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Abstract-Many studies have shown that estrogen may exert cardioprotective effects and reduce the risk of hypertension and coronary events. On the other hand, it has been proposed that cell membrane abnormalities play a role in the pathophysiology of hypertension, although it is not clear whether estrogen would influence membrane function in essential hypertension. The present study was performed to investigate the effects of 17␤-estradiol (E 2 ) on membrane fluidity of erythrocytes in normotensive and hypertensive postmenopausal women. We determined the membrane fluidity of erythrocytes by means of an electron paramagnetic resonance and spin-labeling method. In an in vitro study, E 2 significantly decreased the order parameter for 5-nitroxide stearate and the peak height ratio for 16-nitroxide stearate obtained from electron paramagnetic resonance spectra of erythrocyte membranes in normotensive postmenopausal women. The finding indicates that E 2 might increase the membrane fluidity of erythrocytes. The effect of E 2 was significantly potentiated by the NO donor, S-nitroso-N-acetylpenicillamine, and a cGMP analogue, 8-bromo-cGMP. In contrast, the change in the membrane fluidity evoked by E 2 was attenuated in the presence of the NO synthase inhibitor, 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 that in normotensive postmenopausal women. The effect of E 2 on membrane fluidity was significantly more pronounced in the erythrocytes of hypertensive postmenopausal women than in the erythrocytes of normotensive postmenopausal women. The results of the present study showed that E 2 significantly increased the membrane fluidity and improved the microviscosity of erythrocyte membranes, partially mediated by an NO-and cGMP-dependent pathway. Furthermore, the greater action of E 2 in hypertension might be consistent with the hypothesis that E 2 could have a beneficial effect in regulating rheological behavior of erythrocytes and could have a crucial role in the improvement of the microcirculation in hypertension. here is a strong link between menopause and an increased incidence of cardiovascular diseases, and recent studies have demonstrated that estrogen replacement therapy reduced morbidity or mortality due to coronary heart diseases in postmenopausal women. [1][2][3][4] It has also been shown that estrogen supplementation induced a significant fall in blood pressure in postmenopausal women. 5 These findings propose the idea that estrogen may exert protective effects against arteriosclerosis and hypertension. However, fundamental mechanisms of cellular and molecular events by estrogen are still unclear.It has been proposed that cell membrane abnormalities are an etiological factor in hypertension, including functional abnormalities, such as transmembrane cation fluxes. 6 -8 An electron paramagnetic resonance (EPR) and spin-labeling method have been developed to elucidate the membrane fluid...

SUMMARY The purpose of the present study was to investigate erythrocyte membrane abnormalities in hypertension by means of an electron spin resonance and spin-label technique. The erythrocytes from spontaneously hypertensive rats (SHR) and humans with untreated essential hypertension were examined and compared with their normotensive counterparts, and electron spin resonance spectra were obtained for a fatty spin-label agent (5-nitroxy stearate) incorporated into the erythrocyte membranes. The value of outer hyperfine splitting (2T\) was significantly higher in erythrocytes of SHR and humans with essential hypertension than in erythrocytes of normotensive controls (at 37 °C: SHR, 56.14 ± 0.51 gauss [G], n = 8; Wistar-Kyoto rats, 52.22 ±0.86 G, n = 4, p<0.01; humans with essential hypertension, 56.94 ± 0.27 G, n = 11; normotensive subjects, 55.44 ± 0.36 G, n = 8, p<0.01). The order parameter (5) was also increased in the hypertensive rats and humans compared to their respective normotensive controls. When calcium was loaded to erythrocytes with calcium ionophore A23187 (0.9 fiM) and CaCl 2 (1.0 mM), the parameters of the spectra were increased. These changes were more prominent in the hypertensive groups than in the normotensive controls. These results revealed that the erythrocyte membranes of the hypertensive subjects tolerated different spin motions than those of the normotensive controls in the electron spin resonance study and that membrane fluidity might be decreased in hypertension. Additionally, calcium loading to erythrocytes caused the reduction of membrane fluidity. Therefore, it is suggested that an abnormality of calcium handling at the cellular level might affect physical properties of the biomembranes in hypertension. 1 " 5 It seems likely that generalized abnormalities of the membranes could be involved not only in vascular smooth muscle cells but also in circulating blood cells. Erythrocytes are widely studied because they are a