Related Experiment Videos
Terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function in humans: attenuation by ketotifen
O E Brodde1, S Petrasch, H J Bauch
1Department of Internal Medicine, University of Essen, Germany.
Abstract:
Use of beta-adrenoceptor agonists in long-term treatment of patients with chronic asthma bronchiale or heart failure is of limited value because beta-adrenoceptor desensitization develops. The antiallergic drug ketotifen prevents beta-adrenoceptor agonist-induced desensitization of rat and human pulmonary and lymphocyte beta 2-adrenoceptors. In 10 healthy volunteers in a double-blind, placebo-controlled study, we investigated whether ketotifen also prevents beta-adrenoceptor agonist-induced desensitization of beta 1- and/or beta 2-adrenoceptor-mediated physiologic in vivo effects. beta 1-Adrenoceptor-mediated effects were isoprenaline (ISO) infusion-induced increase in systolic blood pressure (SBP) and bicycle exercise-induced increase in heart rate (HR); beta 2-adrenoceptor-mediated effects were ISO infusion-induced increase in plasma norepinephrine (NE) and decrease in diastolic blood pressure (DBP); ISO infusion-induced increase in HR was assessed as mixed beta 1- and beta 2-adrenoceptor-mediated effect. These parameters were assessed before and after a 14-day treatment with the beta 2-adrenoceptor agonist terbutaline (5 mg three times daily) with or without simultaneous administration of ketotifen (1 mg twice daily). Terbutaline desensitized all in vivo effects involving beta 2-adrenoceptors (ISO-induced decrease in DBP and increase in plasma NE and, to a minor extent, the mixed beta 1- and beta 2-adrenoceptor-mediated increase in HR), but did not affect beta 1-adrenoceptor-mediated in vivo effects; concomitant treatment of the volunteers with ketotifen markedly blunted terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function. We conclude that ketotifen prevents, or at least attenuates, beta-adrenoceptor agonist-induced desensitization of beta 2-adrenoceptor in vivo function.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Ketotifen prevents beta-adrenoceptor desensitization from terbutaline, a common asthma medication. This finding suggests ketotifen may improve long-term treatment efficacy for conditions like asthma and heart failure.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Respiratory Medicine
Background:
- Long-term use of beta-adrenoceptor agonists for asthma and heart failure is limited by receptor desensitization.
- Ketotifen, an antiallergic drug, has shown potential in preventing beta-adrenoceptor desensitization in preclinical models.
- The in vivo effects of beta-adrenoceptor desensitization and potential prevention by ketotifen require further investigation.
Purpose of the Study:
- To investigate if ketotifen prevents beta-adrenoceptor agonist-induced desensitization of in vivo physiological effects mediated by beta 1- and beta 2-adrenoceptors.
- To assess the impact of terbutaline treatment on specific beta-adrenoceptor-mediated responses.
- To evaluate the protective effect of ketotifen against terbutaline-induced desensitization.
Main Methods:
- A double-blind, placebo-controlled study involving 10 healthy volunteers.
- 14-day treatment with terbutaline (beta 2-agonist) alone or combined with ketotifen.
- Assessment of beta 1-adrenoceptor effects (systolic blood pressure, heart rate response to exercise) and beta 2-adrenoceptor effects (plasma norepinephrine, diastolic blood pressure response to isoprenaline).
Main Results:
- Terbutaline treatment led to desensitization of beta 2-adrenoceptor-mediated effects, including decreased diastolic blood pressure and increased plasma norepinephrine in response to isoprenaline.
- Terbutaline did not significantly affect beta 1-adrenoceptor-mediated responses.
- Concomitant ketotifen administration markedly attenuated the terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function.
Conclusions:
- Ketotifen effectively prevents or significantly reduces beta-adrenoceptor agonist-induced desensitization of beta 2-adrenoceptor function in vivo.
- These findings suggest a potential therapeutic role for ketotifen in maintaining the efficacy of beta-adrenoceptor agonist treatments.
- Ketotifen's ability to blunt desensitization could improve long-term management strategies for chronic respiratory and cardiovascular conditions.