IRREVERSIBLE BLOCKADE OF BETA-ADRENORECEPTORS AND THEIR RECOVERY IN THE RAT-HEART AND LUNG INVIVO

Abstract

The interaction of a bromoacetylated derivative of alprenolol (Alm-CO-CH2Br) with cardiac and lung .beta.-adrenoreceptors was partially characterized. After a short incubation period, the concentration of Alm-CO-CH2Br that inhibited specific [3H]dihydroalprenolol binding by 50% in cardiac and lung membranes was 0.5 and 0.11 .mu.M, respectively. The blockade was time-dependent and Scatchard analysis showed no change in the Kd value for specific (-)-[3H]dihydroalprenolol binding but a loss of .beta.-adrenoreceptor content after membrane pretreatment with Alm-CO-CH2Br. The blockade was not reversed by extensive membrane washing, although concurrent treatment with alprenolol fully protected whereas phentolamine had no protective effect. Alm-CO-CH2Br produced a dose-dependent blockade of heart and lung .beta.-adrenoreceptors in vivo and the compound had little or no effect on the growth rate of the rat. Four hours after 1 i.p. injection of Alm-CO-CH2Br at 35 mg/kg, the heart and lung .beta.-adrenoreceptor content was decreased by 88 and 90%, respectively. The time required for complete recovery from irreversible .beta.-adrenoreceptor blockade was .apprx. 200 h in the heart and 650 h in the lung. Alm-CO-CH2Br may be a useful probe for the .beta.-adrenoreceptor both in vitro and for recovery studies in vivo.