Enhanced negative chronotropy by inhibitory receptors in transgenic heart overexpressing beta(2)-adrenoceptors

Transgenic (TG) mice overexpressing beta(2)-adrenoceptors (AR) in the heart have enhanced beta-adrenergic activity. Since the degree of beta-adrenergi c activation influences the negative chronotropic control of heart rate (HR ), we studied the inhibitory effect of cholinergic and purinergic stimulati on on HR in TG and wild-type (WT) control mice. Bradycardia in response to vagal nerve stimulation and administration of acetylcholine or adenosine wa s studied in anesthetised animals and perfused hearts. Basal HR was signifi cantly higher in TG than WT mice (P<0.01). Electrical stimulation of vagal nerves (1-32 Hz) induced a Hz-dependent reduction in HR and the response wa s more pronounced in TG than WT groups (P<0.01). In perfused hearts, HR red uction by acetylcholine (ACh) was more pronounced with EC50 110-fold lower in TG than WT hearts. Adenosine-induced bradycardia, which was abolished by a P-1 antagonist, was more pronounced in TG hearts. After pre-treatment wi th pertussis toxin (PT, 100 mu g/kg), bradycardia by vagal nerve stimulatio n or ACh remained unchanged in WT, but markedly inhibited in TG hearts (bot h P<0.01). Conversely, inhibiting guanylyl cyclase with LY83583 (30 mu M) o r nitric oxide synthase with L-NMMA (100 mu M) attenuated HR reduction by v agal nerve stimulation in WT but not in TG hearts. Immunobloting assay show ed similar G(i alpha 2) abundance in TG and WT hearts. Thus, cardiac overex pression of beta(2)AR with high beta-adrenergic activity leads to hypersens itivity of inhibitory receptors controlling HR due to increase in activity of PT-sensitive G-proteins. (C) 2000 Elsevier Science B.V. All rights reser ved.