Chronic administration of isoproterenol caused major changes in the molecular and functional characteristics of lung beta adrenoceptors. The dose of isoproterenol delivered by the mini-pumps over 7 days corresponded to-60 g. kg1h1. The ago-nist treatment produced an 80% decrease in the number of beta adrenoceptors in lung membranes. However, a significant pro-portion of the remaining receptors could still form complexes with the nucleotide regulatory protein (G5) in the presence of agonist. This was demonstrated by the persistence of high affinity sites (42% versus 53% in controls, P<. 01) in isoproterenol competition binding curves and of the tight binding of isoproterenol in the presence of the reagent N-ethylmaleimide (44% versus 60% in controls, P<. 01). However, part of the receptor population displaying high affinity toward the agonist was insensitive to guanosine 5’-triphosphate. These changes were associated with a decrease in the G5 activity, as demon-strated by the lower degree of cholera toxin-mediated adenosine diphosphate ribosylation. Moreover, chronic agonist treatment caused a 50% reduction in the maximal relaxing effect of isopro-terenol in the isolated lung parenchymal strip, whereas the tissue sensitivity to beta adrenoceptor stimulation was unchanged. It is concluded that chronic administration of isoproterenol to guinea pigs caused marked changes in beta adrenoceptor function in the lung tissue. The molecular events involved in beta adrenoceptor desensitization by chronic in vivo administration of rela-tively low catecholamine doses appear to differ from those reported for cultured cells, as well as those mediated by acute in vivo catecholamine administration.

Prolonged administration of a beta agonist (H) may cause a reduced responsiveness with time of the beta adrenoceptor system to pharmacological or hormonal stimulation. Up to now most information regarding the molecular mechanism of this desensitization has been gathered from cultured cell systems using high catecholamine concentrations(Stiles et al., 1984). In those experiments, it was demonstrated that the initial step