In humans, prolonged administration of the β2-adrenoceptor agonist terbutaline leads to a desensitization of β2-adrenoceptor-mediated cardiovascular responses, which can be blunted by concomitant administration of the antianaphylactic drug ketotifen. This study investigated the effect of disodium cromoglycate, another antiallergic drug, on terbutaline-induced desensitization of β-adrenoceptor-mediated cardiovascular and noncardiovascular responses. In a double-blind, placebo-controlled, randomized design, nine healthy male volunteers received disodium cromoglycate (4 x 200 mg/day, p.o.) or placebo for 3 weeks with terbutaline (3 x 5 mg/day, p.o.) administered concomitantly during the last 2 weeks. β2-Adrenoceptor cardiovascular function was assessed by the increase in heart rate and reduction of diastolic blood pressure induced by an incremental intravenous infusion of the unselective β-adrenoceptor agonist isoprenaline; β1-adrenoceptor cardiovascular function was assessed by exercise-induced tachycardia. Tremulousness was monitored as a β2- adrenoceptor-mediated noncardiovascular effect. After 2 weeks' administration of terbutaline, there was a marked and significant (p < 0.001) attenuation of isoprenaline-induced tachycardia (mean percentage attenuation, 53.3%) and of the isoprenaline-induced decrease in diastolic blood pressure (mean percentage attenuation, 55.6%). Exercise-induced tachycardia also was significantly (p < 0.001) blunted, but the magnitude of this attenuation was only very small (mean attenuation, 5.6%). Disodium cromoglycate affected neither the rightward shift of β2-adrenoceptor-mediated responses nor the small rightward shift in β1-adrenoceptor-mediated exercise tachycardia after 2 weeks' administration of terbutaline. Tremulousness observed during the first few days of terbutaline administration disappeared after 4 to 8 days, indicating development of desensitization of β2-adrenoceptor-mediated noncardiovascular responses. This was not prevented by disodium cromoglycate. These results confirm that long-term β2-adrenoceptor agonist therapy leads to a desensitization of β2-adrenoceptor-mediated cardiovascular and noncardiovascular effects in humans in vivo. However, unlike ketotifen, cromolyn sodium is not able to attenuate this desensitization.
- β-Adrenoceptor desensitization
- β-Adrenoceptor function
- Cromolyn sodium
- Disodium cromoglycate
- Human in vivo