Effects of fenoterol on beta-adrenoceptor and muscarinic M2 receptor function in bovine tracheal smooth muscle.
Prolonged (18 h) incubation of isolated bovine tracheal smooth muscle with the beta2-adrenoceptor agonist fenoterol (10 microM) induced desensitization of isoprenaline-induced adenylyl cyclase activity in bovine tracheal smooth muscle membranes, characterized by a 25% decrease in maximal effect (Emax) (P < 0.05), while the sensitivity to the agonist (pEC50) was unchanged. The Emax value of isoprenaline-induced smooth muscle relaxation of submaximal methacholine-induced contractile tones was similarly reduced by about 25% (P < 0.001), while the pEC50 value was diminished by 1.0 log unit (P < 0.001). As determined by 30 microM gallamine-induced muscarinic M2 receptor antagonism and pertussis toxin-induced inactivation of G(i alpha), muscarinic M2 receptor-mediated functional antagonism did not play a role in isoprenaline-induced relaxation of bovine tracheal smooth muscle contracted by methacholine, both in control and in 18-h fenoterol-treated tissue. In line with these observations, we found no enhanced muscarinic M2 receptor-mediated inhibition of 1 microM forskolin-stimulated adenylyl cyclase activity after 18-h fenoterol treatment. These data indicate that 18-h fenoterol treatment of bovine tracheal smooth muscle induces beta2-adrenoceptor desensitization and reduced functional antagonism of methacholine-induced contraction by beta-adrenoceptor agonists, without a change of muscarinic M2 receptor function.
De Vries
B
B
Department of Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands. B.de.Vries@farm.rug.nl
Roffel
A F
AF
Kooistra
J M
JM
Meurs
H
H
Zaagsma
J
J
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D004347:Drug Interactions; D005280:Fenoterol / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D037342:Pertussis Toxin; D043585:Receptor, Muscarinic M2; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014132:Trachea; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D016210:Methacholine Chloride; D005280:Fenoterol; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases