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

Abstract

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.

β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies

“…The present study confirms and extends earlier studies (Zaagsma et al, 1979;O'Donnell & Wanstall, 1979) NA in this tissue owing to its low potency; and it should be noted that the low slope will increase the error in estimating the pA2 value.…”

“…However, there is no reason to expect that the direct identification of both P-adrenoceptor subtypes in a tissue should necessarily be accompanied by functional heterogeneity and there are good examples of this kind of discrepancy in guinea-pig atria (O'Donnell & Wanstall, 1979;Hedberg et al, 1980) and in the present study, at least in the case of peripheral lung tissue. It is very likely that 1-receptor heterogeneity identified in binding studies may merely reflect the heterogeneous cellular nature of the tissue in question.…”

DEMONSTRATION OF BOTH β1‐ AND β2‐ADRENOCEPTORS MEDIATING RELAXATION OF ISOLATED RING PREPARATIONS OF RAT PULMONARY ARTERY

“…Preparations did not change in sensitivity to either isoprenaline or fenoterol but there was a progressive decline in sensitivity to noradrenaline (1.2 fold in the second curve and a further 1.2 fold in the third curve). Therefore, as advocated by Furchgott (1972), the CR values obtained when noradrenaline was the agonist were corrected to allow for this change in sensitivity as described by O'Donnell & Wanstall (1979b). Plots of log molar antagonist concentration, (log [B]), against log (CR-1) were obtained as proposed by Arunlakshana & Schild (1959).…”

“…A linear least squares regression analysis (Snedecor & Cochran, 1967) was used to obtain the line of best fit, using the combined data points from a number of animals, and this line is referred to as a Schild plot. If a Schild plot had a slope which was not significantly different from 1.0, a pA2 value for the antagonist was calculated from the formula pA2 = log (CR-1) -log [B] as described by O'Donnell & Wanstall (1979b).…”

“…The present study has been carried out on a rat artery preparation, the pulmonary artery, a blood vessel in which the Jadrenoceptor subtype(s) has not previously been classified. The approach used to characterize the adrenoceptor population was that previously used to demonstrate the presence of both Pil-and P2-adrenoceptors in guinea-pig trachea (Furchgott, 1976;O'Donnell & Wanstall, 1979b) and in the atria from some but not all species (O'Donnell & Wanstall, 1979a;Bryan, Cole, O'Donnell & Wanstall, 1981).…”