IMPAIRED ACTIVATION OF ADENYLYL-CYCLASE IN LUNG OF THE BASENJI-GREYHOUND MODEL OF AIRWAY HYPERRESPONSIVENESS - DECREASED NUMBERS OF HIGH-AFFINITY BETA-ADRENOCEPTORS

1 To evaluate mechanisms involved in the impaired beta-adrenoceptor st imulation of adenylyl cyclase in tissues from the Basenji-greyhound (B G) dog model of airway hyperresponsiveness, we compared agonist and an tagonist binding affinity of beta-adrenoceptors, beta-adrenoceptor sub types, percentage of beta- adrenoceptors sequestered, and coupling of the beta-adrenoceptor to G(s) alpha in lung membranes from BG and cont rol mongrel dogs. We found that lung membranes from the BG dog had hig her total numbers of beta-adrenoceptors with a greater percentage of r eceptors of the beta(2) subtype as compared to mongrel lung membranes. 2 Agonist and antagonist binding affinity and the percentage of beta- adrenoceptors sequestered were not different in BG and mongrel dog lun g membranes. However, the percentage of beta-adrenoceptors in the high affinity state for agonist was decreased in BG lung membranes suggest ing an uncoupling of the receptor from G(s) alpha. 3 Impaired coupling between the beta-adrenoceptor and G protein documented by the decreas ed numbers of beta-adrenoceptors in the high affinity state in BG lung membranes, is a plausible explanation for the reduced stimulation of adenylyl cyclase and the resultant reduction in airway smooth muscle r elaxation in this model.