Disodium cromoglycate does not prevent terbutaline-induced desensitization of beta 2-adrenoceptor-mediated cardiovascular in vivo functions in human volunteers.
In humans, prolonged administration of the beta 2-adrenoceptor agonist terbutaline leads to a desensitization of beta 2-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 beta-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. beta 2-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 beta-adrenoceptor agonist isoprenaline; beta 1-adrenoceptor cardiovascular function was assessed by exercise-induced tachycardia. Tremulousness was monitored as a beta 2-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 beta 2-adrenoceptor-mediated responses nor the small rightward shift in beta 1-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 beta 2-adrenoceptor-mediated noncardiovascular responses. This was not prevented by disodium cromoglycate. These results confirm that long-term beta 2-adrenoceptor agonist therapy leads to a desensitization of beta 2-adrenoceptor-mediated cardiovascular and noncardiovascular effects in humans in vivo. However, unlike ketotifen, cromolyn sodium is not able to attenuate this desensitization.
Schäfers
R F
RF
Department of Medicine, University of Essen, Germany.
Piest
U
U
von Birgelen
C
C
Jakubetz
J
J
Daul
A E
AE
Philipp
T
T
Brodde
O E
OE
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000494:pharmacology*; D000328:Adult; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004205:Cromolyn Sodium / Q000494:pharmacology*; D004347:Drug Interactions; D005080:Exercise Test; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D013726:Terbutaline / Q000009:adverse effects / Q000494:pharmacology*; D014202:Tremor / Q000139:chemically induced / Q000503:physiopathology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018926:Anti-Allergic Agents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol; D013726:Terbutaline; D004205:Cromolyn Sodium