Contraction of cardiac myocytes from noradrenaline-treated rats in response to isoprenaline, forskolin and dibutyryl cAMP

Rats were treated with noradrenaline at either 300 micrograms/kg per h for 1 week (Group 1) or 600 micrograms/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 rats 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 less than 0.001). The ratio between maximum response to calcium and that to isoprenaline in the same cell was also significantly reduced (P less than 0.001). There were significant decreases in response to forskolin, with both the maximum contraction amplitude (P less than 0.01) and forskolin/calcium ratio (P less than 0.001) being attenuated in myocytes from noradrenaline-treated rats. The dbcAMP/calcium ratio was also depressed after noradrenaline treatment (P less than 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.