Beta-adrenoceptor desensitization in guinea-pig isolated trachea.
Exposure to (-)-isoprenaline (25 microM, 1 h) caused a stereoselective, time and concentration-related decrease in smooth muscle beta 2-adrenoceptor function in guinea-pig trachea. Furthermore, tracheal relaxant responsiveness to the beta-adrenoceptor agonists (+/-)-fenoterol and (-)-noradrenaline was reduced, while that to theophylline and nitroprusside was unaffected. Responsiveness to forskolin was marginally but significantly reduced. Indomethacin, a cyclooxygenase inhibitor and mepacrine, an inhibitor of phospholipid turnover, had no significant effect on the extent of isoprenaline-induced desensitization. Conversely, cortisol (25 microM) significantly reduced desensitization and enhanced the rate of spontaneous recovery of responsiveness to isoprenaline. Desensitization was not accompanied by a reduction in the density of beta-adrenoceptors in the trachea, as assessed by binding and light microscopic autoradiography using [125I]iodocyanopindolol [( 125I]CYP). Thus, desensitization was probably caused primarily by beta-adrenoceptor/adenyl cyclase uncoupling. This model may be useful in investigations of the effect of glucocorticoids on the beta-adrenoceptor dysfunction recognized in severe asthma.
Fernandes
L B
LB
Department of Pharmacology, University of Western Australia, Perth, Nedlands.
Knight
D A
DA
Rigby
P J
PJ
Spina
D
D
Paterson
J W
JW
Goldie
R G
RG
D000818:Animals; D001345:Autoradiography; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D005280:Fenoterol / Q000494:pharmacology; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D011943:Receptors, Adrenergic, beta; D005280:Fenoterol; D002217:Carbachol; D013806:Theophylline; D011796:Quinacrine; D007545:Isoproterenol; D006854:Hydrocortisone; D009638:Norepinephrine; D007213:Indomethacin