Comparative chronotropic activity of β‐adrenoceptive antagonists

Chronotropic dose-response curves (non-cumulative) for beta-adrenoceptive antagonists were constructed from results in rats anaesthetized with pentobarbitone and depleted of catecholamines by pre-treatment with syrosingopine.2. Depletion of catecholamines lowered resting heart rate and reduced the threshold to the chronotropic action of isoprenaline by about 50%. Eight beta-adrenoceptive antagonists produced a dose-dependent chronotropic response but the maximum response was in all cases smaller than that obtained with isoprenaline. The order of activity was dichloroisoprenaline>LB 46>practolol>INPEA>oxprenolol>pronethalol>alprenolol>I.C.I. 45,763 (Kö 592). Propranolol and sotalol were without significant activity. The duration of the chronotropic response to the antagonists was more prolonged than that to isoprenaline. Propranolol caused a parallel shift to the right of the dose-response curves for the agonist effects of the antagonists.3. Estimation of beta-adrenoceptor blocking activity in anaesthetized cats gave an order of activity dissimilar to that found for maximum agonist responses: LB 46 > oxprenolol > alprenolol > propranolol > I.C.I. 45,763 > practolol > dichloroisoprenaline > sotalol > INPEA > pronethalol.4. Consideration of chemical structure and physico-chemical properties did not explain the differences between the agonist activities of the adrenoceptive antagonists.