Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: Comparisons with β1-selective esmolol and non-selective propranolol and alprenolol

Abstract

Although β1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective β1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and non-selective β1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β1-selective landiolol and esmolol and non-selective propranolol and alprenolol at 0.5-200 μM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Non-selective β1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine (DPPC) liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of DPPC liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the β1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to β2-adrenergic receptor blockade. The differentiation between β1-blocking selectivity and non-selectivity is compatible with that between membrane non-interactivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking β1-adrenergic receptors is responsible for the antioxidant cardioprotection common to non-selective and selective β1-blockers.

Keywords: antioxidant activity; biomimetic membrane; landiolol; membrane interactivity; selective β1-blocker.

FIGURE 1

Structures of selective and non-selective β ₁-blockers and landiolol-related compounds.

FIGURE 2

Interaction of selective and non-selective β₁-blockers with different kinds of biomimetic membranes. All drugs were reacted at the indicated concentrations with 100 mol% DPPC liposomal membranes (A), cardiomyocyte-mimetic membranes (B), lipid raft model membranes (C), and mitochondria-mimetic membranes (D), followed by measuring DPH fluorescence polarization. Values represent means ± SEM (n = 8). *p < 0.05 and **p < 0.01 vs. control.

FIGURE 3

Effects of landiolol, its hydrolysis metabolite and structural fragments (40 and 200 μM for each) on 100 mol% DPPC liposomal membranes. Values represent means ± SEM (n = 8). **p < 0.01 vs. control.

FIGURE 4

Inhibitory effects of selective and non-selective β₁-blockers (100 μM for each) and antioxidant α-tocopherol (2.5 μM) on peroxynitrite-induced lipid peroxidation of 100 mol% DOPC liposomal membranes and mitochondria-mimetic membranes. Values represent means ± SEM (n = 5). *p < 0.05 and **p < 0.01 vs. control.