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.

<p>Evaluating the Therapeutic Efficacy and Safety of Landiolol Hydrochloride for Management of Arrhythmia in Critical Settings: Review of the Literature</p>

“…Landiolol hydrochloride has a β1/β2 ratio of 255, 7 and, compared to propranolol, its β1-selectivity is 74-380 times greater while it has a 33-263 times greater β1 affinity than esmolol. 8 This high β1-selectivity results in a more potent negative chronotropic effect and a less potent hypotensive effect. 7 Work in rabbit animal models revealed a more rapid HR decrease with landiolol than with esmolol while the decrease in mean arterial blood pressure (MAP) seen with esmolol was not observed with landiolol.…”

Membrane Interactivity of Non-steroidal Anti-inflammatory Drugs: A Literature Review

“…These local anesthetics interact with artificial and biological membranes to increase their fluidity at toxicologically-relevant concentrations with the potency correlating to relative cardiotoxicity [125][126][127]. Other cardiotoxic drugs also increase the fluidity of neuro-mimetic membranes [128][129][130][131]. Bupivacaine is localized at lipid-lipid or lipidprotein interfaces in biomembranes to increase membrane fluidity with the resultant functional interference of membrane-embedded sodium channels, which is referred to as one of mechanisms for its cardiotoxic effect [132].…”

Comparative Interactions of Anesthetic Alkylphenols with Lipid Membranes

“…Lipid bilayer membranes were prepared as reported previously [20] with some modifications as follows. An aliquot (250 µl) of the ethanol solution of phospholipids and cholesterol (total lipids of 10 mM) and DPH (50 µM) was repeatedly injected four times into 199 ml of 20 mM sodium phosphate buffer (pH 7.4, containing 100 mM KCl) under stirring above the phase transition temperatures of phospholipids to prepare DPH-labeled unilamellar vesicles suspended in the buffer.…”

“…DMSO of the corresponding volume was added to controls. After the reaction at 37˚C for 15 min, DPH fluorescence polarization was measured by an RF-540 spectrofluorometer (Shimadzu; Kyoto, Japan) equipped with a polarizer and a cuvette thermo-controller as reported previously [20]. Polarization values were calculated by the formula (I VV -GI VH )/(I VV + GI VH ), in which I is the fluorescence intensity and the subscripts V and H refer to the vertical and horizontal orientation of the excitation and emission polarizer, respectively.…”