Desensitization pattern of cardiac β-adrenoceptor subtypes by prolonged in vivo infusion of pindolol and celiprolol in rats

Summary

The regulatory effects of pindolol and celiprolol on cardiac β-adrenoceptor density were studied in vivo in order to assess the subtype selectivity of their partial agonistic activity (PAA). The substances were continuously administered to rats for 1 week by means of implanted osmotic minipumps. The density of β-adrenoceptor subtypes were estimated from ICYP saturation binding experiments performed on cardiac ventricular plasma membranes in the presence of a highly selective antagonist (CGP 20172 A or ICI 118,551). Both antagonists were employed at concentrations as high as to block one subtype only without affecting the complementary subtype. For control purposes, rats were also treated with isoprenaline (0.4 mg/kg/h) and propranolol (0.15 mg/kg/h), or vehicle. Pindolol (0.036 mg/kg/h) and celiprolol (0.36 mg/kg/h) reduced the density of ventricular β₂-adrenoceptors by 46% and 23%, respectively, which — in the case of pindolol — was significant when compared to the non-treated controls. Both compounds, however, produced a small, but distinct increase in the number of β₁-adrenoceptors by approximately 26%. This finding is in contrast to the propranolol-induced upregulation of both β₁- and β₂-adrenoceptors by approximately 80%. Since supramaximal doses of each drug were administered, a significant smaller increase of β₁-adrenoceptors by pindolol and celiprolol —as compared to the increase produced by propranolol — can be interpreted as evidence for a PAA of pindolol and celiprolol on β₁-adrenoceptors as well. Isoprenaline as a full agonist caused a marked loss of of both β-adrenoceptor subtypes. Although it exhibits equal affinity at both subtypes the decrease amounted to 80% of the β₂- but only to 54% of the β₁-adrenoceptors density. This indicates that the down-regulation of cardiac β-adrenoceptors in general seems to be more pronounced at the β₂-than at the β₁-adrenoceptors population. We conclude that the subtype desensitization pattern of agents with intrinsic activity precludes the determination of subtype-selectivity, since β₁- and β₂-adrenoceptors appear to differ in their sensitivity presumably as a result of subtype specific baseline desensitization produced by endogenous catecholamines.