-Authors: Adrian Newmantancredi, C Chaput, Samantha Gavaudan, Laurence Verriele, Millan Mark
    Abstract:

    It has been proposed that the arylalkylamine, (-)Pindolol, potentiates the therapeutic action of antidepressant drugs in humans by blockade of 5-HT1A autoreceptors. Its interactions at human 5-HT1A receptors have not, however, been directly characterized. Herein, we demonstrate that (-)Pindolol exhibits nanomolar affinity at human 5-HT1A receptors expressed in Chinese Hamster Ovary cells (CHO-h5-HT1A; Ki = 6.4 nmol/L). In a functional test of receptor-mediated G-protein activation (stimulation of [35S]-GTP gamma S binding) (-)Pindolol displays an efficacy of 20.3% relative to the endogenous agonist, 5-HT (= 100%). (-)Pindolol also antagonizes 5-HT (100 nmol/L)-stimulated [35S]-GTP gamma S binding, reducing it to 19.8% of control binding. These data indicate that (-)Pindolol acts as a (weak) partial agonist at CHO-h5-HT1A receptors and that it blocks the action of 5-HT at these sites.

Alberto J Kaumann - One of the best experts on this subject based on the ideXlab platform.

  • intrinsic sympathomimetic activity of Pindolol mediated through a propranolol resistant site of the β1 adrenoceptor in human atrium and recombinant receptors
    Naunyn-schmiedebergs Archives of Pharmacology, 2003
    Co-Authors: Shirin S Joseph, James A Lynham, Peter C M Molenaar, Andrew A Grace, William H Colledge, Alberto J Kaumann
    Abstract:

    The beta-blocker (-)-Pindolol produces intrinsic sympathomimetic activity manifested clinically by cardiostimulation, but the beta-adrenoceptor subtype, which mediates these effects, is unknown. Recent work indicates the existence of a (-)-propranolol-resistant site of the cardiac beta(1)-adrenoceptor and we propose that it mediates the cardiostimulation evoked by (-)-Pindolol. We compared the interaction of (-)-Pindolol both with human atrial myocardium and with recombinant beta(1)-adrenoceptors. The effects of (-)-Pindolol on paced human atrial trabeculae were studied in the presence of 3-isobutyl-1-methylxanthine (IBMX; 20 microM). (-)-Pindolol caused small negative and positive inotropic effects at nanomolar and micromolar concentrations respectively, which were unaffected by N(G)-monomethyl-L-arginine (L-NMMA, 10 microM), inconsistent with an involvement of nitric oxide. (-)-Pindolol, in the presence of (-)-propranolol, increased atrial contractile force and cAMP through recombinant beta(1)-adrenoceptors with identical potency (-logEC(50)M=6.5). The positive inotropic effects of (-)-Pindolol were resistant to blockade by L-748,337 (100 nM), a beta(3)-adrenoceptor antagonist. (-)-CGP12177, known to act through the (-)-propranolol-resistant site of the beta(1)-adrenoceptor, also increased with similar potency atrial contractile force (-logEC(50)M=7.6) and cAMP at recombinant beta(1)-adrenoceptors (-logEC(50)M=7.7). (-)-Pindolol blocked the effects of (-)-CGP12177 in human atrium and recombinant beta(1)-adrenoceptors with similar equilibrium dissociation constants (pK(B)=6.5 and 6.3). Thus, stimulant potency and blocking potency of (-)-Pindolol against (-)-CGP12177 agree. In contrast, (-)-Pindolol was 200-400 times more effective at blocking the effects of a catecholamine than the effects of (-)-CGP12177 in both human atrium (pK(B)=9.1) and at recombinant beta(1)-adrenoceptors (pK(B)=8.6). We conclude that the cardiostimulant effects of (-)-Pindolol in human atrial myocardium are mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor with low affinity for (-)-Pindolol. In contrast, (-)-Pindolol blocks the effects of catecholamines through a high-affinity site of the beta(1)-adrenoceptor. beta(3)-Adrenoceptors are not involved in the atrial effects of (-)-Pindolol.