Classification of beta-adrenoceptors in human isolated bronchus.

(+/-)-Isoprenaline (Iso), (-)-adrenaline (Ad), (-)-noradrenaline (NA), (+/-)-phenylephrine (Phe) and the beta 2-selective adrenoceptor agonist (+/-)-fenoterol (Fen) caused a concentration-dependent relaxation of human isolated bronchial preparations. Iso, Ad and NA caused complete relaxation of both spontaneous and carbachol-induced bronchial tone. Fen, which was only tested in preparations where tone was induced with carbachol, also caused complete relaxation. However, Phe was a partial agonist in all preparations tested. When relaxation responses to these amines were calculated as a % of their maximal effects, comparison of EC50 values showed that the order of potency was Iso greater than Ad = Fen greater than NA greater than Phe (92:27:25:1:0.2) in preparations with carbachol-induced tone and Iso greater than Ad greater than NA greater than Phe (112:38:1:0.3) in preparations with spontaneous tone. pA2 values determined for the beta-adrenoceptor antagonists propranolol (non-selective), atenolol (beta-selective) and ICI-118, 551 (beta 2-selective), using Iso as an agonist were, 9.3, 5.3 and 9.1 respectively. These results indicate that beta 2-adrenoceptors mediate relaxation of human isolated bronchus to sympathomimetic amines in preparations obtained 4-14 h post-mortem from non-diseased lung. alpha-Adrenoceptors were apparently sparse or absent in this tissue.     

A comparative study of beta-adrenoceptors in human and porcine lung parenchyma strip

1. Responses to (+/-)-isoprenaline (Iso), (-)-adrenaline (Adr) and (-)-noradrenaline (NA) were compared in isolated preparations of human and porcine lung parenchyma strip. 2. The order of relaxant potencies of these catecholamines in both human and porcine lung parenchyma was Iso greater than Adr greater than NA (1:0.24:0.01, human; 1:0.21:0.01.pig). These results suggest that beta 2-adrenoceptors predominate in both types of lung parenchyma strip. 3. pA2 values for the beta-adrenoceptor antagonist, propranolol (non-selective), with Iso as the agonist, in human and porcine lung strips were 7.84 and 7.83 respectively and for atenolol were 6.50 and 5.35 respectively. Taken as a whole results indicate the existence of an apparently homogeneous population of beta 2-adrenoceptors in porcine parenchyma strip, while both beta 1 and beta 2-adrenoceptors were revealed in human lung parenchyma.     

Beta 1-adrenoceptors mediate smooth muscle relaxation in mouse isolated trachea.

1. The relaxant effects to the beta-adrenoceptor agonists isoprenaline, adrenaline, noradrenaline, RO363, procaterol and fenoterol were investigated in carbachol-contracted mouse isolated tracheal preparations. 2. The order of potencies for those beta-adrenoceptor agonists that induced full relaxation of carbachol-contracted mouse tracheal preparations was isoprenaline greater than RO363 greater than noradrenaline = adrenaline greater than fenoterol. The EC50 value of isoprenaline for relaxation was 46 nM. The beta 1-adrenoceptor-selective agonist, RO363 was ten times more potent than the beta 2-adrenoceptor-selective agonist, fenoterol. The highly beta 2-adrenoceptor-selective agonist procaterol was a partial relaxant and induced only 28 +/- 4% relaxation. 3. Relaxations induced by noradrenaline and isoprenaline were not significantly affected by the neuronal uptake inhibitor, cocaine (10 microM) or by the extraneuronal uptake inhibitor, deoxycorticosterone acetate (25 microM) respectively. The alpha-adrenoceptor agonist methoxamine induced no observable elevation of mouse tracheal smooth muscle tone. 4. Schild plots for the beta-adrenoceptor antagonists, atenolol and betaxolol (beta 1-adrenoceptor-selective) and ICI 118,551 (beta 2-adrenoceptor-selective) were linear, with slope values approaching unity. Mean pA2 values derived for atenolol, betaxolol and ICI 118,551 for antagonism of beta-adrenoceptor-mediated relaxation were 7.1, 8.4 and 7.2, respectively. These data were independent of the use of isoprenaline or noradrenaline as the agonist. 5. These findings indicate that beta-adrenoceptor-mediated relaxations of mouse isolated trachea occur predominantly through activation of beta 1-adrenoceptors.     

The costo-uterine muscle of the rat contains a homogeneous population of beta-adrenoceptors.

The effects of two selective beta-adrenoceptor antagonists on the inhibitory responses to some sympathomimetic amines of electrically-stimulated preparations of costo-uterine muscle, taken from virgin rats, have been examined quantitatively. pA2 values for the antagonist, atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) were obtained using as agonists, fenoterol (beta 2-selective agonist) and noradrenaline (alpha- and beta-adrenoceptor agonist, beta 1-selective); and in addition, with ICI 118,551 only, isoprenaline (beta-agonist, non-selective) and adrenaline (alpha- and beta-adrenoceptor agonist, beta 2-selective). Catecholamine uptake mechanisms and alpha-adrenoceptors were not blocked in any of these experiments. Atenolol competitively antagonized the effects of fenoterol and noradrenaline to a similar extent, the pA2 values being 5.4 and 5.7, respectively. ICI 118,551 competitively antagonized the effects of fenoterol, isoprenaline, adrenaline and noradrenaline to a similar extent; pA2 values ranged from 8.7 with noradrenaline to 9.1 with isoprenaline. These results extend our previous observations which indicated that the adrenoceptors mediating inhibition of electrically-evoked contractions of costo-uterine muscle of the virgin rat are homogeneous and of the beta 2-subtype. The potency of the beta 1-selective agonist RO 363 in producing inhibition of electrically-evoked contractions of this tissue was also examined. RO 363 was 200 times less potent than isoprenaline but was a full agonist. This indicates that there is efficient coupling between beta 2-adrenoceptor activation and tissue response in this non-innervated preparation.     

Effect of steroids on beta-adrenoceptor-mediated relaxation of pig bronchus.

1--Progesterone, testosterone (40 microM), cortisol and cortisol hemisuccinate (80 microM) caused 6-8 fold potentiations of (+/-)-isoprenaline (Iso)-induced relaxations of pig bronchus while several other steroids caused smaller potentiations or had no effect. 2--17 beta-Oestradiol (40 microM) increased the potency of Iso, (-)-adrenaline (Adr) and (-)-noradrenaline (NA) by 10.6, 2.3 and 2.6 fold respectively but had no significant effect on the potency of fenoterol (Fen). 3--Inhibition of catechol-O-methyl transferase (COMT) with U-0521 (30 microM) caused a 6 fold increase in the potency of Iso but failed to alter the potency of Adr, NA or Fen. The extraneuronal uptake inhibitor normetanephrine (50 microM) caused significant 2 fold increases in the potency of Iso and Adr but did not potentiate the responses to NA or Fen. 4--In preparations where the potency of Iso had already been increased by U-0521 (30 microM) or by normetanephrine, 17 beta-oestradiol produced no significant further increase in potency. These results indicate that steroid-induced increases in the potency of catecholamines in pig bronchus can be explained in terms of inhibition of COMT or extraneuronal uptake or both.     

The importance of choice of agonist in studies designed to predict β 2:β 1 adrenoceptor selectivity of antagonists from pA2 values on guinea-pig trachea and atria

1. pA2 values have been obtained for propranolol, butoxamine, H35/25 and atenolol on guinea-pig isolated trachea and atria (rate) using noredrenaline (beta 1-selective), isoprenaline (non-selective) and fenoterol (beta 2-selective) as agonists. 2. pA2 values varied with the agonist used on trachea but not on atria and, therefore, trachea : atria selectivity values varied with the agonist used. 3. It is suggested that the best estimate of the selectivity of an antagonist between beta 2- and beta 1-adrenoceptors is obtained by comparing its pA2 value obtained on trachea using a beta 2-selective agonist with that obtained on atria using a beta 1-selective agonist. The reasons for this are discussed. 4. The quantitative values for beta 2 : beta 1 selectivity obtained using the above pA2 values were butoxamine 17.0 H35/25 13.5, propranolol 2.75 and atenolol 0.036, i.e. butoxamine and H35/25 were beta 2-selective, propranolol was non-selective and atenolol was beta 1-selective. 5. The results support the hypotheses that guinea-pig trachea contains a mixture of beta 1- and beta 2-adrenoceptors and that guinea-pig atria contain only beta 1-adrenoceptors.     

pA2 values of selective beta-adrenoceptor antagonists on isolated atria demonstrate a species difference in the beta-adrenoceptor populations mediating chronotropic responses in cat and guinea-pig.

pA2 values for atenolol (beta 1-selective) and alpha-methylpropranolol (beta 2-selective) have been determined on isolated atria of cat and guinea-pig using noradrenaline (beta 1-selective) and fenoterol (beta 2-selective) as agonists. On guinea-pig atria, the pA2 values did not vary with the agonist used. On cat atria the pA2 for atenolol was greater with noradrenaline than with fenoterol and the pA2 for alpha-methylpropranolol was greater with fenoterol than with noradrenaline. Fenoterol was 20 times more potent on cat than on guinea-pig atria whereas noradrenaline was approximately equipotent in the two species. The results have been intrepreted as suggsesting that both cat and guinea-pig atria contain one receptor type in common (beta 1) but that only cat atria contain beta 2-adrenoceptors as well.     

Different mechanisms of action of agents acting on beta-adrenoceptors in barium-stimulated and electrically-stimulated rat vas deferens.

1. The relaxation induced by beta-adrenoceptor agonists in rat vas deferens was examined under two different experimental conditions: on electrically-induced twitch responses (35 V, 3 ms, 0.07 Hz), and on contractions induced by single doses of barium chloride (300 microM). The experiments were performed in vasa of reserpine-treated rats, after blockade of alpha-adrenoceptors and extraneuronal uptake with dibenamine (10 microM, 30 min), and neuronal uptake with cocaine (10 microM). 2. When twitch responses were used, the values of pD2, interpolated from cumulative concentration-response curves for isoprenaline (Iso), adrenaline (Ad), and noradrenaline (NA) showed a rank order of potency consistent with the presence of beta 2-adrenoceptors (Iso greater than Ad much greater than NA). 3. When twitch responses were used, the non-selective beta-antagonist, propranolol, caused a concentration-dependent parallel shift to the right of Iso concentration-response curves. Similar shifts were obtained by use of the beta 2-antagonist, isopropylmethoxamine (IMA), and higher doses of the beta 1-antagonist, practolol, according to the expectations from receptor occupation theory. Practolol presented the lowest value of pKB, 5.03, corroborating the presence of beta 2-adrenoceptors. 4. When twitch responses were used, and Ad or NA employed instead of Iso, the antagonists produced shifts of concentration-response curves which were smaller than expected from theory, precluding the determination of pKB values. This indicates that other mechanisms are involved besides an interaction with a single population of postsynaptic beta 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoradiographic localization of beta-adrenoceptors in pig lung using [125I]-iodocyanopindolol.

The binding of the beta-adrenoceptor radioligand [125I]-iodocyanopindolol (I-CYP) has been studied in pig lung parenchyma and the distribution of binding sites visualised by light microscopic autoradiography. I-CYP binding was saturable (maximum binding capacity Bmax = 51 +/- 3 fmol mg-1 protein), involving sites with high affinity (dissociation constant KD = 73 +/- 10 pM). Specific I-CYP binding was displaceable both by beta-adrenoceptor agonists ((-)-isoprenaline greater than (-)-adrenaline greater than (+/-)-fenoterol greater than (-)-noradrenaline greater than (+)-isoprenaline greater than (+/-)-RO363) and antagonists ((+/-)-propranolol greater than ICI-118551 greater than atenolol), indicating a predominance of beta 2-adrenoceptors. Further analysis showed that displacement data for the beta 1-selective antagonist atenolol and the beta 2-selective antagonist ICI-118551 were fitted best to a 2 binding site model and that both beta 1- and beta 2-adrenoceptors were present in pig lung in the ratio 28:72 respectively. Autoradiographic grains were localized over tissue and were most dense over alveolar walls greater than vascular endothelium greater than vascular smooth muscle greater than bronchial smooth muscle = bronchial epithelium. Atenolol (10(-5) M) caused a 31% reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI-118551 (10(-6) M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of beta-adrenoceptors with a predominance of the beta 2 subtype.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of beta-adrenoceptor mediated smooth muscle relaxation and the detection of mRNA for beta1-, beta2- and beta3-adrenoceptors in rat ileum.

1. Functional and molecular approaches were used to characterize the beta-AR subtypes mediating relaxation of rat ileal smooth muscle. 2. In functional studies, (-)-isoprenaline relaxation was unchanged by CGP20712A (beta1-AR antagonist) or ICI118551 (beta2-AR antagonist) but shifted by propranolol (pKB=6.69). (+/-)-Cyanopindolol, CGP12177 and ICID7114 did not cause relaxation but antagonized (-)-isoprenaline relaxation. 3. BRL37344 (beta3-AR agonist) caused biphasic relaxation. The high affinity component was shifted with low affinity by propranolol, (+/-)-cyanopindolol, tertatolol and alprenolol. CL316243 (beta3-AR agonist) relaxation was unaffected by CGP20712A or ICI118551 but blocked by SR58894A (beta3-AR antagonist; pA2 = 7.80). Enhanced relaxation after exposure to forskolin and pertussis toxin showed that beta3-AR relaxation can be altered by manipulation of components of the adenylate cyclase signalling pathway. 4. The beta-AR agonist RO363 relaxed the ileum (pEC50=6.18) and was blocked by CGP20712A. Relaxation by the beta2-AR agonist zinterol (pEC50=5.71) was blocked by SR58894A but not by ICI118551. 5. In rat ileum, beta1-, beta2- and beta3-AR mRNA was detected. Comparison of tissues showed that beta3-AR mRNA expression was greatest in WAT>colon=ileum >cerebral cortex>soleus; beta1-AR mRNA was most abundant in cerebral cortex > WAT > ileum = colon > soleus; beta2-AR mRNA was expressed in soleus > WAT > ileum = colon > cerebral cortex. 6. These results show that beta3-ARs are the predominant beta-AR subtype mediating rat ileal relaxation while beta1-ARs may produce a small relaxation. The beta2-AR agonist zinterol produces relaxation through beta3-ARs and there was no evidence for the involvement of beta2-ARs in relaxation despite the detection of beta2-AR mRNA.     

Endothelium-dependent noradrenaline-induced relaxation of rat isolated cerebral arteries: pharmacological characterization of receptor subtypes involved.

1. The endothelium-dependence of catecholamine-induced relaxation of rat cerebral arteries was investigated in vitro. 2. In the basilar artery (BA), the maximal relaxant response was most pronounced with noradrenaline (NA), less with isoprenaline (Iso), and only very little with terbutaline. Methoxamine and the alpha 2-adrenoceptor selective agonists BHT 933 and clonidine, had no relaxant effect. 3. In BA, the relaxation by NA or Iso was markedly attenuated by N omega-nitro-L-arginine (L-NOARG) 10(-4) M. Short term perfusion of the vessels by Triton X 100 (1:1,000) suppressed the NA-induced relaxation. 4. The relaxation induced by NA or Iso was markedly reduced in presence of L-NOARG in the posterior, medial and anterior cerebral artery. 5. In BA, NA-induced relaxation was non-competitively inhibited by propranolol, atenolol, and the beta 1- and beta 2-adrenoceptor selective antagonists, CGP 20712 A and ICI 118551. 6. The relaxant NA-effect was not affected by prazosin but was non-competitively blocked by phentolamine. 7. The Iso-induced relaxation was competitively blocked by propranolol, whereas atenolol, CGP 20712 A and ICI 118551 caused a non-competitive inhibition. 8. The experiments indicate that the catecholamine-induced relaxation in rat isolated cerebral arteries depends upon the endothelium. They suggest that the NA-induced relaxation of BA is mediated by different alpha- and beta-adrenoceptors and that the Iso-induced relaxation is mediated by different beta-receptors. The findings would also be compatible with the idea of a receptor type which cannot be characterized by the pharmacological tools that we have used.     

Partial agonistic properties of (+/-)-pindolol at atypical beta-adrenoceptors in the guinea pig gastric fundus.

(+/-)-Pindolol ([1-(1H-indol-4-yloxy)-3-[(1-methylethyl)- amino]-2-propanol)]) is a partial agonist at atypical beta-adrenoceptors in the guinea pig gastric fundus. (+/-)-Pindolol induced concentration-dependent relaxation in this tissue. However, the relaxant responses of (+/-)-pindolol were not antagonized by a combination of the selective beta(1)-adrenoceptor antagonist atenolol (10(-4) mol/l) and the selective beta(2)-adrenoceptor antagonist butoxamine (10(-4) mol/l). In the presence of both atenolol and butoxamine, the nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist (+/-)-bupranolol (10(-5)-10(-4) mol/l) caused a concentration-dependent rightward shift of the concentration-response curves for (+/-)-pindolol. Schild plot analyses of (+/-)-bupranolol against (+/-)-pindolol gave the pA(2) value of 5.46 +/- 0.03 and Schild slope was not significantly different from unity. Furthermore, (+/-)-pindolol (10(-5) mol/l) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta(3)-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt) and a nonconventional partial beta(3)-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride). These results suggest that (+/-)-pindolol acts as a partial agonist at atypical beta-adrenoceptors in the guinea pig gastric fundus.     

Pharmacological responses of human and porcine lung parenchyma, bronchus and pulmonary artery

1 Responses of preparations of human and porcine isolated bronchus and pulmonary artery to carbachol (CCh), methacholine, histamine, 5-hydroxytryptamine (5-HT), (-)-noradrenaline (NA), (-)adrenaline (Adr) and (+/-)-isoprenaline (Iso) were compared with responses to the same agonists in isolated lung parenchyma strips. 2 All preparations from both human and porcine lung contracted in response to histamine and all, except preparations of porcine pulmonary artery, contracted in response to CCh. Human and porcine pulmonary artery and parenchyma strip contracted in response to NA while bronchial preparations invariably relaxed. Iso caused relaxation of human and porcine bronchus and parenchyma strip. Although 5-HT was completely inactive in tissues isolated from pig lung, this amine was a powerful spasmogen in human pulmonary artery, relaxed human bronchus and caused variable responses in human parenchyma. 3 Results indicate that the pharmacological characteristics of human and porcine parenchyma strips may be explained in terms of responses of vascular or airways smooth muscle.     

Demonstration of both beta 1- and beta 2-adrenoceptors mediating relaxation of isolated ring preparations of rat pulmonary artery.

1 Cumulative concentration-response (relaxation) curves to three beta-adrenoceptor agonists, fenoterol (beta 2-selective), isoprenaline (non-selective) and noradrenaline (beta 1-selective) were obtained on isolated ring preparations of rat pulmonary artery contracted with 15 mM KCl. alpha-Adrenoceptors and neuronal and extraneuronal uptakes were blocked with phenoxybenzamine. The agonist concentration-response curves were reproducible. 2 Responses to each of the three agonists could be blocked by the beta-adrenoceptor antagonists atenolol (beta 1-selective) or ICI 118,551 (beta 2-selective) confirming the presence of beta-adrenoceptors. 3 The relative potencies of the agonists were isoprenaline : fenoterol : noradrenaline = 100 : 38 : 1.4. This indicated that the predominant beta-adrenoceptor type was beta 2. 4 Schild plots were obtained for atenolol and ICI 118,551 using the three different agonists. For each antagonist the location of the Schild plot varied depending on which agonist was used. This indicated that the beta-adrenoceptor population mediating relaxation responses to beta-adrenoceptor agonists was not homogeneous. 5 Atenolol was most potent when noradrenaline was the agonist and ICI 118,551 was most potent when fenoterol was the agonist. 6 It is concluded that isolated pulmonary artery ring preparations of the rat contain a mixed population of beta 1- and beta 2-adrenoceptors both mediating relaxation.     

Partial agonistic effects of carteolol on atypical beta-adrenoceptors in the guinea pig gastric fundus

The properties of the beta1-/beta2-adrenoceptor partial agonist carteolol were investigated in atypical beta-adrenoceptors on the guinea pig gastric fundus. Carteolol induced concentration-dependent relaxation in this tissue (pD2 = 5.55, intrinsic activity = 0.94). However, a combination of the selective beta1-adrenoceptor antagonist atenolol (100 microM) and the selective beta2-adrenoceptor antagonist butoxamine (100 microM) produced only small rightward shifts in the concentration-response curves of carteolol in the gastric fundus (pD2 = 4.91, intrinsic activity = 0.94). In the presence of both atenolol (100 microM) and butoxamine (100 microM), the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol (10-100 microM) caused a concentration-dependent right-ward shift of the concentration-response curves for carteolol in the guinea pig gastric fundus. Schild plot analyses of the effects of (+/-)-bupranolol against carteolol gave the pA2 value of 5.29 and the Schild slope was not significantly different from unity. Furthermore, carteolol (10 microM) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxy-acetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride) in the guinea pig gastric fundus. These results suggest that the partial agonistic effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig gastric fundus.     

Beta1- and beta3-adrenoceptors mediate relaxation in ovine trachealis smooth muscle

Isoprenaline (non-selective) and noradrenaline (beta1-selective) concentration-dependently relaxed ovine tracheal strips precontracted with carbachol. The pD2 values were 7.07 +/- 0.08 and 6.13 +/- 0.10 for isoprenaline and noradrenaline, respectively. In the same preparation, salbutamol either produced weak relaxation or in some cases, contractile responses indicating the presence of very little or no beta2-adrenoceptors in this preparation. Isoprenaline-and noradrenaline-induced relaxations were antagonized by propranolol and atenolol with pA2 values in the range reported in the literature for an action on beta1-adrenoceptors. ICI 118551 also antagonized isoprenaline- and noradrenaline-induced relaxation but at concentrations much higher than are required to block beta2-adrenoceptors, confirming that beta2-adrenoceptors do not contribute significantly to these responses. The selective beta3-adrenoceptor agonist, BRL 37344A produced concentration-dependent relaxation of tracheal strips. BRL 37344A was a full agonist producing 100% relaxation of carbachol-induced tone. BRL 37344A-induced relaxation was weakly antagonized by propranolol confirming an action, mainly, on beta3-adrenoceptors. Cyanopindolol antagonized isoprenaline-induced relaxation (in the presence of propranolol, 10(-7) M) with a pA2 value of 8.06 +/- 0.24. It was therefore concluded that beta1- and beta3-adrenoceptors mediated agonist-induced relaxation in sheep tracheal strips.     

A study of some propranolol analogues for selective beta-adrenoceptor antagonism using A2 values on isolated trachea and atria from guinea-pig

1 PA2 values for beta-adrenoceptor antagonists were obtained on isolated preparations of guinea-pig trachea (intrinsic tone) and atria (rate), with isoprenaline, noradrenaline (beta 1-selective) and fenoterol (beta 2-selective) as agonists. Uptake mechanisms and alpha-adrenoceptors were inhibited. The antagonists studied were (+/-)-threo-alpha-methylpropranolol. (+/-)-1(4-benzimidazoloxy)-3-isopropylamino-2-propanol (4-BIP) and (+/-)-1-(5-benzimidazoloxy)-3-isopropylamino-2-propanol (5-BIP). 2 4-BIP was a potent beta-adrenoceptor antagonist but it was not selective for trachea (pA2 on trachea 7.88 and on atria 7.73, fenoterol as agonist). 5-BIP was less than one tenth as active as 4-BIP and was therefore not studied in detail. 3 alpha-Methylpropranolol was potent and it was also selective for trachea (pA2 on trachea 8.24 and on atria 7.56, fenoterol as agonist). This selectivity was not seen with isoprenaline as agonist. In tracheal preparations contracted by carbachol the slope of the Schild plot for alpha-methylpropranolol was less than 1.0 (isoprenaline as agonist). 4 alpha-Methylpropranolol, although not highly selective for beta 2-adrenoceptors, is considerably more potent than the alternative beta 2-selective antagonists available at present. Therefore, it may be useful in studies designed to classify beta-adrenoceptor subtypes in tissues.     

Are the pA2 values of selective beta-adrenoceptor antagonists valid when obtained on guinea-pig tracheal preparations contracted with carbachol?

On carbachol-contracted tracheal preparations from guinea-pigs, the slope of the Schild plot for propranolol (isoprenaline as agonist) was 1.0. The slope of the plots for atenolol (beta 1-selective) and butoxamine (beta 2-selective) were less than 1.0, whether isoprenaline or fenoterol was agonist. This was in contrast to previous reports on intrinsic tone tracheal preparations. It was established that the low slopes for atenolol and butoxamine on carbachol-contracted preparations were not related to aspects of the experimental procedures. Low slopes on carbachol-contracted preparations tended to occur when the antagonist used was selective and, although the reason for this is not clear, it may be related to the presence of both beta 1- and beta 2-adrenoceptors in this tissue. Therefore, it is suggested that pA2 values obtained for selective beta-adrenoceptor antagonists on guinea-pig tracheal preparations contracted with carbachol may not be strictly valid, and that antagonists should be studied on intrinsic tone tracheal preparations when pA2 values are to be compared with pA2 values from other tissues to quantify the selectivity of the antagonist.     

pA2 values of selective β-adrenoceptor antagonists on isolated atria demonstrate a species difference in the β-adrenoceptor populations mediating chronotropic responses in cat and guinea-pig

pA 2 values for atenolol (β 1 -selective) and α-methylpropranolol (β 2 -selective) have been determined on isolated atria of cat and guinea-pig using noradrenaline (β 1 -selective) and fenoterol (β 2 -selective) as agonists. On guinea-pig atria, the pA 2 values did not vary with the agonist used. On cat atria the pA 2 for atenolol was greater with noradrenaline than with fenoterol and the pA 2 for α-methylpropranolol was greater with fenoterol than with noradrenaline. Fenoterol was 20 times more potent on cat than on guinea-pig atria whereas noradrenaline was approximately equipotent in the two species. The results have been interpreted as suggesting that both cat and guinea-pig atria contain one receptor type in common (β 1 ) but that only cat atria contain β 2 -adrenoceptors as well.     

Effects of some catecholamines on the cat cardiovascular system: interactions with adrenoceptor antagonists

The effects of intravenous infusions of norepinephrine, epinephrine, isoproterenol, N-t-butylnorepinephrine, oxymethyleneisoproterenol, and RO363 on heart rate, mean arterial blood pressure, cardiac output, total peripheral resistance, and stroke volume were evaluated in chloralose-anaesthetized cats before and after phentolamine, propranolol, atenolol, and butoxamine. Pressor responses to both norepinephrine and epinephrine largely resulted from alpha-receptor-mediated increases in total peripheral resistance. Vasomotor reversal was noted with both drugs in the presence of alpha-receptor blockade. Dilator responses to norepinephrine were abolished by the beta 1-receptor selective antagonist atenolol, as were those to the beta 1-receptor selective agonists oxymethyleneisoproterenol and RO363. Dilator responses to epinephrine were abolished by the beta 2-receptor selective antagonist butoxamine, as were those to N-t-butylnorepinephrine (beta 2-selective) and isoproterenol (nonselective). These results indicate that in addition to beta 2-receptors, beta 1-receptors subserving vasodilatation occur in the cat vasculature. Atenolol displayed agonist-dependent inhibition of the cardiac responses. Responses to noradrenaline, RO363, and oxymethyleneisoproterenol were blocked to a greater extent than were those to epinephrine, N-t-butylnorepinephrine, and isoproterenol. Butoxamine did not display any marked agonist-dependent inhibition of cardiac responses. Nevertheless, the results are in accord with previous suggestions that cardiostimulant beta 2-receptors exist in the cat heart. Interpretation of the actions of catecholamines may be complicated by mixed beta-adrenoceptor populations in the cat cardiovascular system.