Do local anesthetics interact preferentially with membrane lipid rafts? Comparative interactivities with raft-like membranes

Abstract

Membranous lipid bilayers have been reconsidered as the site of action of local anesthetics (LAs). Recent understanding of biomembranes indicates the existence of lipid raft microdomains enriched in cholesterol and sphingolipids as potential platforms for channels and receptors. Based on the hypothesis that LAs may interact preferentially with lipid rafts over non-raft membranes, we compared their effects on raft model membranes and cardiolipin-containing biomimetic membranes. Liposomes were prepared with phospholipids, sphingomyelin, cerebroside, and cholesterol to have compositions corresponding to lipid rafts and cardiomyocyte mitochondrial membranes. After reacting LAs (50-200 microM) with the membrane preparations, their interactivities were determined by measuring fluorescence polarization with 1,6-diphenyl-1,3,5-hexatriene. Although bupivacaine and lidocaine acted on different raft-like liquid-ordered membranes to reduce polarization values, their effects on biomimetic less ordered membranes were much greater. LAs interacted with biomimetic membranes with the potency being R(+)-bupivacaine > racemic bupivacaine > S(-)-bupivacaine > ropivacaine > lidocaine > prilocaine, which is consistent with the rank order of pharmacotoxicological potency. However, raft model membranes showed neither structure-dependence nor stereoselectivity. The relevance of membrane lipid rafts to LAs is questionable at least in their effects on raft-like liquid-ordered membranes.

Slime mould: The fundamental mechanisms of biological cognition

“…Besides microtubules, also the actin filaments behave as excitable medium which transports ionic waves and mediates eukaryotic chemotaxis in response to diverse gradients [161] [162] [163] [164]. Actin cytoskeleton supports lipid rafts, which are ordered domains of biological membranes particularly sensitive to anesthetics [165] [166] [167] [168].…”

Stereostructure-based differences in the interactions of cardiotoxic local anesthetics with cholesterol-containing biomimetic membranes

“…30 Therefore, membrane-fluidizing bupivacaine and ropivacaine are considered to increase the rotational mobility of membrane lipids with a resultant decrease of DPH polarization values. 31 The membrane interactions of local anesthetics also produce the rearrangement of an intermolecular hydrogen-bonded network among phospholipid molecules and the change of a P-N dipole orientation of phospholipid molecules, resulting in the fluidization of membrane lipid bilayers. 32 While CL increases the binding of local anesthetics to membranes, 32 both bupivacaine and ropivacaine stereoselectively interacted with cholesterol-containing biomimetic membranes in the absence of CL.…”

Interaction of Local Anesthetics with Biomembranes Consisting of Phospholipids and Cholesterol: Mechanistic and Clinical Implications for Anesthetic and Cardiotoxic Effects

“…In order to verify the hypothesis that local anesthetics could interact preferentially with lipid rafts over nonraft membranes, Tsuchiya et al [108] compared the effects of 50–200  μ M local anesthetics on raft model membranes, cardiolipin-containing biomimetic membranes, and cardiomyocyte mitochondria-mimetic membranes. Local anesthetics interacted with nonraft membranes to increase the membrane fluidity with the potency being R (+)-bupivacaine > rac -bupivacaine > S (−)-bupivacaine > ropivacaine > lidocaine > prilocaine, which is consistent with the rank order of cardiotoxic potency.…”