CONTRACTION OF CARDIAC MYOCYTES FROM NORADRENALINE-TREATED RATS IN RESPONSE TO ISOPRENALINE, FORSKOLIN AND DIBUTYRYL CAMP

Rats were treated with noradrenaline at either 300 μg/kg Per h for 1 week (Group 1) or 600 μg/kg per h for 2 weeks (Group 2) using subcutaneously implanted osmotic minipumps. Control rats were sham-operated. Ventricular myocytes were isolated and contraction amplitude and rates of shortening and relaxation measured using a video and edge-detection device. Maximum contraction amplitude achieved in high calcium was similar for all groups, indicating that there was little change in the basic contractility of cells from noradrenaline-treated animals. Cells from Group 1 treated rats showed a depressed concentration-response curve to isoprenaline but maximum contraction amplitudes in forskolin and dbcAMP were unchanged. In cells from Group 2 treated rats the concentration for half-maximal effect (EC50) of isoprenaline was increased and the maximum contraction amplitude was depressed (P < 0.001). The ratio between maximum response to calcium and that to isoprenaline in the same cell was also significantly reduced (P < 0.001). There were significant decreases in response to forskolin, with both the maximum contraction amplitude (P < 0.0 1) and forskolin/calcium ratio (P < 0.001) being attenuated in myocytes from noradrenaline-treated rats. The dbcAMP/calcium ratio was also depressed after noradrenaline treatment (P < 0.02). The extent of the reduction in response was greatest for isoprenaline and least for dbcAMP. These results suggest that desensitisation progresses from a homologous to a heterologous form with increased dose and time of exposure to circulating catecholamines and that, in the latter, lesions occur at several stages of the adenylate cyclase cascade. © 1990.