title: Selective beta 1-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through beta 2-adrenoceptors in human atrial myocardium.
abstract: We determined the relative contribution of beta 1- and beta 2-adrenoceptor stimulation to the positive inotropic responses of human atrial myocardium to catecholamines. (-)Norepinephrine produced stimulation predominantly through beta 1-receptors and (-)epinephrine through both beta 1- and beta 2-receptors. However, there were marked differences in the responses of tissues from patients treated with the beta 1-selective antagonist atenolol compared with non-beta-blocker-treated patients; surprisingly, beta 2-mediated responses were enhanced, and beta 1-mediated responses were unaltered. There was an enhanced responsiveness to (-)epinephrine (atenolol treated: -log M EC50, 7.57 +/- 0.07; non-beta-blocker treated: -log M EC50, 6.77 +/- 0.17; p less than 0.001), and the relative importance of beta 2-adrenoceptor stimulation was increased for both (-)norepinephrine and (-)epinephrine. In tissues from atenolol-treated patients, salbutamol, a beta 2-selective partial agonist, had an enhanced potency and a greater intrinsic activity (atenolol treated: -log M EC50, 7.13 +/- 0.09; intrinsic activity, 0.86 +/- 0.04; non-beta-blocker treated: -log M EC50, 5.76 +/- 0.44; intrinsic activity, 0.39 +/- 0.13). We investigated possible mechanisms underlying the enhanced responsiveness to beta 2 stimulation. Determination of beta 2-adrenoceptor affinity for salbutamol showed no change of affinity in atenolol-treated patients. Responses of the tissues to the cyclic AMP analogue dibutyryl cyclic AMP were not different between atenolol-treated and non-beta-blocker-treated patients. The results suggest that chronic blockade of beta 1-adrenoceptors causes enhanced coupling of beta 2-adrenoceptors to adenylate cyclase or to other mechanisms leading to increased contractile force.
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Hall
authors.forename: A J
authors.initials: AJ
authors.lastname: Kaumann
authors.forename: M J
authors.initials: MJ
authors.lastname: Brown
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D001262:Atenolol / Q000627:therapeutic use; D001696:Biomechanical Phenomena; D003994:Bucladesine / Q000494:pharmacology; D002395:Catecholamines / Q000502:physiology*; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006325:Heart Atria; D006801:Humans; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D001262:Atenolol; D003994:Bucladesine; D000420:Albuterol; D004837:Epinephrine