Partial agonist activity of carteolol on atypical β-adrenoceptors in the guinea pig duodenum

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Abstract

The partial agonist activities of carteolol were investigated on atypical β-adrenoceptors of duodenum on the guinea pig. Carteolol produced a concentration-dependent relaxation of the guinea pig duodenum (pD2=4.85), which was not significantly affected by propranolol (1 μM). In the presence of propranolol (1 μM), however, the non-selective β1-, β2- and β3-adrenoceptor antagonist, bupranolol (30 μM), caused a rightward shift of the concentration–response curves for carteolol (apparent pA2=5.31). Moreover, carteolol (10 μM) weakly, but significantly, antagonized the relaxations in response to catecholamines (isoprenaline, noradrenaline and adrenaline), to a selective β3-adrenoceptor agonist, (R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt (BRL37344), and to a non-conventional partial β3-adrenoceptor agonist, [4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride (CGP12177A), also in the guinea pig duodenum (apparent pA2=5.77, 5.92, 6.05, 6.56 and 5.58, respectively). These results suggest that the partial agonist effects of carteolol are mediated by atypical β-adrenoceptors in the guinea pig duodenum.

Introduction

Carteolol induces relaxation and behaves as a β-adrenoceptor partial agonist in the guinea pig taenia caecum (Takayanagi and Koike, 1983). Carteolol is generally accepted as a partial β1-/β2-adrenoceptor agonist and exhibits both stimulatory and inhibitory effects (Lipworth and Grove, 1997). Moreover, we showed that β2- and β3-adrenoceptors were involved in the β-adrenoceptor-mediated relaxation of the guinea pig taenia caecum Koike et al., 1994, Koike et al., 1995a, Koike et al., 1995b and that carteolol did not act as a β3-adrenoceptor agonist in the guinea pig taenia caecum (Koike et al., 1996).

However, Zhao et al. (1998) demonstrated that carteolol, described earlier as a partial agonist on β1- and β2-adrenoceptors, also possesses β3-adrenoceptor partial agonist properties on brown fat cells from mouse, rat and hamster. These facts suggest that carteolol-stimulated thermogenesis is mediated by β3-adrenoceptors in brown adipose tissue, but that carteolol-induced relaxation is mediated by β2-adrenoceptors in the taenia caecum. However, it remains possible that there are species differences in β3-adrenoceptors that β3-adrenoceptors of the guinea pig taenia caecum cannot recognize carteolol.

Recently, we have suggested that atypical β-adrenoceptors were involved in mediating the relaxant response of the guinea pig duodenum (Horinouchi and Koike, 1999a). We also showed that the relaxations in response to catecholamines (isoprenaline, noradrenaline and adrenaline), to a selective β3-adrenoceptor agonist, (R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt (BRL37344), and to a non-conventional partial β3-adrenoceptor agonist, [4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride (CGP12177A), were competitively antagonized by a non-selective β-adrenoceptor antagonist, bupranolol (Horinouchi and Koike, 1999a), although at a concentration much higher than that necessary for the blockade of β1- or β2-adrenoceptors (Kaumann, 1989).

Therefore, we attempted to clarify whether carteolol acts as a β3-adrenoceptor partial agonist at atypical β-adrenoceptors in the guinea pig duodenum by using catecholamines (isoprenaline, noradrenaline and adrenaline), BRL37344, CGP12177A and bupranolol.

Section snippets

Mechanical responses

Male Hartley guinea pigs weighing 300–500 g were killed by cervical dislocation and the entire duodenum was rapidly isolated and placed in oxygenated (a mixture of 95% O2 and 5% CO2) Ringer–Locke solution of the following composition (in mM): NaCl, 154; KCl, 5.6; CaCl2, 2.2; MgCl2, 2.1; NaHCO3, 5.9; and glucose, 2.8. The intraluminal contents were flushed out with Ringer–Locke solution and the connective tissue was dissected away. The outer layer of duodenum containing longitudinal smooth

Agonistic effect of carteolol

In the absence of propranolol, carteolol relaxed the histamine-induced tone in the guinea pig duodenum, with a pD2 value of 4.85±0.03 and an intrinsic activity of 0.96±0.03 (Fig. 1). The relaxant response to carteolol was insensitive to propranolol (1 μM; Fig. 1). The pD2 value and the intrinsic activity in the presence of propranolol were 4.90±0.01 and 0.93±0.03, respectively (Fig. 1).

Effect of bupranolol on relaxation to carteolol

In the presence of propranolol (1 μM) to block typical β-adrenoceptors, bupranolol (30 μM) antagonized the

Discussion

In the present study, partial agonist effects of carteolol on β-adrenoceptors mediating relaxation in the guinea pig duodenum have been examined. Carteolol induced concentration-dependent relaxation of histamine-precontracted guinea pig duodenum. However, the classical β-adrenoceptor antagonist, propranolol (1 μM), failed to produce significant shifts of the carteolol concentration–response curve, indicating the possible involvement of atypical β-adrenoceptors. Strong evidence for atypical

Acknowledgements

Kaken Pharmaceutical (Tokyo, Japan) is thanked for the gift of bupranolol hydrochloride.

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