Functional analysis of desensitization of the beta-adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion.
1. This study examined beta-adrenoceptor signalling in cardiac tissues following infusion of isoprenaline (400 microg kg(-1) h(-1)) or vehicle to rats for 14 days. 2. 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. 3. 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-beta-D-ribofuranosylbenzimidazole-3', 5'-cyclic monophosphorothioate were unchanged. 4. 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 Ca2+ were unchanged. 5. 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 Ca2+ were not significantly altered. 6. This study indicates differences in beta-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.
McMartin
L
L
Department of Pharmacology, University of Melbourne, Parkville, Australia.
Summers
R J
RJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D003994:Bucladesine; D007545:Isoproterenol