Comparison of the affinity of β‐blockers for two states of the β 1 ‐adrenoceptor in ferret ventricular myocardium

We compared the potency of 11 clinically available β‐blockers as antagonists of the positive inotropic effects of (−)‐isoprenaline and CGP12177 on ferret ventricular myocardium. (−)‐CGP12177, (−)‐pindolol and (−)‐alprenolol were non‐conventional partial agonists with intrinsic activity of 0.7, 0.2 and 0.1 respectively. All β‐blockers antagonized in a concentration‐dependent and surmountable manner the positive inotropic effects of both (−)‐isoprenaline and CGP12177. The potency of each β‐blocker was consistently higher against (−)‐isoprenaline than against CGP12177. Two groups of β‐blockers were identified. In one group the difference between the pK B values of blockade against (−)‐isoprenaline and CGP12177 was 1.1–1.6 log units ((−)‐alprenolol, (−)‐pindolol, (−)‐bupranolol, nadolol and carvedilol). In the other group the pK B difference was of 2.1–3.0 log units ((−)‐atenolol, metoprolol, bisoprolol, sotalol, (−)‐propranolol and (−)‐timolol). The β‐blockers competed with (−)‐[ 125 I]‐cyanopindolol for binding to ventricular β 1 ‐adrenoceptors. The binding affinities correlated with the corresponding blocking potencies against (−)‐isoprenaline. On average the pK i values were 0.5 log units smaller than the pK B values against (−)‐isoprenaline but 1.6 log units greater than the pK B values against CGP12177. In ferret ventricle the effects of (−)‐isoprenaline appear to be antagonized by β‐blockers through the state of the β 1 ‐adrenoceptor for which (−)‐[ 125 I]‐cyanopindolol and β‐blockers have high affinity. The cardiostimulant effects of CGP12177 appear to be mediated through a low‐affinity state of the β 1 ‐adrenoceptor for which β‐blockers have low affinity.British Journal of Pharmacology (2002) 135 , 451–461; doi: 10.1038/sj.bjp.0704450