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CARDIOVASCULAR

Role of -Adrenergic Receptors in the Effect of the -Adrenergic Receptor Ligands, CGP 12177, Bupranolol, and SR 59230A, on the Contraction of Rat Intrapulmonary Artery

Institut National de la Santé et de la Recherche Médicale EMI-0356, Université Victor Segalen Bordeaux 2, Laboratoire de Pharmacologie de la Faculté de Pharmacie (V.L., F.P., B.M.) and Laboratoire de Physiologie Cellulaire Respiratoire (C.G., R.M.), Bordeaux, France; and Departament de Farmacologia, Facultat de Farmacia, Universitat de Valencia, Valencia, Spain (M.D.I.)

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 ₃- and/or atypical -adrenergic receptors (-AR) ligands] on the contractile function of rat intralobar pulmonary artery. Affinities of -AR ligands for ₁-adrenergic receptors (₁-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 ₁-AR agonist phenylephrine (PHE). In arteries precontracted with PHE, CGP 12177 elicited relaxation, whereas in those precontracted with prostaglandin F₂ (PGF₂), it further enhanced contraction. CGP 12177 induced an increase in intracellular calcium concentration in pressurized arteries loaded with Fura PE-3 and precontracted with PGF₂. In PGF₂ precontracted arteries, phentolamine (an -AR antagonist) and phenoxybenzamine (an irreversible -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 pK_i 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 ₃-AR agonists) displayed very low affinity for [³H]prazosin binding sites (pK_i values below 4). These data suggest that CGP 12177 exhibits partial agonist properties for ₁-AR in rat pulmonary artery. They also show that bupranolol and SR 59230A exert an ₁-AR antagonist effect. As a consequence, these aryloxypropanolamine compounds should be used with caution when investigating the role of ₃- and atypical -AR in the regulation of vascular tone.

Address correspondence to: Dr. Véronique Leblais, Laboratoire de Pharmacologie de la Faculté de Pharmacie, INSERM EMI-0356, Université Victor Segalen Bordeaux 2—Casier 83, 146 rue Léo Saignat, 33076 Bordeaux cedex, France. E-mail: veronique.leblais{at}phcodyn.u-bordeaux2.fr

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