In vitro evidence that carteolol is a nonconventional partial agonist of guinea pig cardiac beta1-adrenoceptors: a comparison with xamoterol.

The present study was designed to verify our previous hypothesis that carteolol, a beta1/beta2-adrenoceptor-blocking agent, is a nonconventional partial agonist of cardiac beta1-adrenoceptors. To this purpose, we characterized the effects of carteolol in guinea pig myocardial preparations and measured the affinities of carteolol for high- and low-affinity sites of beta1-adrenoceptors labeled by CGP12177 [(-)4-(3-t-butylamino-2-hydroxypropoxy)-2-benzimidazol-2-one]. All experiments were performed in comparison with xamoterol, a cardioselective beta1-adrenoceptor partial agonist. Both drugs caused cAMP-dependent positive inotropic and chronotropic effects, but carteolol was less effective and less potent than xamoterol, and its cardiac actions were not affected by conventional concentrations of the beta-blocker propranolol. Both carteolol and xamoterol antagonized the cardiac effects of isoprenaline, but although the antagonistic concentrations of xamoterol were almost equal to those producing cardiostimulation, the antagonistic concentrations of carteolol were 3 log units lower than those causing cardiostimulant effects. Both carteolol and xamoterol competed with (-)[3H]CGP12177 for a high-affinity site of beta1-adrenoceptors, but carteolol showed a higher affinity than xamoterol. Moreover, carteolol, unlike xamoterol, bound also to a low-affinity site of the receptors. The binding affinity constants of the drugs for the high-affinity site correlated well with the respective blocking potencies against isoprenaline, whereas the affinity constant of carteolol for the low-affinity site was well related to its agonist potency. In conclusion, our findings demonstrate that carteolol, unlike xamoterol, is a nonconventional partial agonist, which causes agonistic effects through interaction with the low-affinity propranolol-resistant site of beta1-adrenoceptors and antagonistic actions through the high-affinity site of the same receptors.