TERBUTALINE-INDUCED DESENSITIZATION OF BETA-2-ADRENOCEPTOR INVIVO FUNCTION IN HUMANS - ATTENUATION BY KETOTIFEN

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. Thus, concomitant administration of ketotifen to beta-adrenoceptor agonist treatment might prevent, or at least delay, development of tolerance and therefore may improve efficacy of treatment.