Inhibitory effects of G(s) on desensitization of beta-adrenergic receptors in tracheal smooth muscle

We examined the reduction of mechanical responsiveness to beta-agonists after continuous or repeated exposure to agonists in guinea pig tracheal smooth muscle, using an isometric tension record. The inhibitory action of 0.1 mu M isoproterenol (Iso) on contraction induced by 1 mu M methacholine (MCh) was suppressed markedly after incubation with 0.0003-3 mu M Iso for 1 h. The effects of Iso on MCh-induced contraction gradually decreased after repeated application of these agents at intervals of 1 h. When Iso was perfused cumulatively to tissues repeatedly precontracted by MCh, the effects of Iso were reduced at the second application. This reduced responsiveness to beta-agonists was not mimicked by forskolin and did not occur after preexposure of the strips to 2 mu g/ml cholera toxin for 6 h. We concluded that this reduced responsiveness to beta-agonists is homologous desensitization and that the irreversible activation of the stimulatory G proteins, G(s), may play an important role in prevention of the reduced responsiveness to beta-agonists.