title: A selective estrogen receptor modulator, tamoxifen, and membrane fluidity of erythrocytes in normotensive and hypertensive postmenopausal women: an electron paramagnetic resonance investigation.
abstract: BACKGROUND
  Recent studies have shown that tamoxifen, which belongs to a group called selective estrogen receptor modulators (SERM), may exert protective effects against cardiovascular diseases and stroke in postmenopausal women. On the other hand, abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. The present study was performed to investigate the effects of tamoxifen on cell membrane fluidity (a reciprocal value of membrane microviscosity) in normotensive and hypertensive postmenopausal women.
  
  
  RESULTS
  We used an electron paramagnetic resonance (EPR) and spin-labeling method. Tamoxifen significantly decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (h(o)/h(-1)) for 16-NS obtained from EPR spectra of erythrocyte membranes in normotensive postmenopausal women (mean +/- SEM, order parameter value; control 0.719 +/- 0.002, n = 41; tamoxifen 1 x 10(-7) mol/L 0.704 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-6) mol/L 0.696 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-5) mol/L 0.692 +/- 0.002, n = 41, P < .0001). The finding indicated that tamoxifen increased the membrane fluidity and improved the membrane microviscosity of erythrocytes. The membrane action of tamoxifen was antagonized by the estrogen receptor antagonist ICI 182,780. The effect of tamoxifen was significantly potentiated by the nitric oxide (NO) donors, l-arginine and S-nitroso-N-acetylpenicillamine, and a cGMP analog 8-bromo-cGMP. In contrast, the change evoked by tamoxifen was counteracted by the NO synthase inhibitors N(G)-nitro-l-arginine-methyl-ester and asymmetric dimethyl-l-arginine. In hypertensive postmenopausal women, the membrane fluidity of erythrocytes was significantly lower than in normotensive postmenopausal women. The effect of tamoxifen on the membrane fluidity was more pronounced in hypertensive postmenopausal women than in normotensive postmenopausal women.
  
  
  CONCLUSIONS
  These results showed that tamoxifen increased the membrane fluidity of erythrocytes and improved the rigidity of cell membranes in postmenopausal women, to some extent, through the NO- and cGMP-dependent mechanisms. Furthermore, the greater effect of tamoxifen in hypertensive postmenopausal women suggests that tamoxifen could have a beneficial effect in regulating the blood rheologic behavior and in the improvement of the microcirculation in hypertension.
authors.affiliation: Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan. luc.vanbortel@ugent.be
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tsuda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishio
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001120:Arginine / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000737:chemistry / Q000187:drug effects*; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D006973:Hypertension / Q000097:blood*; D008560:Membrane Fluidity / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017698:Postmenopause / Q000097:blood*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D020030:Nitric Oxide Donors; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; C016276:8-bromocyclic GMP; D004958:Estradiol; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester