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Biomedical subjects

J C Wanstall

Publications and source records attributed to J C Wanstall.

72 records · Page 4Linked to original sources
PubMed1980

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.

Adrenergic beta-Antagonists↗
PubMed1980

Pharmacological evidence for differences in the beta-adrenoceptor populations influencing atrial rate in guinea pig and cat.

The pA2 values of the selective beta-adrenoceptor antagonists, atenolol and alpha-methylpropranolol, have been assessed using the selective agonists, norepinephrine and fenoterol, as positive chronotropic agents in atria. In cat atria both beta 1- and beta 2-adrenoceptors influence atrial rate, whereas in guinea pig atria only beta 1-receptors are involved.

Animals↗
PubMed1980

K+-depolarization: an alternative method of inhibiting extraneuronal uptake on isolated tissue preparations?

Responses to isoprenaline were not potentiated by extraneuronal uptake (ENU) inhibitor drugs (phenoxybenzamine and metanephrine) in preparations of guinea-pig uterus which were contracted by K+-Krebs solution. Fluorescence histochemical experiments demonstrated that isoprenaline could accumulate extraneuronally in uterine smooth muscle and that this accumulation was inhibited by phenoxybenzamine and metanephrine. However, accumulation was also inhibited by K+-Krebs solution. Therefore, it was concluded that the failure of ENU inhibitor drugs to potentiate isoprenaline responses on K+-depolarized uterine preparations might occur because the uptake mechanism had already been inhibited by the K+-Krebs solution. Support for this hypothesis was obtained from experiments on guinea-pig tracheal preparations in which ENU inhibitor drugs had previously been shown to potentiate isoprenaline responses. In K+-depolarized tracheal preparations this potentiation did not occur presumably because the K+-Krebs solution had already inhibited the uptake. Thus K+-depolarization of a tissue may provide an alternative to the use of extraneuronal uptake inhibitor drugs when it is necessary to eliminate this site of loss in quantitative studies on beta-adrenoceptors in isolated tissues.

Animals↗
PubMed1979

The importance of choice of agonist in studies designed to predict beta 2 : beta 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.

Adrenergic beta-Agonists↗
PubMed1979

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.

Adrenergic beta-Antagonists↗
PubMed1978

Evidence that the efficacy (intrinsic activity) of fenoterol is higher than that of salbutamol on beta-adrenoceptors in guinea-pig trachea.

The functional antagonism of carbachol by fenoterol and salbutamol (beta-adrenoceptor agonists) has been used to demonstrate that the efficacy (intrinsic activity) of fenoterol was about twice that of salbutamol on guinea-pig trachea. The mean maximum shifts of the carbachol concentration--response lines by fenoterol and salbutamol were (log units) 1.07 +/- 0.07 (n = 5) and 0.64 +/- 0.07 (n = 5) respectively. This difference in their efficacies could be demonstrated as differences in maximum relaxation on tracheal preparations contracted with carbachol, although this was dependent on the concentration of carbachol used. beta-Adrenoceptor blocking properties of salbutamol (1 mM) but not fenoterol (1 mM) could be demonstrated on trachea in that salbutamol, but not fenoterol, antagonised the shift in the carbachol concentration--response line produced by isoprenaline. The implications of these findings in relation to the use of fenoterol and salbutamol as bronchodilators is discussed.

Adrenergic beta-Antagonists↗
PubMed1978

An in vitro comparison of beta-adrenoceptor stimulants on potassium-depolarized uterine preparations from guinea-pigs.

1 A comparison of six beta-adrenoceptor stimulants has been carried out on in vitro preparations of guinea-pig uterus which were depolarized in K(+)-Krebs solution. Results have also been obtained on uterine preparations in which contractions to acetylcholine were inhibited. The establishment of the conditions for the K(+)-depolarized preparations are described.2 There was no significant difference between potency values (mean neg log EC(50) values) for any of the drugs on the two types of uterine preparation i.e. the preparations had the same sensitivity to the drugs.3 There was a less than two-fold difference between the relative potency values for the beta-adrenoceptor stimulants on the two types of uterine preparation. The relative potency values (isoprenaline = 100) on the K(+)-depolarized preparation were fenoterol 74.1, salbutamol 15.1, rimiterol 13.5, terbutaline 8.2 and orciprenaline 5.6.4 The relative potency values obtained on uterine preparations were less than three-fold different from those previously found for guinea-pig trachea (after inhibition of extraneuronal uptake).5 The pA(2) value for propranolol on the K(+)-depolarized uterine preparations was 9.13.6 It is concluded that the K(+)-depolarized guinea-pig uterine preparation can be used for quantitative studies on beta-adrenoceptor stimulant drugs. It lacks spontaneous activity, drugs can be added cumulatively and several drugs can be compared on a single preparation. In addition, the results obtained support the classification of the beta-adrenoceptors in guinea-pig uterus and trachea in the same sub-group (beta(2)).

Adrenergic beta-Agonists↗
PubMed1977

The use of functional antagonism to determine whether beta-adrenoceptor agonists must have a lower efficacy than isoprenaline to be trachea-atria selective in vitro in guinea-pigs.

1 The relative efficacies of three trachea-atria selective beta-adrenoceptor agonists, fenoterol, Me 506 and Me 454, compared to isoprenaline, were determined on both trachea and atria of guinea-pigs. 2 On tracheal preparations the beta-adrenoceptor agonists were used as functional antagonists of carbachol and a comparison of the maximum shifts in the carbachol concentration-response line produced by each of the beta-adrenoceptor agonists provided a comparison of their efficacies. 3 On atrial preparations carbachol was used as a functional antagonist of the beta-adrenoceptor agonists and comparison of the maximum responses to the beta-adrenoceptor agonists in the presence of carbachol provided a comparison of their efficacies. 4 On trachea and atria the order of efficacy of the compounds was Me454 greater than Me506 greater than or equal to isoprenaline=fenoterol. 5. The results indicated that high efficacy in a non-catechol beta-adrenoceptor agonist is possible provided there is a favourable N-substituent group. 6 Since Me 454, Me 506 and fenoterol, which are trachea-atria selective, have effficacies equal to or greater than that of isoprenaline, which is non-selective, it is concluded that low efficacy in a compound is not essential for it to show trachea-atria selectivity in vitro in guinea-pigs.

Adrenergic beta-Agonists↗
PubMed1976

The contribution of extraneuronal uptake to the trachea-blood vessel selectivity of beta-adrenoceptor stimulants in vitro in guinea-pigs.

1 The potencies relative to isoprenaline of isoetharine, tertiary butyl noradrenaline, salbutamol, orciprenaline, Me 506, rimiterol, fenoterol, carbuterol and terbutaline on isolated preparations of guinea-pig trachea and blood vessels (perfused hind limb) were determined. All the compounds were selective for trachea and selectivity values, i.e. relative potency on trachea divided by relative potency on hind limb, ranged from 2.3 to 21.4. 2 Responses to isoprenaline (the reference compound), tertiary butyl noradrenaline and isoetharine were potentiated on trachea by 50 muM phenoxybenzamine (PHB) and by other inhibitors of extraneuronal uptake (ENU). Under these conditions the selectivity values of all the compounds was close to unity. 3 Selectivity values were also close to unity if they were calculated from data obtained without ENU inhibition, provided that only those compounds not potentiated by PHB on trachea were used. 4 It is proposed that the trachea-blood vessel selectivity shown by beta-adrenoceptor stimulants can be caused by the influence of ENU upon them, rather than by their ability to distinguish between two beta2-adrenoceptors. 5 The suggestion that differences exist between beta2-adrenoceptors in respiratory and vascular smooth muscle is not supported by the in vitro experiments described.

Adrenergic beta-Agonists↗
PubMed1974

Potency and selectivity in vitro of compounds related to isoprenaline and orciprenaline on beta-adrenoceptors in the guinea-pig.

1 Amines related in structure to either isoprenaline (catechol series) or orciprenaline (resorcinol series) were examined for activity on isolated trachea (relaxation), atria (chronotropic action) and perfused hind-limb (vasodilatation) of the guinea-pig.2 Compounds with a resorcinol nucleus were less potent on all three preparations but more selective for trachea than were compounds with a catechol nucleus.3 In both catechol and resorcinol compounds potency on trachea was enhanced by and selectivity for trachea was favoured by substitution of a p-OH phenyl group in the N-iso propyl, or by replacement of the N-iso propyl with an N-t-butyl, with or without a p-OH phenyl group.4 Most of the compounds, particularly the resorcinols, had much lower potencies, relative to isoprenaline, on hind-limb than on trachea.5 Some of the problems associated with the quantitative measurement of selectivity and with sub-classification of beta-adrenoceptors are discussed.

Animals↗
PubMedDate not supplied

Hexoprenaline: beta-adrenoreceptor selectivity in isolated tissues from the guinea-pig.

1. A catecholamine beta-adrenoreceptor agonist, hexoprenaline, was examined in vitro on five guinea-pig tissues and its potency relative to isoprenaline (as 100) obtained. 2. Hexoprenaline clearly delineated between those tissues classified as containing beta2-adrenoreceptors (trachea, hind limb blood vessels and uterus; relative potencies 219, 110 and 76 respectively) and those classified as containing beta1-adrenoreceptors (atria and ileum; relative potencies 3.3 and 1.0 respectively). 3. Hexoprenaline differed from some previously studied noncatecholamine beta-adrenoreceptor agonists in being only two-fold less potent, relative to isoprenaline, as a vasodilator in perfused hind limb than as a tracheal relaxant.

Animals↗