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

To examine the response to β-adrenergic receptor agonists (β-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 73573-87-2), a long-acting β-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, CAS 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 μg/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, via β-adrenergic receptors does not cause cross-desensitization to short-acting β-agonists. However, it also fails to inhibit the desensitization of β-adrenergic receptors after excessive exposure to short-acting β-agonists. Activation of G s via a pathway that bypasses the receptors may be beneficial for the prevention of this phenomenon.