Differential Changes in Lymphocyte β2-Adrenoceptor Density by β-Blocker Administration: Role of Intrinsic Sympathomimetic Activity

To study the role of intrinsic sympathomimetic activity (ISA) in β-blocker-induced changes of β-adrenoceptors, the effects of administration of several β-blockers for 9 days on lymphocyte β2-adrenoceptor density—assessed by iodocyanopindolol binding-were investigated in 47 normotensive volunteers. Propranolol (unselective; no ISA; 4 Х 40 mg/day) increased β2-adrenoceptor density by 25-40%; after withdrawal β2-adrenoceptor density declined slowly, being still elevated for 3 days. In contrast, the unselective β-blockers pindolol (ISA (isoprenaline = 1.0) = 0.39; 2 Х 5 mg/day) and mepindolol (ISA = 0.27; 2 Х 5 mg/day) decreased β2-adrenoceptor density by 50% and 35%, respectively, while alprenolol with weak ISA (=0.066; 4 Х 100 mg/day) had no effect. Among the β1-selective blockers studied, celiprolol with ISA (=0.32; 1 Х 200 mg/day) decreased β2-adrenoceptor density by 30% whereas bisoprolol without ISA (1 Х 10 mg/day) had no effect. It is concluded that the ISA determines the direction and amount of β-adrenoceptor alterations induced by β-blockers. Furthermore, changes in human lymphocyte β-adrenoceptors reflect subtype-selective changes in β2-adrenoceptors, since the β1-selective blocker bisoprolol without ISA—in contrast to propranolol—did not affect lymphocyte β2-adrenoceptors. Accordingly, the fact that the β1-selective blocker celiprolol with ISA decreased lymphocyte β2-adrenoceptors, is consistent with the hypothesis that celiprolol possesses in addition to its β1-antagonistic activity a β2-agonistic activity.