AUTHOR=Tsuchiya Hironori , Mizogami Maki 

TITLE=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

JOURNAL=Frontiers in Pharmacology

VOLUME=4

YEAR=2013

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2013.00150

DOI=10.3389/fphar.2013.00150

ISSN=1663-9812

ABSTRACT=<p>Although β<sub>1</sub>-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 β<sub>1</sub>-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and non-selective β<sub>1</sub>-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β<sub>1</sub>-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 β<sub>1</sub>-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 β<sub>1</sub>-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 β<sub>2</sub>-adrenergic receptor blockade. The differentiation between β<sub>1</sub>-blocking selectivity and non-selectivity is compatible with that between membrane non-interactivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking β<sub>1</sub>-adrenergic receptors is responsible for the antioxidant cardioprotection common to non-selective and selective β<sub>1</sub>-blockers.</p>