Effects of direct and indirect activation of G protein of adenylyl cyclase on the subsequent response to β-adrenergic receptor agonists in human trachealis

To examine the response to beta-adrenergic receptor agonists (beta-agonists) following prolonged activation of the stimulatory G protein of adenylyl cyclase (G(s)), relaxation by isoproterenol (isoprenaline, CAS 949-36-0) and formoterol (CAS 73573-872), a long-acting beta-agonist, after exposure to formoterol was measured in human tracheal smooth muscle, using isometric tension records. Prior exposure to formoterol (0.3-30 nmol/l) for 45 min reduced the subsequent relaxation induced by this drug in a concentration-dependent manner, but only modestly reduced that induced by isoproterenol. Next, the effects of cholera toxin (CTX, GAS 9012-63-9) an irreversible direct activator of G(s) and formoterol on the reduced responsiveness to isoproterenol after continuous and repeated exposure to isoprotenerol were examined. Preincubation with cholera toxin (0.02-2 mug/ml) caused concentration-dependent inhibition of the desensitization induced by isoproterenol, but preincubation with formoterol did not. These results indicate that prolonged activation of G(s) via beta-adrenergic receptors does not cause cross-desensitization to short-acting beta-agonists. However, it also fails to inhibit the desensitization of beta-adrenergic receptors after excessive exposure to short-acting beta-agonists. Activation of G(s) via a pathway that bypasses the receptors may be beneficial for the prevention of this phenomenon.