Terbutaline-induced desensitization of human cardiac β2-adrenoceptor-mediated positive inotropic effects: attenuation by ketotifen

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Abstract
Background: In patients with chronic heart failure cardiac β1-adrenoceptors are desensitized whereas β2-adrenoceptors are only marginally affected. The mechanism underlying this differential regulation is not known. Objectives: To find out whether or not human cardiac β2-adrenoceptors might be ‘resistant’ to agonist-induced desensitization and whether or not the antiallergic drug ketotifen might attenuate possible desensitization. Methods: We investigated, in a single blinded, randomised, placebo-controlled, cross-over study of ten healthy male volunteers (mean age, 25.3±0.7 years), the effects of two weeks treatment with the β2-adrenoceptor agonist terbutaline (3×5 mg/day p.o.) with and without simultaneous treatment with ketotifen (2×1 mg/day p.o. for three weeks) or placebo on β-adrenoceptor-mediated cardiovascular effects. Cardiovascular effects were assessed as isoprenaline (3.5–35 ng/kg/min)- and terbutaline (25–150 ng/kg/min)-infusion-induced increases in heart rate and systolic blood pressure, decreases in diastolic blood pressure and shortening of the systolic time intervals (STIs), heart rate corrected duration of electromechanical systole (QS2c) and pre-ejection period (PEP; as a measure of inotropism). Results: Ketotifen did not significantly affect basal haemodynamics in the volunteers. Isoprenaline- and terbutaline-infusion caused dose-dependent increases in systolic blood pressure and heart rate, decreases in diastolic blood pressure and shortening of QS2c and PEP, whereby isoprenaline effects were more pronounced. After two weeks of treatment with terbutaline p.o., isoprenaline- and terbutaline-infusion-induced increases in heart rate, shortening of QS2c and PEP were significantly reduced whereby terbutaline-infusion effects were markedly more attenuated than isoprenaline-infusion effects. Ketotifen significantly reduced terbutaline p.o. treatment-induced attenuation of all terbutaline-infusion effects (largely β2-adrenoceptor-mediated) and the isoprenaline-infusion-induced increase in heart rate (β1- and β2-adrenoceptor-mediated), but did not (or only marginally) affect reduction in isoprenaline-induced shortening of QS2c and PEP (largely β1-adrenoceptor-mediated). Conclusion: Human cardiac β2-adrenoceptors are not ‘resistant’ to agonist-induced desensitization: Ketotifen might prevent such β2-adrenoceptor-agonist-evoked desensitization.

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