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33-Adrenoceptor-Mediated Relaxation Induced by Isoprenaline And J. Smooth Muscle Res. 33 : 99-106. 99 The )32 and [33-Adrenoceptor-Mediated Relaxation Induced by Isoprenaline and Salbutamol in Guinea Pig Taenia Caecum Katsuo KOIKE, Tsukasa IcHiNo, Takahiro HORINOUCHI and Issei TAKAYANAGI Departmentof Chemical Pharmacology, Toho University School of PharmaceuticalSciences, 2-2-1, Miyama,Funabashi, Chiba 274, Japan Abstract To understand the receptor subtypes responsible for /3adrenoceptormediated relaxa tion of guinea pig taenia caecum, we investigated the effects of isoprenaline and salbutamol . Isoprenaline and salbutamol caused dose-dependent relaxation of the guinea pig taenia caecum. Propranolol, bupranolol and butoxamine produced shifts of the concentration response curves for isoprenaline and salbutamol. Schild regression analyses carried out for propranolol against isoprenaline and salbutamol gave pA2 values of 8.43 and 8.88, respective ly. Schild regression analyses carried out for butoxamine against isoprenaline and sal butamol gave pA2 values of 6.46 and 6.68, respectively. Schild regression analyses carried out for bupranolol against isoprenaline and salbutamol gave pA2 values of 8.60 and 8.69, respectively. However, in the presence of 3 x 10' M atenolol, 10-4 M butoxamine and 10-6 M phentolamine to block the fir , /32 and a -adrenoceptor effects, respectively, Schild regression analyses carried out for bupranolol against isoprenaline and salbutamol gave pA2 values of 5.77 and 5.97, respectively. These results suggest that the relaxant responses to isoprenaline and salbutamol in the guinea pig taenia caecum are mediated by both the /.32 and the A-adrenoceptors. Key words : f2-adrenoceptor, A-adrenoceptor, isoprenaline, salbutamol , guinea pig taenia caecum Introduction The /3adrenoceptors were subclassified as and /32subtypes based on the agonist potency and tissue localization. Lands et al. (1967) examined the relative potency of sympath omimetic amines on fatty acid mobilization (lipolysis), cardiac stimulation , vasodepression, and bronchodilation and designated the receptors mediating lipolysis and cardiac stimulation as /31, whereas those linked to bronchodilation and vasodilation as fl2. Recently, existence of the /33 adrenoceptor has been suggested in different tissues by binding and functional studies (Arch and Correspondence to : Katsuo Koike, Depatment of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, 2-2-1, Miyama, Funabashi, Chiba 274, Japan Phone : 0474-72-1435 Fax : 0474-72-1448 100 K. KOIKE et al. Kaumann, 1993). A large body of evidence indicates that the ƒÀ3-adrenoceptors occur in the intestinal smooth muscle of different species, including humans, with a function of inhibiting muscle contractility (Bianchetti and Manara, 1990; De Ponti et al., 1996). We had demonstrated that the ƒÀ2- and ƒÀ3-adrenoceptors are involved in the ƒÀ-adrenoce ptor-mediated relaxation of the guinea pig taenia caecum (Koike at al., 1994; 1995a; 1995b), although the ƒÀ1-adrenoceptors are not involved (Koike et al., 1994). Our previous studies also showed that the relaxant responses to BRL37344, CGP12177 and norepinephrine in the guinea pig taenia caecum are mediated by ƒÀ3-adrenoceptors (Koike et al., 1995b; 1995c; 1997). However, it is not known whether the ƒÀ3-subtype is involved in the ƒÀ-adrenoceptor-mediated relaxation induced by isoprenaline, a typically ƒÀ-adrenoceptor agonist, and salbutamol, a ƒÀ2- adrenoceptor selective agonist. Therefore, we have studied in detail the ƒÀ-adrenoceptor mediated relaxation of guinea pig taenia caecum by measuring the potencies of isoprenaline and salbutamol. Materials and methods Mechanical responses Male guinea pigs weighing 300-500g were killed by cervical dislocation and a 2 to 3-cm piece of the taenia caecum was isolated and suspended in a 20-ml organ bath filled with a Ringer-Locke solution (NaCl, 154; KCl, 5.6; CaCl2, 2.2; MgCl2, 2.1; NaHCO3, 5.9 and glucose, 2.8mM) kept at 32•Ž and bubbled with a mixture of 95% O2 and 5% CO2. The mechanical responses of the smooth muscle preparations were recorded isotonically under a tension of 0.7 g. The experiments were started after the preparations had been allowed to develop their spontaneous tone for 2h. The concentration-response curves for the agonists were obtained cumulatively and the relaxation induced by these drugs was expressed as a percentage of the maximal relaxation produced by 3•~10-7M isoprenaline, the reference drug. To test the antagonism, one of the antagonists was added to the bath 30min before the addition of the agonist. The concentration-response curves for the agonist were then obtained in the presence of an antagonist. The time interval between two consecutive curves was usually set at 60min. The spontaneous smooth muscle tone was reproducible when taenia caecum pieces were without the load. In our previous experiments, after the control concentration-response curves were determined, two or three successive cumulative concentration-response curves for isoprenaline were determined. The curves were nearly superimposable and changes in sensi tivity (sensitization or desensitization) were slight (data not shown). Six or more concentra tion-response curves could be made in succession. In some experiments, atenolol (3•~10-4M), butoxamine (10-4M) and phentolamine (10-6M) were added to inhibit the ƒÀ1-, ƒÀ2- and ƒ¿- adrenoceptors, respectively. Agonistic potency was expressed as the pD2 value (Van Rossum, 1963). The competitive antagonistic potency was expressed as the pA2 value. It was calcu lated according to the method of Tallarida et al. (1979), which was originally described by Arunlakshana and Schild (1959). ƒÀ2- and ƒÀ3-Receptor-mediated Relaxation 101 Data analysis Numerical results are expressed as means•}S.E. and statistical analyses wereperformed with the Newman-Keuls test when appropriate. A P value of less than 0.05 was considered significant. Drugs The drugs used were obtained from the following sources: isoprenaline hydrochloride , salbutamol hemisulfate salt, butoxamine hydrochloride, propranolol hydrochloride (Sigma Chemical Co., St. Louis, MO, U.S.A.); bupranolol hydrochloride (Looser; Kaken Seiyaku Co., Tokyo, Japan); atenolol (Research Biochemicals, Natik, MA , U.S.A.); prazosin hydrochloride, yohimbine hydrochloride (Wako Pure Chemical Industries, Osaka, Japan); and phentolamine mesylate (Ciba Geigy, Basel, Switzerland). All the drugs were dissolved in distilled water . The other chemicals used were of analytical grade. Results Responses to isoprenaline Isoprenaline caused graded relaxation of the guinea pig taenia caecum piece in which the tone had been raised spontaneously, with the pD2 value of 8.14•}0.06 (Fig.1). Propranolol (10-8-10-7M) competitively antagonized the relaxant responses to isoprenaline (Fig.1). The Schild plot of the data gave the pA2 value of 8.43•}0.11 and the slope of the regression line (1.17•}0.07) was not significantly different from unity. Bupranolol (10-8-10-7M) caused com petitive antagonism of the relaxant responses (Fig.2). The Schild plot of the data gave the pA2 value of 8.60•}0.08 and the slope of the regression line (1.06•}0.02) was not significantly different Fig. 1. Antagonism of isoprenaline-induced relaxation by propranolol. Control (•œ), propranolol 10-8M (•›), 3•~10-8M (•¢), 10-7M (• ). Ordinate: relaxation (%), expressed as percentage of the maximum relaxation induced by isoprenaline, and abscissa: concentration (M) of isoprenaline. Each point represents the mean•}S.E. of six experiments. 102 K. KOIKE et al. Fig. 2. Antagonism of isoprenaline-induced relaxation by bupranolol. Control (•œ), bupranolol 10-8 M (•›), 3•~10-8M (•¢), 10-7M (• ). Ordinate: relaxation (%), expressed as percentage of the maximum relaxation induced by isoprenaline, and abscissa: concentration (M) of isoprenaline. Each point represents the mean•}S.E. of six experiments. from unity. Butoxamine (10-6-10-5M), a ƒÀ2-selective antagonist, caused competitive antago nism of the relaxant responses (data not shown). The Schild plot of the data gave the pA2 value of 6.46•}0.06 and the slope of the regression line (0.99•}0.13) was not significantly different from unity. In the presence of 3•~10-4M atenolol, 10-4M butoxamine and 10-6M phentolamine to block the ƒÀ1, ƒÀ2 and ƒ¿-adrenoceptor effects, respectively, bupranolol (3•~ 10-6-3•~10-5M) also caused competitive antagonism of the relaxant responses (Fig.3). How Fig. 3. Antagonism of isoprenaline-induced relaxation by bupranolol in the presence of 3•~10-4M atenolol, 10-4M butoxamine and 10-6M phentolamine. Isoprenaline, in the absence of blockers (•œ), isoprenaline in the presence of blockers (•¡), bupranolol 3•~10-6M (•›), 10-5M (•¢), 3•~10-5M (• ). Ordinate: relaxation (%), expressed as percentage of the maximum relaxation induced by isoprenaline, and abscissa: concentration (M) of isoprenaline. Each point represents the mean•}S.E. of six experiments. ƒÀ2- and ƒÀ3-Receptormediated Relaxation 103 ever, the Schild plot of the data gave the pA2 value of 5.77•}0.04 and the slope of the regression line (1.14•}0.09) was not significantly different from unity. The difference between the pA2 values for bupranolol in the presence and in the absence of the ƒÀ1-, ƒÀ2- and ƒ¿-blockers was statistically significant (P<0.05). Responses to salbutamol Salbutamol caused graded relaxation of the guinea pig taenia caecum piece in which the tone had been raised spontaneously, with the pD2 value of 7.21•}0.05 (Fig.4). Propranolol (10-8-10-7M) competitively antagonized the relaxant responses to salbutamol (Fig.4). The Schild plot of the data gave the pA2 value of 8.88•}0.04 and the slope of the regression line (1.12•}0.08) was not significantly different from unity. Bupranolol (10-8-10-7M) caused com petitive antagonism of the relaxant responses (Fig.5). The Schild plot of the data gave the pA2 value of 8.69•}0.07 and the slope of the regression line (1.27•}0.13) was not significantly different from unity. Butoxamine (10-6-10-5M), a ƒÀ2-selective antagonist, caused competitive antago nism of the relaxant responses (data not shown). The Schild plot of the data gave the pA2 value of 6.68•}0.09 and the slope of the regression line (1.09•}0.06) was not significantly different from unity.
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