Regulation of beta-adrenoceptors in the guinea-pig sinoatrial node.

Abstract

This study examined the changes of beta-adrenoceptors in the guinea-pig sinoatrial nodal region following 7 day (-)-isoprenaline (400 micrograms/kg/h s.c.) infusion and the relationship between beta-adrenoceptor desensitization and receptor down-regulation. Changes in beta 1- and beta 2-adrenoceptor density were measured using quantitative autoradiography and function in organ bath studies. (-)-Isoprenaline treatment produced a marked decrease in total (from 57.5 to 33.9 fmol/mg protein), beta 1- (from 49.4 to 32.8 fmol/mg protein), and beta 2-adrenoceptor density (from 8.1 to 1.05 fmol/mg protein) in the sinoatrial node. In adjacent right atrium, treatment produced no change in total (39.5 and 36.7 fmol/mg protein) or beta 1-adrenoceptors (35.9 and 36.4 fmol/mg protein) but did decrease beta 2-adrenoceptors (from 3.7 to 0.3 fmol/mg protein). Chronotropic effects were measured in spontaneously beating right atrium. Procaterol, a selective beta 2-adrenoceptor agonist, caused a biphasic chronotropic response in control right atria, the first part of which was abolished in the tissue from treated animals. The maximum increase in right atrial rate to RO363, a beta 1-adrenoceptor selective partial agonist, was reduced from 114 bpm in control to 43 bpm in treated animals. In electrically driven right atrium with the sinoatrial node removed procaterol failed to produce a positive inotropic response via beta 2-adrenoceptors, but the maximum response to RO363 was reduced from 0.75 g in the control tissue to 0.12 g in the treated tissue. This study showed that changes in beta 2-adrenoceptor density following 7 day (-)-isoprenaline infusion are compatible with reduced functional responsiveness in the SA node. The reduction of beta 1-adrenoceptor number in the SA node was also compatible with the reduced chronotropic response in this tissue. However the lack of effect on beta 1-adrenoceptor density in the right atrium was not consistent with the decrease in beta 1-adrenoceptor mediated inotropic response in this tissue. This suggests that beta-adrenoceptor desensitization is not always associated with receptor down-regulation but depends also on the changes in the cell signalling system beyond the level of the receptor which differ according to the cardiac location.