Rat lung parenchymal strips were used to study beta-adrenoceptor desensitization from both a functional and a biochemical point of view. Prolonged "in vitro' exposure of rat lung to the beta-agonist isoproterenol (10(-6) M for 20 min) markedly reduced the antagonistic activity of isoproterenol on carbachol-induced contractions. The loss of responsiveness to isoproterenol was associated with a 33% decrease of the beta-receptor number with concomitant reduction of isoproterenol-stimulated adenylate cyclase activity, whereas the enzyme response to NaF was identical in control and in desensitized rat lung. On the basis of these results obtained by comparing the functional and biochemical aspects of the desensitization process, we suggest that the marked reduction of pharmacological activity of isoproterenol after desensitization was primarily due to the decrease in the number of binding sites. The possible molecular mechanisms underlying desensitization are also discussed.