Abstract
This study investigates the effect of the aryloxypropanolamines 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177), bupranolol, and 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate (SR 59230A) [commonly used as β3- and/or atypical β-adrenergic receptors (β-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of β-AR ligands for α1-adrenergic receptors (α1-AR) were also evaluated using [3H]prazosin binding competition experiments performed in rat cortical membranes. In intralobar pulmonary artery, CGP 12177 did not modify the basal tone, but antagonized the contraction induced by the α1-AR agonist phenylephrine (PHE). In arteries precontracted with PHE, CGP 12177 elicited relaxation, whereas in those precontracted with prostaglandin F2α (PGF2α), it further enhanced contraction. CGP 12177 induced an increase in intracellular calcium concentration in pressurized arteries loaded with Fura PE-3 and precontracted with PGF2α. In PGF2α precontracted arteries, phentolamine (an α-AR antagonist) and phenoxybenzamine (an irreversible α-AR antagonist) antagonized the contractile responses to PHE and CGP 12177. Both responses were also decreased by bupranolol and SR 59230A. Specific [3H]prazosin binding was displaced by CGP 12177, bupranolol, and SR 59230A with pKi values of 5.2, 5.7, and 6.6, respectively. In contrast, (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium (BRL 37344) and disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316243) (nonaryloxypropanolamines β3-AR agonists) displayed very low affinity for [3H]prazosin binding sites (pKi values below 4). These data suggest that CGP 12177 exhibits partial agonist properties for α1-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an α1-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of β3- and atypical β-AR in the regulation of vascular tone.
Footnotes
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The authors thank the “Association des Enseignants de Pharmacologie des Facultés de Pharmacie” for partially supporting the collaboration between Valencia and Bordeaux Faculties. This work was also partially supported by a research grant from the “Generalitat Valenciana” (GV01-292).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.061192.
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ABBREVIATIONS: CGP 12177, 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one; AR, adrenergic receptor; l.a.s., low affinity state; SR 59230A, 3-(2-ethylphenoxy)-1[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate; BRL 37344, (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium; PBZ, phenoxybenzamine; CL 316243, disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate; PGF2α, prostaglandin F2α; PHE, phenylephrine; PSS, physiological salt solution; pD2, negative logarithm of E50 value; PE-3, pentakisester-3.
- Received October 7, 2003.
- Accepted December 19, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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Role of α-Adrenergic Receptors in the Effect of the β-Adrenergic Receptor Ligands, CGP 12177, Bupranolol, and SR 59230A, on the Contraction of Rat Intrapulmonary Artery
