Functional analysis of desensitization of the β ‐adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion

This study examined β‐adrenoceptor signalling in cardiac tissues following infusion of isoprenaline (400 μg kg −1  h −1 ) or vehicle to rats for 14 days. Isoprenaline infusion caused marked hypertrophy of atria and ventricles and reduced the resting rate of spontaneously beating right atria and the basal force of left atrial contraction. In spontaneously beating right atria, concentration‐response curves to isoprenaline and forskolin were shifted 7.9 and 3.2 fold to the right following treatment whereas responses to the cyclic AMP analogue 5,6‐dichloro‐1‐ß‐D‐ribofuranosylbenzimidazole‐3′, 5′‐cyclic monophosphorothioate were unchanged. In electrically driven left atria, concentration‐response curves to isoprenaline and forskolin were shifted 4 fold to the right and maximum responses reduced. Responses to dibutyryl cyclic AMP were shifted 3.2 fold to the right but those to Ca 2+ were unchanged. Inotropic responses of left and right ventricular papillary muscles to isoprenaline were abolished and markedly reduced respectively by isoprenaline treatment. Responses to forskolin were shifted 5 fold to the right. Responses to dibutyryl cyclic AMP were shifted to the right 3.2 and 2 fold in left and right ventricular papillary muscles. Responses to isobutyl methyl xanthine were shifted to the right 15.8 and 6.3 fold in left and right papillary muscles whereas those to Ca 2+ were not significantly altered. This study indicates differences in β‐adrenoceptor desensitization in different regions of the heart following chronic infusion of isoprenaline. Chronotropic responses showed impaired signalling between the receptor and adenylate cyclase whereas inotropic responses exhibited additional desensitization at the level of cyclic AMP dependent protein kinase.British Journal of Pharmacology (1999) 127 , 1012–1020; doi: 10.1038/sj.bjp.0702618