Effects of β₃-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several β₃-adrenergic agonists include antagonism of α₁-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some β₃-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of β₃-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α₁-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α₁-adrenergic agonists, resulting in increased EC₅₀ values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting E_max values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced E_max values. All effects of ZD7114 were resistant to the β₃-adrenergic antagonist L-748337, including increases in EC₅₀ values for α₁-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α₁-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC₅₀ values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α₁-adrenoceptor antagonism to β₃-agonists. Effects of β₃-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α₁-adrenoceptor antagonism by ZD7114 and BRL37344.

01 Jul 2005·Journal of Cardiovascular Pharmacology

Ligands at β2-, β3-, and the Low-Affinity State of β1-Adrenoceptors Block the α1-Adrenoceptor-Mediated Constriction in Human Pulmonary and Rat Mesenteric Arteries

Article

Author: Malinowska, Barbara ; Siedlecka, Urszula ; Kozlowski, Miroslaw ; Laudanski, Jerzy ; Schlicker, Eberhard ; Kozlowska, Hanna

We examined whether the beta2-adrenoceptor agonists fenoterol and salbutamol, the beta3-adrenoceptor agonists CL 316243 and ZD 2079, and the agonists of the low-affinity state of beta-adrenoceptors, cyanopindolol and CGP 12177 block alpha1-adrenoceptors in that concentration range in which they relax the human pulmonary and rat mesenteric arteries preconstricted with phenylephrine 10 microM and 1 microM, respectively. For quantification of vasodilatation pEC25 values and for the antagonism toward alpha1-adrenoceptors, pA2 values were determined. We found that in the rat mesenteric artery, (1) the pEC25 values of the beta-adrenoceptor ligands resemble their respective pA2 values (difference < or = 0.9 log units), and (2) the order of potencies is the same for both parameters, ie, cyanopindolol approximately fenoterol > CGP 12177 > salbutamol > ZD 2079 > CL 316243. In the human pulmonary artery, (1) the pEC25 values are slightly lower (by 0.6-1.3 log units) than their respective pA2 values, and (2) the rank order of potencies is the same for both parameters. In conclusion, the present study suggests that ligands of beta2-adrenoceptors and of non-beta1-non-beta2-adrenoceptors relax rat and human vessels preconstricted with phenylephrine or norepinephrine mainly through their alpha1-adrenolytic effects. Hence, for the investigation of the role of beta-adrenoceptors in vessels, the constrictor agent should be chosen with great caution.

01 Apr 2005·Fundamental & Clinical PharmacologyQ3 · MEDICINE

A search for presynaptic β₃‐adrenoceptors in the rat

Q3 · MEDICINE

Article

Author: Barbara Malinowska ; Agnieszka Zakrzeska ; Grzegorz Kwolek ; Dorota Zelaszczyk ; Eberhard Schlicker

AbstractPresynaptically localized adrenoceptors occur on a variety of neurones. In particular, α2‐adrenoceptors, occurring on neurones of the peripheral and central nervous system, inhibit the release of the respective transmitters whereas β2‐adrenoceptors on some types of postganglionic sympathetic neurones facilitate noradrenaline release. Since only little information is available whether there are also presynaptic β3‐adrenoceptors, we examined the effect of β3‐adrenoceptor agonists on noradrenaline release from the resistance vessels and the hippocampus of the rat and on serotonin and acetylcholine release from the rat hippocampus. In rat hippocampal slices preincubated with 3H‐noradrenaline, 3H‐serotonin and 3H‐choline and superfused in the presence of an inhibitor of the neuronal transporter of the respective neurone, the β3‐adrenoceptor agonist CL 316243 did not affect the electrically evoked tritium overflow. The latter was, however, inhibited by at least 50% by agonists of the respective autoreceptors. CL 316243 and another three β3‐adrenoceptor agonists (BRL 37344, ZD 2079 and CGP 12177) failed to affect the electrically evoked tritium overflow also in slices preincubated with 3H‐noradrenaline and superfused in the presence of the α2‐adrenoceptor antagonist rauwolscine whereas prostaglandin E2 caused a marked inhibition. In pithed and vagotomized rats, the increase in diastolic blood pressure induced by electrical stimulation of the sympathetic outflow was also not affected by CL 316243 but markedly inhibited by the cannabinoid receptor agonist WIN 55212–2. CL 316243 and WIN 55212–2 were devoid of an effect on the rise in diastolic blood pressure induced by exogenous noradrenaline. In conclusion, our data suggest that the noradrenergic neurones innervating the resistance vessels of the rat and the noradrenergic, serotoninergic and cholinergic neurones of the rat hippocampus are not endowed with presynaptic β3‐adrenoceptors.

100 Deals associated with Talibegron Hydrochloride

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