IN VITRODESENSITIZATION OF β‐ADRENOCEPTORS IN GUINEA PIG TRACHEA: INTERACTIONS BETWEEN β‐ADRENOCEPTOR AGONISTS AND INFLUENCE OF ADENOSINE AND OTHER DRUGS

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Abstract
Summary—The aim of this study was to investigate quantitatively the action of and the interaction between beta‐adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 times 10−5M) or acetylcholine (5×10−5M) and concentration‐response (C/R) curves for various beta‐adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta‐adrenoceptor agonist (autodesensitization), with other beta‐adrenoceptor agonists (cross‐desensitization), or with a beta‐adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 ± 0.06 (N= 5) for salbutamol (10−5M), 0.78 ± 0.09 (N= 5) for fenoterol (10−6M), 0.30 ± 0.04 (N= 9) for isoprenaline (10−5M), and 0.33 ± 0.05 (N= 5) for adrenaline (10−5M). Our studies of cross‐desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10−5M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 ± 0.08,N= 5) and salbutamol (0.62 ± 0.05,N= 5) than for adrenaline (0.35 ± 0.07,N= 5) and isoprenaline itself (0.30 ± 0.05,N= 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10−8M) reduced it significantly, although to a negligible extent. Adenosine (3 times 10−4M) did not shift the C/R curve to isoprenaline by itself, but incubation of trachea! strips with adenosine and isoprenaline caused a significantly greater shift of C/R curves to isoprenaline (0.30 ± 0.04) than incubation with isoprenaline alone (0.20 ± 0.04) (P< 0.05,N= 5). These experiments suggest that adenosine may have increased the uncoupling and/or down‐regulation phenomena induced by isoprenaline, or modified adenylate cyclase‐cAMP activity.