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

The regulatory effects of pindolol and celiprolol on cardiac beta-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 beta-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 beta 2-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 beta 1-adrenoceptors by approximately 26%. This finding is in contrast to the propranolol--induced up-regulation of both beta 1- and beta 2-adrenoceptors by approximately 80%. Since supramaximal doses of each drug were administered, a significant smaller increase of beta 1-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 beta 1-adrenoceptors as well. Isoprenaline as a full agonist caused a marked loss of of both beta-adrenoceptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)