Chronic isoproterenol administration causes altered beta adrenoceptor-Gs-coupling in guinea pig lung

Chronic administration of isoproterenol caused major changes in the molecular and functional characteristics of lung beta adrenoceptors. The dose of isoproterenol delivered by the minipumps over 7 days corresponded to approximately 60 micrograms.kg-1h-1. The agonist treatment produced an 80% decrease in the number of beta adrenoceptors in lung membranes. However, a significant proportion of the remaining receptors could still form complexes with the nucleotide regulatory protein (Gs) in the presence of agonist. This was demonstrated by the persistence of high affinity sites (42% versus 53% in controls, P less than .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 less than .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 Gs activity, as demonstrated by the lower degree of cholera toxin-mediated adenosine diphosphate ribosylation. Moreover, chronic against treatment caused a 50% reduction in the maximal relaxing effect of isoproterenol 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 relatively low catecholamine doses appear to differ from those reported for cultured cells, as well as those mediated by acute in vivo catecholamine administration.