Effects of in vivo treatment with isoprenaline or prenalterol on beta-adrenoceptor mechanisms in the heart and soleus muscle of the cat

Abstract

The full agonist isoprenaline (5.3–6.6 nmol/kg min) and the partial β-adrenoceptor agonist prenalterol (10.6–13.3 nmol/kg · min) were administered to cats continuously via osmotic minipumps (i.p.). After seven days the functional and adenylate cyclase responsiveness to the agonists, as well as the β-adrenoceptor-binding characteristics, were studied in cardiac and soleus muscle preparations in vitro. After isoprenaline pretreatment, the papillary muscles and soleus muscle strips were 15–18 times less sensitive to isoprenaline compared with muscles from control cats. The stimulatory potency (pD₂) of prenalterol in the papillary muscle was not changed significantly. The affinity of the agonists to the β-adrenoceptors was unaffected in both tissues by the pretreatment, but the densities of β-adrenoceptors were significantly reduced, by 36% (myocardium) and 47% (soleus) respectively. In the cat papillary muscle the intrinsic sympathomimetic activity (ISA) of prenalterol on contractile parameters was reduced from 84 (T _max), 69 (dT/dt _max) and 71% (dT/dt _min) in control animals, to 33, 22 and 28%, respectively in the animals pretreated with isoprenaline. Prenalterol pretreatment did not induce any marked changes, either in the stimulatory potency or affinity of the agonists in the two tissuer or in the maximal response (ISA) of prenalterol in the papillary muscle. The marked reduction in the stimulatory potency of isoprenaline and the reduced ISA of prenalterol in the myocardium after isoprenaline pretreatment can not be explained by the reduction in β-adreoceptor density alone. Since the affinity to the β-adrenoceptors is unaffected, a reduced efficiency in the signal transmission must be the main cause. This alteration in signal transmission seems to be an event located distal to adenylate cyclase, since the relative decrease in the enzyme activity is even less than the loss of β-adrenoceptors in both the myocardium and soleus muscle. The present results demonstrate that the effects on β-adrenoceptors and functional responsiveness are different after prolonged treatment with a full β-adrenoceptor agonist and a partial agonist, such as prenalterol.