EFFECTS OF CHRONIC INFUSION OF (-)-ISOPRENALINE ON RAT CARDIAC MUSCARINIC (M(2))-CHOLINOCEPTOR AND BETA(1)-ADRENOCEPTORS AND BETA(2)-ADRENOCEPTORS

1 The effects of chronic (-)-isoprenaline infusion (400 mu g kg(-1) h(-1); 4 h-14 days) on rat ventricular muscarinic M(2)-cholinoceptors and beta(1)- and beta(2)-adrenoceptors was determined. [H-3]-N-methylscopolamine (NMS) was used to measure M(2)-cholinoceptor binding and (-)-[I-125]-cyanopindolol (CYP) was used for beta(1)- and beta(2)-adrenoceptor binding. 2 Chronic infusion of (-)-isoprenaline did not affect either the affinity of [H-3]-NMS for M(2)-cholinoceptors, or the maximal density of these receptors (B-max) at all treatment periods investigated (4 and 20 h; 7 and 14 days). The affinity of (-)-[I-125]-CYP for beta-adrenoceptors was not changed following chronic (-)-isoprenaline infusion (4, 12 and 20 hours; 7 and 14 days). 3 Competition between (-)-[I-125]-CYP and the selective beta(1)-adrenoceptor antagonist CGP 20712A resulted in biphasic curves at all treatment periods corresponding to the presence of beta(1)- and beta(2)-adrenoceptor binding sites. beta(1)-adrenoceptors made up the greater proportion of beta-adrenoceptors in rat ventricle. There was no change in the ratio of beta(1)- to beta(2)-adrenoceptors following 4 h (-)-isoprenaline infusion [(beta(1):beta(2)), vehicle: 77.5 +/- 4.0%:22.5 +/- 4.0%, n = 6; (-)-isoprenaline: 79.2 +/- 1.2%:20.8 +/- 1.2%, 6], however infusion for 12 h increased the ratio [(beta(1):beta(2)>), vehicle: 65.2 +/- 6.1%:34.8 +/- 6.1%, n = 6; (-)-isoprenaline: 85.6 +/- 1.8%:14.4 +/- 1.8%, n = 6, P < 0.05], which was maintained for longer infusion periods (20 h-14 days). 4 Both beta(1)- and beta(2)-adrenoceptors were down-regulated in rat ventricular tissue following (-)-isoprenaline infusion. beta(2)-adrenoceptors were down-regulated by 12 h (vehicle: 11.8 +/- 2.4 fmol mg protein(-1), n = 6; (-)-isoprenaline: 3.5 +/- 0.4 fmol mg protein(-1), n = 6, P < 0.05) however beta(1)-adrenoceptors were not affected (vehicle: 21.7 +/- 2.0 fmol mg protein(-1), n = 6; (-)-isoprenaline: 20.9 +/- 0.6 fmol mg protein(-1), n = 6, P > 0.05) until 20 h infusion (vehicle: 19.4 +/- 2.2 fmol mg protein(-1), n = 6; (-)-isoprenaline: 12.6 +/- 2.2 fmol mg protein(-1), n = 6, P < 0.05). 5 These results show that transregulation of M(2)-cholinoceptors following (-)-isoprenaline infusion does not occur, however down-regulation of both beta(1)- and beta(2)-adrenoceptors does occur in rat ventricular tissue. In comparison with beta(1)-adrenoceptors, beta(2)-adrenoceptors were shown to be more susceptible to down-regulation.