5-HT_1A Receptor

1. The aim of the present work was to characterize the 5-hydroxytryptamine1A (5-HT1A) antagonistic actions of (-)-pindolol and WAY 100635 (N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide). Studies were performed on 5-HT1A receptors located on 5-hydroxytryptaminergic neurones in the dorsal raphe nucleus (DRN) and on pyramidal cells in the CA1 and CA3 regions of the hippocampus in rat brain slices. 2. Intracellular electrophysiological recording of CA1 pyramidal cells and 5-hydroxytryptaminergic DRN neurones showed that the 5-HT1A receptor agonist 5-carboxamidotryptamine (5-CT) evoked in both cell types a concentration-dependent cell membrane hyperpolarization and a decrease in cell input resistance. On its own, (-)-pindolol did not modify the cell membrane potential and resistance at concentrations up to 10 microM, but it antagonized the 5-CT effects in a concentration-dependent manner. Similar antagonism of 5-CT effects was observed in the CA3 hippocampal region. (-)-Pindolol also prevented the 5-HT1A receptor-mediated hyperpolarization of CA1 pyramidal cells due to 5-HT (15 microM). In contrast, the 5-HT-induced depolarization mediated by presumed 5-HT4 receptors persisted in the presence of 3 microM (-)-pindolol [1].

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. [1]

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Background: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. Methods: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). Results: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). Conclusions: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength[2].

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3. In the hippocampus, (-)-pindolol completely prevented the hyperpolarization of CA1 pyramidal cells by 100 nM 5-CT (IC50=92 nM; apparent KB=20.1 nM), and of CA3 neurones by 300 nM 5-CT (IC50=522 nM; apparent KB= 115.1 nM). The block by (-)-pindolol was surmounted by increasing the concentration of 5-CT, indicating a reversible and competitive antagonistic action. 4. Extracellular recording of the firing rate of 5-hydroxytryptaminergic neurones in the DRN showed that (-)-pindolol blocked, in a concentration-dependent manner, the decrease in firing elicited by 100 nM 5-CT (IC50=598 nM; apparent KB= 131.7 nM) or 100 nM ipsapirone (IC50= 132.5 nM; apparent KB= 124.9 nM). The effect of (-)-pindolol was surmountable by increasing the concentration of the agonist. Intracellular recording experiments showed that 10 microM (-)-pindolol were required to antagonize completely the hyperpolarizing effect of 100 nM 5-CT. 5. In vivo labelling of brain 5-HT1A receptors by i.v. administration of [3H]-WAY 100635 ([O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1 -piperazinyl)ethyl-N-(2-pyridyl)cyclo-hexane-carboxamide) was used to assess their occupancy following in vivo treatment with (-)-pindolol. (-)-Pindolol (15 mg kg[-1]) injected i.p. either subchronically (2 day-treatment before i.v. injection of [3H]-WAY 100635) or acutely (20 min before i.v. injection of [3H]-WAY 100635) markedly reduced [3H]-WAY 100635 accumulation in all 5-HT1A receptor-containing brain areas. In particular, no differences were observed in the capacity of (-)-pindolol to prevent [3H]-WAY 100635 accumulation in the DRN and the CAI and CA3 hippocampal areas. 6. Intracellular electrophysiological recording of 5-hydroxytryptaminergic DRN neurones showed that WAY 100635 prevented the hyperpolarizing effect of 100 nM 5-CT in a concentration-dependent manner (IC50=4.9 nM, apparent KB=0.25 nM). In CA1 pyramidal cells, hyperpolarization induced by 50 nM 5-CT was also antagonized by WAY 100635 (IC50 = 0.80 nM, apparent KB= 0.28 nM)[3].

Receptor binding assays [1]
CHO cells, stored at −80°C in 1 mM EDTA, 25 mM Tris. HCl, pH 7.4 (20°C) were thawed and pelleted for 30 min at 17,000 × g, 4°C, and then homogenized by Polytron (7 mm probe, 3×10 s, speed setting 8) in a binding buffer containing (mM): EGTA 5, EDTA 1, MgCl2 4, ascorbic acid 1, phenylmethyl-sulfonyl fluoride 0.5, Tris-HCl 50, pH 7.5 (37°C). For receptor saturation assays, homogenates were incubated for 2 h at 37°C in a final volume of 0.5 ml (10 μg protein) with 1–200 pM (-)-[125I]-cyanopindolol. Non-specific binding was defined as binding not removed with 200 μM (-)-isoprenaline. Bound radioligand was isolated by filtration through Whatman GF/B paper and radioactivity counted. To estimate the affinity of (-)-pindolol, (-)-CGP12177 and (-)-propranolol for the β1-adrenoceptor, cell membranes were labeled with ~30 pM (-)-[125I]-cyanopindolol in the absence and presence of concentrations (0.03 nM–100 μM) of competing ligand. Saturation binding assays and binding inhibition data were analyzed with non-linear regression and dissociation equilibrium constants calculated from saturation assays (KD) and binding inhibition assays (Ki).

Right atrial trabeculae were prepared and set up to contract at 1 Hz at 37°C as described (Gille et al. 1985). After a 20 min exposure to 20 μM IBMX, a single cumulative concentration-effect curve to (-)-pindolol was determined, followed by the addition of 6 μM (-)-CGP12177 and finally 600 μM (-)-isoprenaline. The effects of (-)-pindolol were further investigated in the presence of 200 nM (-)-propranolol and 20 μM IBMX in which a single cumulative concentration-effect curve to (-)-pindolol up to 6 μM was determined, followed by a curve for (-)-CGP12177 in the presence of 6 μM (-)-pindolol. For 5 of 8 patients, a curve for (-)-CGP12177 was also determined on another trabeculum from the same atrium in the presence of both (-)-propranolol and IBMX. The experiments were concluded by the administration of (-)-isoprenaline (600 μM). The −log (molar concentration) of (-)-pindolol and (-)-CGP12177 producing half-maximal increases in contractile force (−logEC50M) were determined. An estimate of the affinity of (-)-pindolol (−log dissociation equilibrium constant KB,M = pKB) for the β1-adrenoceptor site activated by (-)-CGP12177, was calculated from −logEC50 values for (-)-CGP12177 in the presence and absence of (-)-pindolol, using the law of propagation of errors (Kaumann 1990). To investigate whether β3-adrenoceptors contribute to the effects of (-)-pindolol (Gauthier et al. 1998) in human atrium two sets of experiments were carried out. Firstly, the ability of the nitric oxide-synthase inhibitor L-NMMA to abrogate possible β3-adrenenoceptor-mediated negative inotropic effects (Gauthier et al. 1998) was determined. Secondly, the cardiostimulant effects of (-)-pindolol were determined in the absence or presence of the selective human β3-adrenoceptor antagonist L-748,337 (Candelore et al. 1999) [1].

Male C57BL/6J mice were 7–12 weeks of age and 23.9 ± 0.6 g in weight for KPC and 17.5 ± 0.4 g in weight for LLC at the start of experimental procedures. Thirty‐one mice were randomized to sham (n = 8) or orthotropic tumour inoculation (n = 23) of 3 million KPC cells in a volume of 40 μL into the tail of the pancreas, as described before. 5 Tumour‐bearing mice were further randomized to treatment with placebo (n = 11) or 3 mg/kg/day of S‐pindolol (n = 12) once daily for 13 days. Body composition, that is, lean and fat mass, was assessed by nuclear magnetic resonance (NMR) spectroscopy 1 day before tumour cell inoculation and on the day of euthanasia. For the LLC model, 30 C57BL/6 mice (mean body weight of 17.5 ± 0.4 g) were randomized to treatment: no tumour injection, sham (n = 5), placebo (sterilized water, n = 15) or 3 mg/kg/day of S‐pindolol (n = 10) for 13 days. Mice received an intramuscular (hind leg) inoculum of 5 × 105 LLC cells obtained from exponential tumours, as described before. 6 , 7 Grip strength test was performed by a pull bar connected to an isometric force transducer. The animals were allowed to grasp the bar and were then pulled backwards in the horizontal plane. 8 In both models, S‐pindolol was given once daily by gavage. Results, represented as mean ± SD, were analysed using GraphPad Prism 8.0. All data were tested for normal distribution using the Kolmogorov–Smirnov test. Group comparisons were performed by one‐way analysis of variance (ANOVA) with adjustment for multiple testing of sham‐treated controls and S‐pindolol‐treated tumour‐bearing animals against tumour‐bearing vehicle controls. A P‐value of <0.05 was considered significant. [2]

Absorption, Distribution and Excretion
Absorption
The mean oral bioavailability of pindolol is 87-92%. A 5 mg oral dose reaches a Cmax of 33.1 ± 5.2 ng/mL, with a Tmax of 1-2 hours.

Route of Elimination
80% of an oral dose is eliminated in the urine, with 25-40% of the dose as the unchanged parent compound. 6-9% of an intravenous dose is eliminated in the feces. Overall, 60-65% of a dose is eliminated as glucuronide and sulfate metabolites.

Volume of Distribution
The volume of distribution of pindolol is approximately 2-3 L/kg.

Clearance
In otherwise healthy patients, the systemic clearance of pindolol is 400-500 mL/min. In patients with cirrhosis, the clearance of pindolol varies from 50-300 mL/min.

Pindolol is rapidly absorbed from the GI tract. Reported bioavailability ranges from 50-95%; bioavailability in uremic patients may be at the lower end of this range. Food does not reduce bioavailability but may increase the rate of GI absorption. Pindolol reportedly does not undergo substantial metabolism on first pass through the liver; ... only about 20% of an oral dose is metabolized on first pass. Peak plasma concentrations of 45-167 ng/ml are reached within 1-2 hr after administration of a single 20-mg dose. The extent of absorption may be decreased in patients with impaired renal function. The effect of pindolol on heart rate usually is seen within 3 hr and acute hemodynamic effects persist for 24 hr after administration of the drug.

Approximately 40-60% of pindolol is bound to plasma proteins. In healthy adults, the drug has an apparent volume of distribution of 1.2-2 l/kg; volume of distribution may be decreased by 50% in uremic patients. Pindolol is distributed into milk.

Elimination of pindolol appears to be a first-order process over a dose range of 5-20 mg. The drug has a plasma half-life of 3-4 hr in healthy adults. Plasma half-life increases to 3-11.5 hr in patients with renal failure, to 7-15 hr in geriatric patients, and varies from 2.5-30 hr in patients with hepatic cirrhosis. Approximately 60-65% of pindolol is metabolized in the liver to hydroxylated metabolites which are then excreted in urine as glucuronides and ethereal sulfates. In healthy adults, about 35-50% of the drug is excreted in urine unchanged; in patients with creatinine clearances less than 20 ml/min, less than 15% is excreted in urine unchanged.

Pindolol is rapidly and reproducibly absorbed (greater than 95%), achieving peak concentrations within 1 hr of drug administration ... The blood concentrations are proportional in a linear manner to the administered dose in the range of 5-20 mg ... Pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.

The polar metabolites are excreted with a half-life of approximately 8 hr and thus multiple dosing therapy ... results in a less than 50% accumulation in plasma. About 6%-9% of an administered intravenous dose is excreted by the bile into the feces. PDR; Physicians' Desk Reference Generics. 2nd Ed. Montvale, NJ: Medical Economics Co. p. 2488 (1996)

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Metabolism / Metabolites
30-40% of a dose of pindolol is not metabolized. The remainder is hydroxylated and subsequently undergoes glucuronidation or sulfate conjugation.

Pindolol reportedly does not undergo substantial metabolism on first pass through the liver; ... only about 20% of an oral dose is metabolized on first pass.

Approximately 60-65% of pindolol is metabolized in the liver to hydroxylated metabolites which are then excreted in urine as glucuronides and ethereal sulfates.

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Biological Half-Life
The half life of pindolol varies from 3-4 hours but can be as high as 30 hours in patients with cirrhosis of the liver.

The drug has a plasma half-life of 3-4 hr in healthy adults. Plasma half-life increases to 3-11.5 hr in patients with renal failure, to 7-15 hr in geriatric patients, and varies from 2.5-30 hr in patients with hepatic cirrhosis

Hepatotoxicity
Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on pindolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, pindolol has not been convincingly linked to instances of clinically apparent liver injury. Other beta-blockers have been implicated in rare instances of clinically apparent liver injury with a latency to onset ranging from 4 to 24 weeks, a hepatocellular pattern of serum enzyme elevations, and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Recommendation for Use During Lactation: Limited information indicates that maternal pindolol produces low levels in milk. It also has a short half-life and only moderate renal excretion, so it would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.

◉ Effects in Breastfed Infants
Relevant published information on pindolol was not found as of the revision date. A study of mothers taking beta-blockers during nursing found a numerically, but not statistically significant increased number of adverse reactions in those taking any beta-blocker. Although the ages of infants were matched to control infants, the ages of the affected infants were not stated. None of the mothers were taking pindolol.

◉ Effects on Lactation and Breastmilk
Relevant published information on the effects of beta-blockade or pindolol during normal lactation was not found as of the revision date. A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol.

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Protein Binding
Pindolol is 40% bound to proteins in plasma. Pindolol mainly binds more strongly to alpha-1-acid glycoprotein than it does to serum albumin.

[1]. Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists. J Med Chem. 2018;61(6):2518-2532.

[2]. Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models. J Cachexia Sarcopenia Muscle. 2023 Jun;14(3):1244-1248.

[3]. Antagonist properties of (-)-pindolol and WAY 100635 at somatodendritic and postsynaptic 5-HT1A receptors in the rat brain. Br J Pharmacol. 1998 Feb;123(3):449-62.

It has been suggested previously (Kaumann 1989) that the (-)-pindolol-evoked tachycardia observed in man (Man In’t Veld and Schalekamp 1981; Man In’t Veld et al. 1982; Iskos et al. 1998; Benditt et al. 1999) is mediated through an atypical β-adrenoceptor. Our results support the hypothesis that (-)-pindolol acts as a cardiostimulant through a (-)-propranolol-resistant site of the β1-adrenoceptor because:
1.(-)-Pindolol increased with identical potency both atrial force and cAMP levels through recombinant β1-adrenoceptors in the presence of (-)-propranolol and IBMX
2.(-)-Pindolol antagonized similarly the stimulant effects of (-)-CGP12177 on atrial force and cAMP levels in CHO cells expressing recombinant β1-adrenoceptors. The blocking potency of (-)-pindolol against (-)-CGP12177 matched its stimulant potency (pKB≈-logEC50, Table 1) in both systems. Because (-)-CGP12177 acts through a (-)-propranolol-resistant site of the β1-adrenoceptor (Konkar et al. 2000; Kaumann 2000; Granneman 2001), this quantitative agreement supports the proposal that (-)-pindolol not only acts through this site but also competes with (-)-CGP12177 for it.
At variance with our evidence, Baker et al. (2003) reported very recently that pindolol acts as an agonist through two sites at β1-adrenoceptors, one with high affinity and the other with low affinity. Our evidence is consistent with the hypothesis that (-)-pindolol only causes agonist effects through activation of the low affinity site at both recombinant β1-adrenoceptors and human atrium. Reasons for the different results are not known. Unfortunately, it is not clear whether Baker et al. (2003) used racemic pindolol or the (-)-pindolol isomer. Furthermore, it is also unknown which polymorphic variant was used in the study of Baker et al. (2003).
We also demonstrated for both (-)-pindolol and (-)-propranolol, high-affinity binding at, and blockade of recombinant β1-adrenoceptors. These nanomolar affinity estimates are in agreement with previous affinity estimates from human atrium for both (-)-pindolol (Kaumann and Lobnig 1986) and (-)-propranolol (Gille et al. 1985). The subnanomolar affinity binding of (-)-CGP12177, which we estimated for recombinant β1-adrenoceptors, agrees with a similar high affinity estimate (KB=0.2 nM) obtained from blockade of the positive inotropic effects of (-)-noradrenaline by (-)-CGP12177 in human right atrium. Taken together, this evidence is consistent both in atrium and CHO cells with blockade of catecholamine effects by (-)-pindolol, (-)-propranolol and (-)-CGP12177 through a β1-adrenoceptor site for which these antagonists have high affinity. A second site of the β1-adrenoceptor, for which the 3 β-blockers have an affinity approximately 200–400 times lower than for the high affinity site, is only activated to mediate cardiostimulation by (-)-pindolol and (-)-CGP12177 but not (-)-propranolol.
(-)-Pindolol not only increased atrial contractile force but also hastened relaxation, consistent with a cAMP-dependent phosphorylation of phospholamban and troponin I, observed to occur through β-adrenoceptor stimulation in human atrium (Kaumann et al. 1996; Sarsero et al. 2003). The increases of cAMP through β1-adrenoceptors in CHO cells, produced by (-)-pindolol and (-)-CGP12177, are consistent with activation of a cAMP pathway. However, the intrinsic activities of the two agents in CHO cells are lower, relative to the effects of (-)-isoprenaline, than the corresponding intrinsic activities on atrial contractile force (Table 1). This discrepancy is probably related to the more physiological coupling of the (-)-propranolol-resistant receptor site to the cAMP pathway in the native atrial cell environment than in the CHO cells hosting β1-adrenoceptors.
(-)-Pindolol can elicit tachycardia, resistant to blockade by propranolol, as observed in anaesthetized dogs and in a patient with dysautonomia and undetectable plasma noradrenaline (Clark et al. 1982). The magnitude of tachycardia may depend on pathology, as for example conditions with low (-)-noradrenaline levels and consequent “supersensitivity” favoring the observation of tachycardia (Man In’t Veld and Schalekamp 1981; Man In’t et al. 1982). Our model of in vitro human right atrium relied on the use of a phosphodiesterase inhibitor to reveal positive inotropic effects to (-)-pindolol, indicating these were not as strong as those of (-)-CGP12177 (this study; Kaumann 1996; Sarsero et al. 2003) or (-)-noradrenaline (this study; Molenaar et al. 2002).
It must, however, be taken into account that clinically used pindolol is the racemate, containing equal proportions of (-)-pindolol and (+)-pindolol (Kaumann 1989). (+)-Pindolol has been found to bind selectively to cardiac β2-adrenoceptors in feline ventricular membranes (Morris and Kaumann 1984) and to elicit sinoatrial tachycardia in guinea pig mediated through β2-adrenoceptors (Walter et al. 1984). It is unlikely that racemic pindolol produces tachycardia through interaction of its (+)-enantiomer with human sinoatrial β2-adrenoceptors because the tachycardia of racemic pindolol in the dog is not blocked by propranolol (Clark et al. 1982). Although pindolol has been shown to produce small elevations of cAMP through β2-adrenoceptors of S49 cells primed with forskolin (Jasper et al. 1990), these effects are antagonized by propranolol with hardly any dissociation between stimulant potencies and affinities estimated both from binding and antagonism (Jasper et al. 1990). Pindolol has also been reported to bind to recombinant β2-adrenoceptors with a 40 times higher affinity (Ballesteros et al. 2001) than the affinity estimated by us for recombinant β1-adrenoceptors, pointing to a different interaction mode of (-)-pindolol with the two subtypes. Taken together these considerations make it unlikely that β2-adrenoceptors are involved in pindolol-evoked cardiostimulation in man.
For a variety of reasons it is also unlikely that β3-adrenoceptors are involved in the cardiostimulant effects of (-)-pindolol. The β3-adrenoceptor has been reported to mediate cardiodepressant effects through a nitric oxide (NO)-dependent pathway in human ventricular preparations (Gauthier et al. 1998). Our experiments with L-NMMA are inconsistent with an involvement of NO and β3-adrenoceptors in the effects of both (-)-pindolol and (-)-CGP12177. The β3-adrenoceptor has been found to enhance cardiac contractility only when overexpressed in the hearts of transgenic mice (Kohout et al. 2001). We found that the β3-adrenoceptor selective blocker, L-748,337 (Candelore et al. 1999) had no effect on the positive inotropic effects of (-)-pindolol. Pindolol is also a partial agonist with lower intrinsic activity than the typical β3-selective agonist BRL37344 on recombinant β3-adrenoceptors expressed at high density in CHO cells (Emorine et al. 1989). Unlike the affinity estimated for the low-affinity site of the β1-adrenoceptor (KB=300–500 nM, this work), the affinity of (-)-pindolol for recombinant β3-adrenoceptors is considerably higher (Ki=11 nM) (Emorine et al. 1989). In contrast to our results with β1-adrenoceptors, in which low micromolar and nanomolar concentrations of (-)-pindolol antagonize the effects of (-)-CGP12177 and (-)-isoprenaline, respectively, 100 μM pindolol did not block the isoprenaline effects on recombinant β3-adrenoceptors (Emorine et al. 1989).
Unbound plasma concentrations of (-)-pindolol obtained following therapeutic administration of racemic (±)-pindolol would be expected to partially occupy the low affinity site of the β1-adrenoceptor. We calculate that concentrations of 60–120 nM are reached following the oral administration of one 15 mg (Gross et al. 2001) or 2×10 mg pindolol tablets, respectively (Hsyu and Giacomini 1985), sufficient to evoke direct cardiostimulant effects. Stronger effects would be even more likely to occur with higher doses (45 mg/day) used therapeutically. We speculate that 60–120 nM of plasma (-)-pindolol would in particular cause significant increases in nocturnal sinoatrial heart rate when parasympathetic nerve activity is high while sympathetic nerve activity is quiescent (Van de Borne et al. 1994; Vanolie et al. 1995). Nocturnally, the bradycardic effects of (-)-pindolol will be reduced due to negligible interaction with endogenous catecholamines. Consistent with this idea, pindolol induced increases in heart rate are higher at night (Fitscha et al. 1982; Kantelip et al. 1984; Channer et al. 1994).
We conclude that the dissociation between blockade and stimulation, previously observed with (-)-pindolol in vitro in isolated myocardium of several species, has been confirmed both in human atrium and recombinant β1-adrenoceptors. (-)-Pindolol exerts intrinsic sympathomimetic activity through a (-)-propranolol-resistant low-affinity receptor site, and blockade of the effects of catecholamines through a high-affinity β1-adrenoceptor site. We propose that the low-affinity β1-adrenoceptor site mediates the tachycardia caused by racemic pindolol.[1]

248.15

C, 67.71; H, 8.12; N, 11.28; O, 12.89

13523-86-9

Pindolol-d7; 1185031-19-9

4828

White to off-white solid powder

1.2±0.1 g/cm3

457.1±35.0 °C at 760 mmHg

167-171 °C(lit.)

230.3±25.9 °C

0.0±1.2 mmHg at 25°C

1.597

3

3

6

18

248

0

JZQKKSLKJUAGIC-UHFFFAOYSA-N

InChI=1S/C14H20N2O2/c1-10(2)16-8-11(17)9-18-14-5-3-4-13-12(14)6-7-15-13/h3-7,10-11,15-17H,8-9H2,1-2H3

1-(1H-indol-4-yloxy)-3-(propan-2-ylamino)propan-2-ol

Prinodolol; Betapindol; Pindolol; Visken; Calvisken; LB-46; LB46; Pindolol; Prindolol; Carvisken; LB 46; Visken; urapindol; Pinbetol;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~50 mg/mL (~201.4 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (8.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (8.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (8.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)