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(±)-Pindolol Acts As a Partial Agonist at Atypical >-Adrenoceptors in The

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(±)-Pindolol Acts As a Partial Agonist at Atypical >-Adrenoceptors in The Jpn. J. Pharmacol. 85, 35 – 40 (2001) (±)-Pindolol Acts as a Partial Agonist at Atypical >-Adrenoceptors in the Guinea Pig Duodenum Takahiro Horinouchi and Katsuo Koike* Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan Received July 19, 2000 Accepted September 29, 2000 ABSTRACT—The agonistic and antagonistic effects of (±)-pindolol (1-(1H-indol-4-yloxy)-3-[(1-methyleth- yl)amino]-2-propanol) were estimated to clarify whether (±)-pindolol acts as a partial agonist on atypical b-adrenoceptors in the guinea pig duodenum. (±)-Pindolol induced concentration-dependent relaxation with a pD2 value of 5.10 ± 0.03 and an intrinsic activity of 0.83 ± 0.03. However, the relaxations to (±)-pindolol were not antagonized by the non-selective b 1- and b 2-adrenoceptor antagonist (±)-propranolol (1 mM). In the presence of (±)-propranolol (1 mM), the non-selective b1-, b2- and b3-adrenoceptor antagonist (±)-bupranolol (30 mM) induced a rightward shift of the concentration-response curves for (±)-pindolol (apparent pA2 = 5.41 ± 0.06). In the presence of (±)-propranolol, (±)-pindolol (10 mM) weakly but significant- ly antagonized the relaxant effects to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective b 3-adrenoceptor agonist BRL37344 ((R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl) amino]propyl]phenoxyacetic acid sodium salt) and a non-conventional partial b 3-adrenoceptor agonist (±)-CGP12177A ([4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride). These results demonstrate that (±)-pindolol possesses both agonistic and antagonistic effects on atypical b-adrenoceptors in the guinea pig duodenum. Keywords: (±)-Pindolol, Partial agonist, Atypical b-adrenoceptor, b 3-Adrenoceptor, Guinea pig duodenum b-Adrenoceptors were initially subdivided by Lands and tagonists (e.g., SR59230A) (2, 6). Evidence for the exist- co-worker (1) into b 1- and b 2-adrenoceptors based on the ence of further atypical b-adrenoceptor subtypes is accumu- selectivity of action to different b-adrenoceptor agonists as lating: e.g., putative b 4-adrenoceptors in cardiac and adi- cardiac stimulant and bronchodilators, respectively. In ad- pose tissue that fulfill criteria (ii) and (iii) but not (i) and dition, many lines of evidence for the existence of atypical (iv) (6 – 8). Since our previous study fulfilled three criteria, b-adrenoceptors, distinct from b 1- and b 2-adrenoceptors, (i), (ii) and (iii), but not (iv) in the guinea pig duodenum (9), are accumulating. Thus, atypical b-adrenoceptors including we called b-adrenoceptors which share criteria (i), (ii) and b 3-adrenoceptors have been identified in a variety of tis- (iii) by the term ‘atypical b-adrenoceptors’ but not ‘b 3- sues including gastrointestinal smooth muscle (for review, adrenoceptors’. see Arch and Kaumann (2)), and it is suggested that this Recently, we have reported that functional atypical b- novel receptor subtype can be a suitable target for the de- adrenoceptors exist in the guinea pig duodenum and that velopment of new drugs active in the treatment of gastro- the relaxations to b-adrenoceptor agonists in this tissue are intestinal tract disorders and non-insulin-dependent dia- mediated via atypical b-adrenoceptors (9). betes (3 – 5). For an effect to be mediated through b 3- Recently, the pharmacological effects of (±)-pindolol adrenoceptors, the following criteria need to be fulfilled: (1-(1H-indol-4-yloxy)-3-[(1-methylethyl)amino]-2-pro- i) stimulation by selective b 3-adrenoceptor agonists (e.g., panol), cyanopindolol and analogues of cyanopindolol BRL37344), ii) stimulation by non-conventional partial were tested on b 3-adrenoceptors in the rat ileum (10, 11). agonists (e.g., CGP12177A), iii) low sensitivity to an- Cyanopindolol and their analogues act as partial agonists tagonists with affinity for b 1- or b 2-adrenoceptors (e.g., pro- with intrinsic activities ranging from 0.39 to 0.84; however, pranolol) and iv) sensitivity to selective b 3-adrenoceptor an- the intrinsic activity of (±)-pindolol was 0 (11). Thus, (±)- pindolol has been described to act as an antagonist at b 3- *Corresponding author. FAX: +81-47-472-1419 adrenoceptors with the pKb value of 6.68 against effects of E-mail: [email protected] (-)-isoprenaline in the rat ileum (10). However, Blin et al. 35 36 T. Horinouchi & K. Koike (12) showed that (±)-pindolol possessed both a b 3-adreno- Experimental protocol ceptor agonistic property with an intrinsic activity of 0.55 After two histamine concentration-response curves had and a potent b 1- and b 2-adrenoceptor antagonistic effect in been obtained, the preparations were contracted with hista- Chinese hamster ovary cells expressing the human b 1-, b 2- mine (10 mM), which induced the submaximal contraction. and b 3-adrenoceptors, respectively. It is possible that there The relaxant responses to b-adrenoceptor agonists were is a species difference in b 3-adrenoceptors or atypical b- determined by measuring inhibition of histamine-induced adrenoceptors. Furthermore, it has been shown that cyclic contraction. The concentration-response curves for cat- AMP production is potently stimulated by BRL37344 echolamines were obtained cumulatively and the relaxation ((R*, R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl) induced by these drugs was expressed as a percentage of the amino]propyl]phenoxyacetic acid sodium salt) in the human maximal relaxation produced by (-)-isoprenaline (3 mM), cloned b 3-adrenoceptors (13). However, this same drug the reference drug, in the absence of (±)-propranolol. To has been shown to lack an intrinsic activity on atypical test the antagonism of (±)-propranolol (1 mM) against b-adrenoceptors in human colon (14) and adipocytes (15). (±)-pindolol, (±)-propranolol was added to the bath 30 min Effects of drugs may differ between cloned atypical b- before the addition of (±)-pindolol. To test the antagonism adrenoceptors and native atypical b-adrenoceptors. of (±)-pindolol (10 mM) in the presence of (±)-propranolol Therefore, we performed the present study to confirm (1 mM), however, one of the agonists was added to the bath whether (±)-pindolol possesses both agonistic and antago- after a maximal relaxant response to (±)-pindolol (10 mM) nistic effects at native atypical b-adrenoceptors in the was established. The concentration-response curves for the guinea pig duodenum and to obtain further evidence to agonists were then obtained in the presence of antagonists. determine if there is a species difference between the The time interval between two consecutive curves was gastrointestinal smooth muscle of the guinea pig and the rat usually set at 30 min. In our previous experiments, after the in atypical b-adrenoceptors or b 3-adrenoceptors. To define control concentration-response curves were determined, the effects of (±)-pindolol under experimental conditions four or five successive cumulative concentration-response similar to those used by Hoey et al. (10, 11), we employed curves for catecholamines were determined. The curves functional experiments that were established by Horinouchi were nearly superimposable and changes in sensitivity and Koike (9) for atypical b-adrenoceptors in guinea pig (sensitization or desensitization) were slight (data not duodenum. shown). Seven or more concentration-response curves could be made in succession. However, the effects of (±)- MATERIALS AND METHODS pindolol, BRL37344 and (±)-CGP12177A faded during the course of the same experiment in previous studies (data not Tissue preparation shown); therefore, only a single concentration-response Male Hartley guinea pigs weighing 300 – 500 g were curve to each agonist was constructed per tissue. When killed by cervical dislocation and the entire duodenum was studying the effects of antagonists for relaxation induced by removed and placed in oxygenated (a mixture of 95% O2 (±)-pindolol, BRL37344 and (±)-CGP12177A, two untreat- and 5% CO2) Ringer-Locke solution of the following ed preparations always served as controls. composition: 154 mM NaCl, 5.6 mM KCl, 2.2 mM CaCl2, 2.1 mM MgCl2, 5.9 mM NaHCO3 and 2.8 mM glucose. Data analyses The intraluminal contents were flushed out with Ringer- Agonistic potency was expressed as the pD2 value (16). Locke solution and the connective tissue was dissected The intrinsic activity of each agonist was expressed as the away. The outer layer of duodenum containing longitudinal ratio between its maximal relaxation and the maximal smooth muscle was carefully removed with a cotton swab. response of the full agonist (-)-isoprenaline. The competi- Strips of 10-mm length were mounted on tissue hooks tive antagonistic potency is expressed as the apparent and suspended in jacketed 20-ml organ baths containing pA2 value. Apparent pA2 values for (±)-bupranolol and Ringer-Locke solution kept at 32°C and bubbled continu- (±)-pindolol were calculated according to the method of ously with a mixture of 95% O2 and 5% CO2. The mecha- Van Rossum (16) from the equation: nical responses of strips were recorded isometrically under apparent pA2 a load of 0.5 g. Desmethylimipramine (1 mM, a neuronal = log (agonist concentration ratio - 1) - log [antagonist] uptake inhibitor), normetanephrine (10 mM, an extraneuronal Numerical results are expressed as means ± S.E.M. of 8 uptake inhibitor) and phentolamine (10 mM, an a-adreno- to 12 experiments. Statistical analyses were performed with ceptor
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