?-Adrenoceptor antagonists (non-selective as well as ? 1-selective? 2-adrenoceptor density in human lymphocytes

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Abstract
In the present study the effects of pindolol [nonselective β-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on β2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the β1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA. 1) Administration of pindolol (2×5 mg/day) caused an about 25% decrease in lymphocyte β2-adrenoceptor density after 2 days; during treatment β2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte β2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte β2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3×40 mg/day) indicating that the PAA of pindolol is the cause of its β-adrenoceptor decreasing effect. 2) Administration of the non-selective β-adrenoceptor antagonist bopindolol (1×2 mg/day) with PAA caused decreases in lymphocyte β2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 μmol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the β-adrenoceptor antagonist-induced decrease in β-adrenoceptor density is accompanied by a loss in β-adrenoceptor function. 3) Administration of the β1-selective antagonist celiprolol (1×200 mg/day) with PAA produced effects comparable to those of pindolol and bopindolol: during celiprolol treatment lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases decreased significantly (maximum effect after 7 days: 35%). On the other hand, the β1-selective antagonist bisoprolol (1×10 mg/day) without PAA did not affect lymphocyte β2-adrenoceptor density which strongly supports the view that drug-induced changes in lymphocyte β-adrenoceptors are subtype-selective changes in β2-adrenoceptors. 4) The celiprolol evoked reduction in lymphocyte β2-adrenoceptor density and 10 μmol/l (-)-isoprenaline evoked cyclic AMP increases were abolished by simultaneous administration of propranolol (3×40 mg/day), but not by concomitant application of the β1-adrenoceptor antagonist bisoprolol (1×10 mg/day). 5) It is concluded that the PAA of β-adrenoceptor antagonists possesses a β2-agonistic component since all β-adrenoceptor antagonists with relatively strong PAA-irrespective of to whether they are non-selective (pindolol, bopindolol) or β1-selective (celiprolol)-decrease lymphocyte β2-adrenoceptor density. Whether the PAA of β-adrenoceptor antagonists is solely a β2-effect or tissuedependently a β1- or β2-effect, remains to be elucidated

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