The <i>in vitro</i> pharmacology of xamoterol (ICI 118,587)

Malta, Errol; Mian, M.; Raper, C.

doi:10.1111/j.1476-5381.1985.tb08845.x

Cited by 33 publications

(28 citation statements)

References 23 publications

(25 reference statements)

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“…This is consistent with pA 2 values reported by Strosberg (1997). Likewise, xamoterol (␤ 1 agonist) (Malta et al, 1985), causes a concentration-dependent relaxation of the IAS smooth muscle that is selectively antagonized by CGP 20712A (␤ 1 -AR antagonist).…”

Section: Discussionsupporting

confidence: 80%

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Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Rathi

Kazerounian²,

Banwait³

et al. 2003

J Pharmacol Exp Ther

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The purpose of the present study was to characterize different ␤-adrenoceptors (␤-ARs) and determine their role in the spontaneously tonic smooth muscle of the internal anal sphincter (IAS). ]iodocyanopindolol to ␤-AR subtypes revealed the presence of a high-affinity site (K d1 ϭ 96.4 Ϯ 8.7 pM; B max1 ϭ 12.5 Ϯ 0.6 fmol/mg protein) and a low-affinity site (K d2 ϭ 1.96 Ϯ 1.7 nM; B max2 ϭ 58.7 Ϯ 4.3 fmol/mg protein). Competition binding with selective ␤-AR antagonists revealed that the high-affinity site correspond to ␤ 1 /␤ 2 -AR and the low affinity site to ␤ 3 -AR. Receptor binding data suggest the predominant presence of ␤ 3 -AR over ␤ 1 /␤ 2 -AR. Western blot studies identified ␤ 1 -, ␤ 2 -, and ␤ 3 -AR subtypes. The presence of ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs was further demonstrated by mRNA analysis using RT-PCR. The studies demonstrate a comprehensive functional and molecular characterization of ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs in IAS smooth muscle. These studies may have important implications in anorectal and other gastrointestinal motility disorders.It is well known that postjunctional ␤-adrenoceptors (␤-ARs) mediate the inhibitory effects of sympathetic nerve stimulation in different smooth muscles including those of the gastrointestinal tract (Manara et al., 1995b;Gauthier et al., 2000). The intestinal ␤-AR was originally described as a ␤ 1 -and ␤ 2 -AR (Lands et al., 1967). Further studies with gastrointestinal preparations from several species established the relaxant effect of classical ␤-AR (␤ 1 and ␤ 2 ) agonists (Bennett, 1965;Hedges and Turner, 1969;De Ponti et al., 1996a). Subsequently, studies investigating ␤-ARs in gastrointestinal smooth muscle from several species demonstrated relaxation responses that were resistant to propranolol and displayed lower affinity to other conventional ␤-AR antagonists (Arch and Kaumann, 1993;Goldberg and Frishman, 1995;Strosberg, 1997;Manara et al., 2000). This finding, along with the emergence of a new class of ␤-AR agonists described first in adipocytes (Feve et al., 1991), suggested the presence of an "atypical" class of ␤-ARs. In 1989, Emorine et al. (1989) cloned and sequenced ␤ 3 -AR and found that it shared the pharmacological characteristics of the atypical ␤-AR.The ␤ 3 -AR has been found in a variety of mammalian tissues (Berkowitz et al., 1995) including white and brown adipocytes (Muzzin et al., 1991), trachea (Webber and Stock,

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Section: Discussionsupporting

confidence: 80%

“…The ␤ 1 -AR agonist xamoterol (Malta et al, 1985) produced a concentration-dependent fall in the basal tension of the IAS smooth muscle (Fig. 3A) with an EC 50 value of 1.02 ϫ 10 Ϫ7 M (n ϭ 5-8).…”

Section: Effect Of Xamoterol On the Basal Tone Of Ias Smooth Musclementioning

confidence: 99%

Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Rathi

Kazerounian²,

Banwait³

et al. 2003

J Pharmacol Exp Ther

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“…In contrast, xamoterol rescues contextual memory retrieval in NE-deficient Dbh 2/2 mice at 0.3 and 1 mg/kg. The potency of xamoterol for b 1 relative to b 2 receptors is 10-fold in rat tissue ex vivo and at mouse adrenergic receptors in vitro (Malta et al 1985;Beer et al 1988;Murchison et al 2004). As a result, we hypothesized that the higher doses of xamoterol activate b 2 as well as b 1 receptors and that the activation of b 2 receptors impairs retrieval.…”

Section: Discussionmentioning

confidence: 99%

Xamoterol impairs hippocampus-dependent emotional memory retrieval via G_i/o-coupled β₂-adrenergic signaling

Schutsky¹,

Ouyang²,

Thomas³

2011

Learn. Mem.

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Xamoterol, a partial b 1 -adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) and in a transgenic mouse model of Down syndrome in which NE levels are reduced. Restoration of retrieval by xamoterol in these two models complements the observation that NE and b 1 signaling are required for hippocampusdependent retrieval of contextual and spatial reference memory in wild-type mice and rats. Additional evidence indicates that cAMP-mediated PKA and Epac signaling are required for the retrieval of hippocampus-dependent memory. As a result, we hypothesized that xamoterol has effects in addition to the stimulation of b 1 receptors that, at higher doses, act to counter the effects of b 1 signaling. Here we report that xamoterol-induced disruption of memory retrieval depends on b 2 -adrenergic receptor signaling. Interestingly, the impairment of memory retrieval by xamoterol is blocked by pretreatment with pertussis toxin, an uncoupling agent for G i/o signaling, suggesting that b 2 signaling opposes b 1 signaling during memory retrieval at the level of G protein and cAMP signaling. Finally, similar to the time-dependent roles for NE, b 1 , and cAMP signaling in hippocampus-dependent memory retrieval, xamoterol only impairs retrieval for several days after training, indicating that its effects are also limited by the age of the memory. We conclude that the disruption of memory retrieval by xamoterol is mediated by G i/o -coupled b 2 signaling, which opposes the G s -coupled b 1 signaling that is transiently required for hippocampus-dependent emotional memory retrieval.

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“…Our results have confirmed that denopamine has a high intrinsic activity on P1-adrenoceptors, even if it is not a full agonist. Thus, the high intrinsic activity of denopamine seems to be responsible for it acting as an agonist in man (Hori et al, 1991 , 1987), uterus and ileum (Malta et al, 1985) and in the dog femoral artery (Nuttall & Snow, 1982) which are all P2-adrenoceptor containing preparations. Moreover, denopamine and xamoterol, when tested for antagonist activity in the right atria and trachea, exhibited different pA2 values, indicating that both agonists show PI-and P2-adrenoceptor antagonist actions.…”

Section: Discussionmentioning

confidence: 99%

“…In the present paper, we have studied the pharmacological properties of T-0509 by using guinea-pig cardiac muscle, trachea and aorta as systems with functions of fI-, P2-and a-adrenoceptors (Buckner & Patil, 1971;Patil et al, 1971;1972;Malta et al, 1985;Hattori et al, 1987), respectively.…”

Section: Introductionmentioning

confidence: 99%

Selective and full β₁‐adrenoceptor agonist action of a catechol derivative of denopamine (T‐0509) in the guinea‐pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline

Yabana¹,

Watanabe²,

Narita³

et al. 1992

British J Pharmacology

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1The pharmacological actions of T-0509, a 3-hydroxy derivative of denopamine, were studied in various guinea-pig tissues; these effects were compared with those of isoprenaline, denopamine and xamoterol. 2 The intrinsic activities of the positive inotropic actions of T-0509, denopamine and xamoterol compared with isoprenaline (= 100%) in the papillary muscle were 99%, 83% and 28%, respectively, while their relative potencies (ECQ0 agonist ECQ0 isoprenaline) were 0.23, 33 and 1.4, respectively. The intrinsic activities of T-0509, denopamine and xamoterol as positive chronotropic agents in the right atria were 98%, 69% and 48%, respectively, and their equipotent concentrations (isoprenaline = 1) were 0.24, 50 and 4, respectively. 3 The positive chronotropic actions of T-0509 and denopamine were antagonized by bisoprolol (3 x 10-8 M), but not by ICI 118,551 (3 x 10-8 M).4 The intrinsic activity of T-0509 in histamine-contracted tracheae was similar to that of isoprenaline, but its equipotent concentration was 38; the effects of both agents were antagonized by ICI 118,551 (3 X 10-8 M), but not by bisoprolol (3 X 10-M). Denopamine and xamoterol did not show any agonist activity on guinea-pig trachea. 5 Denopamine and xamoterol antagonized the positive chronotropic (pA2, denopamine: 6.98, xamoterol: 7.75) and tracheal relaxant (pA2, denopamine: 5.39, xamoterol: 6.25) effects of isoprenaline. 6 Isoprenaline, T-0509 and denopamine, but not xamoterol, contracted the guinea-pig aorta in a decreasing order in the presence of propranolol (10-6 M).7 Based on the above studies, T-0509 appears to be a highly selective fI-adrenoceptor agonist with full agonist properties, while denopamine and xamoterol appear to be selective, but partial i3I-adrenoceptor agonists.

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The in vitro pharmacology of xamoterol (ICI 118,587)

Cited by 33 publications

References 23 publications

Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Xamoterol impairs hippocampus-dependent emotional memory retrieval via G_i/o-coupled β₂-adrenergic signaling

Selective and full β₁‐adrenoceptor agonist action of a catechol derivative of denopamine (T‐0509) in the guinea‐pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline

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The in vitro pharmacology of xamoterol (ICI 118,587)

Cited by 33 publications

References 23 publications

Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Functional and Molecular Characterization of β-Adrenoceptors in the Internal Anal Sphincter

Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling

Selective and full β1‐adrenoceptor agonist action of a catechol derivative of denopamine (T‐0509) in the guinea‐pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline

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Xamoterol impairs hippocampus-dependent emotional memory retrieval via G_i/o-coupled β₂-adrenergic signaling

Selective and full β₁‐adrenoceptor agonist action of a catechol derivative of denopamine (T‐0509) in the guinea‐pig cardiac muscle and trachea: comparison with denopamine, xamoterol and isoprenaline