Inverse agonist activities of β ‐adrenoceptor antagonists in rat myocardium

Negative inotropic effects of several β‐adrenoceptor (βAR) antagonists on electrically‐stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine‐treated rats were used as a measure of their inverse agonist activities. β 1 AR antagonists acebutolol, atenolol and metoprolol, β 2 AR antagonist ICI‐181,551 and nonselective βAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. The nonselective βAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI‐118,551, atenolol and propranolol. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI‐118,551 against isoprenaline was greater on right atria than on other cardiac regions. β 1 AR proteins were expressed in all regions of the heart but of β 2 AR were primarily localized in the right atrium. It is concluded that β 2 AR play a greater role in right atria than in other cardiac regions and almost all βAR antagonists behave as inverse agonists.British Journal of Pharmacology (1999) 127 , 895–902; doi: 10.1038/sj.bjp.0702616