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 beta-adrenergic receptor agonists (beta-agonists) following prolonged activation of the stimulatory G protein of adenylyl cyclase (Gs), relaxation by isoproterenol (isoprenaline, CAS 949-36-0) and formoterol (CAS 73573-87-2), 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, CAS 9012-63-9) an irreversible direct activator of Gs and formoterol on the reduced responsiveness to isoproterenol after continuous and repeated exposure to isoprotenerol were examined. Preincubation with cholera toxin (0.02-2 micrograms/ml) caused concentration-dependent inhibition of the desensitization induced by isoproterenol, but preincubation with formoterol did not. These results indicate that prolonged activation of Gs 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 Gs via a pathway that bypasses the receptors may be beneficial for the prevention of this phenomenon.
Sudo
Yukio
Y
Second Department of Internal Medicine, School of Medicine, Nagoya University, Nagoya, Japan.
Kume
Hiroaki
H
Ito
Satoru
S
Ito
Yasushi
Y
Yamaki
Kenichi
K
Takagi
Kenzo
K
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002772:Cholera Toxin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D014132:Trachea / Q000187:drug effects* / Q000201:enzymology
D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D016210:Methacholine Chloride; D002772:Cholera Toxin; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol