1 According to the two state receptor model, the beta (2)-adrenergic receptor (beta (2)-AR) isomerizes between an inactive state and a constitutively active state, which couples to the stimulatory G-protein in the absence of agonist. In bovine tracheal smooth muscle (BTSM), we investigated the effect of short and long term beta (2)-AR activation by fenoterol on constitutive receptor activity.
2 Preincubation of the BTSM strips for 5 min, 30 min and 18 h with 10 muM fenoterol, followed by extensive washout (3 h, 37 degreesC), caused a rapid and time-dependent inhibition of KCl-induced contraction, reaching 68 +/- 10, 51 +/- 6 and 46 +/- 4% of control, respectively, at 40 mM KCI (P <0.05 all). At all time points, the ECS, values to KCI were significantly reduced as well.
3 Preincubation of BTSM with 0.1, 1.0 and 10 M fenoterol during 18 h caused a concentration-dependent decrease of the 40 mM KCI response to 70 +/- 5, 47 +/- 12 and 43 +/- 9% of control, respectively (P <0.05 all).
4 The reduced KCI contractions were reversed in the presence of 1 M timolol. Moreover, the sensitivity to KCl in the presence of timolol was enhanced after fenoterol incubation. Inverse agonism was also found for other beta -blockers, with a rank order of efficacy of pindolol greater than or equal to timolol = propranolol > alprenolol greater than or equal to sotalol > labetalol.
5 At 25 mM KCI-induced tone, the contraction induced by cumulative timolol administration was competitively antagonized by the less efficacious inverse agonist labetalol, indicating that the fenoterol-induced effects cannot be explained by residual beta -agonist binding.
6 In conclusion, fenoterol treatment of BTSM causes a time- and concentration-dependent development of constitutive beta (2)-AR activity, which can be reversed by various inverse agonists. The beta -agonist-induced changes could represent a novel regulation mechanism of beta (2)-AR activity.
|Number of pages||6|
|Journal||British Journal of Pharmacology|
|Publication status||Published - Nov-2000|
- beta(2)-adrenergic receptor
- constitutive receptor activity
- inverse agonism
- beta-adrenergic receptor antagonists
- bovine tracheal smooth muscle
- TERNARY COMPLEX MODEL
- PHOSPHOINOSITIDE METABOLISM