The interactivities with lipid membranes differentially characterize selective and nonselective beta1-blockers.

BACKGROUND AND OBJECTIVE

beta-Adrenoceptor-blocking agents have been used for perioperative management during anaesthesia, in which selective beta1-blockers are advantageous over nonselective beta-blockers. Apart from the different affinity for beta-adrenoceptors, beta1-blockers were differentially characterized in light of their different interaction with lipid membranes.

METHODS

Selective (atenolol, metoprolol and esmolol) and nonselective (alprenolol, oxprenolol and propranolol) beta1-blockers were reacted at 0.2-1 mmol l with 1,2-dipalmitoylphosphatidylcholine liposomes and biomimetic membranes consisting of phospholipids, sphingolipid and cholesterol. Their membrane interactivities were comparatively determined using the potency to modify membrane fluidity by measuring fluorescence polarization. Their relative hydrophobicities were evaluated by reversed-phase liquid chromatography.

RESULTS

The chromatographic evaluation divided the tested drugs into more hydrophobic ones containing nonselective beta-blockers and less hydrophobic ones containing selective beta1-blockers. Nonselective beta-blockers, but not selective beta1-blockers, fluidized liposomal membranes, with the potency being oxprenolol < alprenolol < propranolol. Membrane-active alprenolol preferentially acted on the hydrophobic deeper regions of phospholipid bilayers. The potency of nonselective beta-blockers to fluidize biomimetic membranes was greatest in propranolol, followed by alprenolol and oxprenolol, whereas all selective beta1-blockers were inactive.

CONCLUSION

The membrane-fluidizing effects of beta-blockers are correlated with their relative hydrophobicities and their respective conformations to perturb the alignment of phospholipid acyl chains. The membrane-interacting characteristics differentiate beta-blockers as nonselective propranolol, alprenolol and oxprenolol vs. beta1-selective atenolol, metoprolol and esmolol. Such differentiation reflects not only the structural difference but also the beta-adrenoceptor-blocking difference. The membrane fluidization may be partly responsible for the nonselective blockade of beta-adrenoceptors.