Selective j31-Adrenoceptor Blockade Enhances Positive Inotropic Responses toEndogenous Catecholamines Mediated Through j2-Adrenoceptors inHumanAtrial Myocardium

We determined therelative contribution ofPl- and 2-adrenoceptor stimulation tothepositive inotropic responsesofhumanatrial myocardium tocatecholamines. (-)Norepinephrine produced stimulation predominantly through f,-receptors and(-)epinephrine through both I31- and 2-receptors. However, there weremarkeddifferences intheresponses oftissues from patients treated withthep31-selective antagonist atenolol compared withnon-/-blocker-treated patients; surprisingly, f3-mediated responses wereenhanced, and 3,1-mediated responses were unaltered. There was an enhanced responsiveness to(-)epinephrine (atenolol treated: -logM EC50, 7.57±0.07; non-,B-blocker treated: -logM EC50, 6.77±0.17; p<0.001), andtherelative importance ofP2-adrenoceptor stimulation was increased forboth(-)norepinephrine and (-)epinephrine. Intissues fromatenolol-treated patients, salbutamol, a p3-selective partial agonist, hadan enhancedpotency anda greater intrinsic activity (atenolol treated: -logM EC50, 7.13±0.09; intrinsic activity, 0.86±0.04; non-,-blocker treated: -logM EC50, 5.76+0.44; intrinsic activity, 0.39±0.13). We investigated possible mechanisms underlying theenhanced responsiveness to12 stimulation. Determination ofjB2-adrenoceptor affinity forsalbutamol showed no change ofaffinity inatenolol-treated patients. Responses ofthetissues tothecyclic AMP analogue dibutyryl cyclic AMP were notdifferent betweenatenolol-treated andnon13-blocker-treated patients. Theresults suggest thatchronic blockade of1,1-adrenoceptors causesenhancedcoupling of12-adrenoceptors toadenylate cyclase or toothermechanisms leading toincreased contractile force. (Circulation Research 1990;66:1610-1623)