Article date: January 1999
By: Rafael F. Schäfers, Ingeborg Karl, Kirsten Mennicke, Anton Erich Daul, Thomas Philipp, Otto‐Erich Brodde, in Volume 47, Issue 1, pages 59-66
Aims To study whether desensitization occurs after long‐term administration of the β1‐adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen.
Methods In a double‐blind, randomized design 10 young, healthy males received ketotifen (2×1 mg day−1 p.o.) or placebo for 3 weeks with xamoterol (2×200 mg day−1 p.o.) administered concomitantly during the last 2 weeks. β1‐adrenoceptor mediated responses were assessed as exercise‐induced tachycardia and isoprenaline‐induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline‐induced tachycardia was measured as a mixed β1‐/β2‐adrenoceptor‐mediated effect.
Results The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise‐ and isoprenaline‐induced tachycardia (mean dose ratios±s.e.mean: 1.20±0.05 and 2.46±0.23) and the isoprenaline‐evoked shortening of QS2c (dose ratio 3.59±0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (−0.03; 0.04); isoprenaline tachycardia 0.03 (−0.15; 0.21); isoprenaline induced shortening of QS2c 0.13 (−0.22; 0.48)).
Conclusions In humans xamoterol is a partial β1‐adrenoceptor agonist with positive chrono‐ and inotropic effects at rest and antagonistic properties under conditions of β‐adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of β1‐adrenoceptor desensitization. Ketotifen does not change the β‐adrenoceptor mediated responses of xamoterol after chronic dosing.
DOI: 10.1046/j.1365-2125.1999.00854.x
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