THE SELECTIVE ACTION OF β‐ADRENOCEPTOR BLOCKING DRUGS AND THE NATURE OF β1 and β2 ADRENOCEPTORS

Abstract

1 Purified membranes retaining a catecholamine responsive adenylate cyclase have been prepared from rabbit heart, lung and (pseudo-pregnant) uterus. 2 These preparations have the characteristics of plasma membranes and both heart and lung respond to β-adrenoceptor agonists in the order: (±)-isoprenaline> (—)-noradrenaline> (—)-adrenaline> (+)-isoprenaline> salbutamol. The sensitivity of the adenylate cyclase to β-adrenoceptor stimulation is improved by pre-treatment of the animals with reserpine and syrosingopine. 3 Dose-ratios for several concentrations of propranolol (non-selective β-adrenoceptor blocker), practolol and atenolol (cardio-selective β-adrenoceptor blockers) have been measured on all three membrane preparations. Schild plots of log (dose ratio — 1) vs. log dose were virtually coincident for heart and lung with a dissociation constant (K_b) for propranolol very close to the pharmacological value. The ratio of K_b values was 0.65 for practolol and 1.23 for atenolol compared with pharmacological cardio-selectivity ratios (measured on isolated atria and tracheal chain) of 67.6 and 110 respectively. The uterus/heart K_b ratio was 51.5 for atenolol. Inhibition of the uterus by practolol gave a Schild plot with slope significantly less than 1, indicating a different mechanism of action from the heart. 4 K_b values obtained by measuring adenylate cyclase stimulation in chopped tissue (including preparations of bronchial tree and alveolar tissue as well as whole lung) resembled the membrane values rather than those found in whole organs. 5 The results show that the pharmacological selectivity of practolol and atenolol is maintained at the receptor-adenylate cyclase level, at least as far as heart and uterus are concerned, though the smaller selectivity ratios in the biochemical system suggest that receptor difference is not the only factor and that phase distribution of the drug may also be important. Membranes prepared from whole lung show an overall β₁ response which may simply reflect the predominance of β₁ cell types containing β₁-adrenoceptors over bronchial smooth muscle.