title: Interactions of angiotensin II non-peptide AT(1) antagonist losartan with phospholipid membranes studied by combined use of differential scanning calorimetry and electron spin resonance spectroscopy.
abstract: We used differential scanning calorimetry (DSC) and electron spin resonance (ESR) spectroscopy to investigate the interactions of Losartan, a potent, orally active Angiotensin II AT(1) receptor antagonist with phospholipid membranes. DSC results showed that Losartan sensitively affected the chain-melting behavior of dimyristoylphosphatidylcholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. ESR spectroscopy showed that phosphatidylcholines spin-labeled at the 5-position of the sn-2 acyl chain (n-PCSL with n=5), incorporated either in DMPC or DPPC bilayers containing Losartan, were restricted in motion both in the gel and in the liquid-crystalline membrane phases, indicating a location of the antagonist close to the interfacial region of the phosphatidylcholine bilayer. At high drug concentrations (mole fraction >/= x=0.60), the decrease in chain mobility registered by 5-PCSL in fluid-phase membranes is smaller than that found at lower concentrations, whereas that registered by 14-PCSL is further increased. This indicates a different mode of interaction with Losartan at high concentrations, possibly arising from a location deeper within the bilayer. Additionally, Losartan reduced the spin-spin broadening of 12-PCSL spin labels in the gel-phase of DMPC and DPPC bilayers. As a conclusion, our study has shown that Losartan interacts with phospholipid membranes by affecting both their thermotropic behavior and molecular mobility.
authors.affiliation: Abteilung Spektroskopie und Photochemische Kinetik, Max-Planck Institut für Biophysikalische Chemie, Am Fassberg 11, D-37077, Göttingen, Germany. etheodo@gwdg.de
authors.forename: E
authors.initials: E
authors.lastname: Theodoropoulou
authors.forename: D
authors.initials: D
authors.lastname: Marsh
mesh_terms: D057911:Angiotensin Receptor Antagonists; D002152:Calorimetry, Differential Scanning; D004578:Electron Spin Resonance Spectroscopy; D008051:Lipid Bilayers / Q000737:chemistry; D019808:Losartan / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry*; D015394:Molecular Structure; D010743:Phospholipids / Q000737:chemistry; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013113:Spin Labels
chemical_list: D057911:Angiotensin Receptor Antagonists; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010743:Phospholipids; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013113:Spin Labels; D019808:Losartan