Losartan's affinity to fluid bilayers modulates lipid-cholesterol interactions

Area of Science:

• Biophysics
• Membrane Biophysics
• Pharmacology

Background:

• Losartan is an angiotensin II receptor antagonist used for hypertension.
• Its membrane diffusion mechanism necessitates understanding its interaction with lipid bilayers.
• Model membranes provide a controlled system to study drug-lipid interactions.

Purpose of the Study:

• To investigate the impact of losartan on model lipid membranes.
• To determine how cholesterol affects losartan's interaction with different lipid compositions.
• To elucidate the physical basis of losartan's membrane partitioning and its implications for drug action.

Main Methods:

• Small-angle X-ray scattering (SAXS) was employed to analyze structural changes.
• Losartan was incorporated into dimyristoyl-phosphatidylcholine (DMPC) and palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers.
• Binary mixtures of these lipids with cholesterol were studied at varying concentrations.

Main Results:

• Losartan incorporation into DMPC and POPC bilayers induced negative surface charge, leading to unilamellar vesicles and a 3-4% reduction in bilayer thickness.
• The partial area of losartan was estimated to be approximately 40 Å(2).
• Cholesterol's effect on losartan partitioning differed between POPC and DMPC; it hindered membrane condensation in POPC but led to losartan depletion in DMPC at higher cholesterol concentrations (≥20 mol%).

Conclusions:

• Losartan's interaction with lipid bilayers is dependent on lipid composition and cholesterol content.
• Losartan exhibits chain-saturation dependent competition with lipid-cholesterol interactions.
• Losartan is insoluble in the liquid-ordered phase, suggesting its action primarily occurs in fluid membrane domains rather than cholesterol-rich rafts.