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Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor.

ABSTRACT: 1. The beta2-agonist salmeterol is a potent relaxant of airway smooth muscle with a long duration of action. Previous studies of cyclic AMP accumulation, however, have indicated that salmeterol is a low efficacy beta2-agonist when compared to isoprenaline. Here we have compared the properties of salmeterol and isoprenaline as stimulants of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor to different levels (50 and 310 fmol mg protein(-1)). 2. Gene transcription was monitored using a secreted placental alkaline phosphate (SPAP) reporter gene under the transcriptional control of six cyclic AMP response element (CRE) sequences. 3. In the lower expressing cells (CHO-beta2/6), salmeterol produced a maximal cyclic AMP response that was only 22% that of that obtained with isoprenaline. In contrast in the higher expressing cells (CHO-beta2/ 4), the two maxima were of similar magnitude. 4. Salmeterol was a more potent stimulant of gene transcription, producing the same maximal response as isoprenaline in both cell lines. Furthermore, in the CHO-beta2/4 cells, Salmeterol was 50 fold more potent as a stimulant of SPAP secretion than of cyclic AMP accumulation. In contrast, isoprenaline was 24 fold less sensitive as a stimulant of SPAP secretion than of cyclic AMP accumulation. In the presence of serum (10%), the effects of both salmeterol and isoprenaline on gene transcription were augmented. 5. These data suggest that the low efficacy and/or long duration of action of salmeterol, favours a potent stimulation of gene transcription when compared to more efficacious but shorter-lived agonists such as isoprenaline.

SUBMITTER: McDonnell J

PROVIDER: S-EPMC1571039 | biostudies-other | 1998 Oct

REPOSITORIES: biostudies-other

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Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor.

McDonnell J J Latif M L ML Rees E S ES Bevan N J NJ Hill S J SJ

British journal of pharmacology 19981001 4

1. The beta2-agonist salmeterol is a potent relaxant of airway smooth muscle with a long duration of action. Previous studies of cyclic AMP accumulation, however, have indicated that salmeterol is a low efficacy beta2-agonist when compared to isoprenaline. Here we have compared the properties of salmeterol and isoprenaline as stimulants of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor to different levels (50 and 310 fmol mg protein(-1)). 2. Gene transcription w ...[more]

PMID: 9831907

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Project description:1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.

Dataset Information

Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor.

Publications

Influence of receptor number on the stimulation by salmeterol of gene transcription in CHO-K1 cells transfected with the human beta2-adrenoceptor.

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