Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women

Although early studies demonstrated that exogenous estrogen lowered a woman's risk of cardiovascular disease, recent trials indicate that HRT actually increases the risk of coronary heart disease or stroke. However, there is no clear explanation for this discrepancy. Is estrogen a helpful or a harmful hormone in terms of cardiovascular function? This review discusses some recent findings that propose a novel mechanism which may shed significant light upon this controversy. We propose that nitric oxide synthase (NOS) expressed within the vascular wall is a target of estrogen action. Under normal conditions in younger women, the primary product of estrogen action is NO, which produces a number of beneficial effects on vascular biology. As a woman ages, however, there is evidence for loss of important molecules essential for NO production (e.g., tetrahydrobiopterin, l-arginine). As these molecules are depleted, NOS becomes increasingly “uncoupled” from NO production, and instead produces superoxide, a dangerous reactive oxygen species. We propose that a similar uncoupling and reversal of estrogen response occurs in diabetes. Therefore, we propose that estrogen is neither “good” nor “bad”, but simply stimulates NOS activity. It is the biochemical environment around NOS that will determine whether estrogen produces a beneficial (NO) or deleterious (superoxide) product, and can account for this dual and opposite nature of estrogen pharmacology. Further, this molecular mechanism is consistent with recent analyses revealing that HRT produces salutary effects in younger women, but mainly increases the risk of cardiovascular dysfunction in older postmenopausal women.     

A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy

Recent neurophysiological data suggest that the prefrontal cortex (PFC) may be susceptible to modulation by estrogen. In humans, the PFC mediates a number of cognitive processes that contribute to memory function, particularly working memory. The present study examined whether memory tasks that recruit PFC-dependent information processing might exhibit estrogen sensitivity in women. Performance on several memory tasks, including measures of working memory, was evaluated in three groups of postmenopausal women: (1) women who were tested when taking estrogen only (n = 38, M(age) = 55.1 years), (2) women who were tested when taking estrogen and a progestin concurrently (n = 23, M(age) = 55.9 years), and (3) women who were not taking hormone replacement therapy (n = 35, M(age) = 56.0 years). Estrogen users exhibited significantly better performance on a verbal task and on a spatial task, each with a prominent working memory component, but did not differ from nonusers on control tasks involving simple passive recall. These findings are consistent with the hypothesis that estrogen is active within PFC and is capable of influencing functions dependent on this region. The results of this study raise the possibility that estrogen may play a role in maintaining certain frontal lobe functions in women.     

Differential motor and blood pressure effects of intrathecal oxytocin and TRH in the rat

While previous reports have immunocytochemically localized oxytocin and TRH in the spinal cord, the functional significance of these peptides is unclear. The present paper examined this issue and tested the effects of these peptides upon intrathecal administration. We found both peptides produced lasting motor and blood pressure changes. Oxytocin elicited prolonged jerks of the hindlimbs and the tail, while TRH produced an increase of hindlimb muscle tone and tail tremor. TRH in larger doses (5, 10 μg) also caused tail erections and whipping. The motor effects of both peptides were dose-dependent. Intrathecal oxytocin (0.75 or 1.5 IU) caused a transient drop in blood pressure followed by a rise, in 4 out of 7 rats. The other 3 only showed a hypertensive effect. In contrast, intrathecal TRH produced a rise in blood pressure in all the animals tested. These findings suggest that both oxytocin and TRH may play a role in the regulation of motor and automatic functioning at the spinal level.     

Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women

Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine levels in 145 postmenopausal and premenopausal Chinese women living in Hong Kong. We also investigated the effect of hormonereplacement therapy (HRT) with estrogen or estrogen combined with progestin on plasma lipoprotein profile and homocysteine concentrations in those individuals. Postmenopausal women displayed significantly higher plasma levels of total cholesterol, LDLcholesterol and apoB as well as higher plasma homocysteine levels than that of premenopausal women. HRT with either estrogen (17-estradiol or conjugated equine estrogen) alone or estrogen combined with progestin for 3.5–4.5 years significantly improved the lipoprotein profile in postmenopausal women by decreasing the levels of total cholesterol (12–20% reduction), LDL-cholesterol (26–29% reduction) and apoB (21–25% reduction). In women treated with 17estradiol or conjugated equine estrogens their plasma levels of apoAI were significantly elevated (18% elevation) as compared to non-users. HRT also reduced plasma concentrations of homocysteine (13–15% reduction). In conclusion, we found that long-term HRT was associated with improvement in plasma lipoprotein profile and a reduction in homocysteine concentration in postmenopausal women. These results support the notion that the improvement of lipoprotein profile and a reduction in homocysteine concentration may contribute to the beneficial effect of HRT on cardiovascular risk.     

Effects of long-term estrogen replacement on social investigation and social memory in ovariectomized C57BL/6 mice

Estrogen has been shown to play a role in modulating social recognition memory. However, the literature regarding the influence of estrogen on social memory is sparse and only covers two experimental manipulations: acute injections and receptor knockout. Long-term effects of estrogen replacement on social investigation and social recognition are unknown. Furthermore, existing social recognition protocols focus on memory of very short durations (<2 h). In the present study, we examined long-term effects of estrogen replacement on both short- (<30 min) and long-term (24 h) social recognition in ovariectomized female C57BL/6 mice by implanting 60-day time-release pellets containing physiological doses of estradiol (0, 0.18, or 0.72 mg of 17beta-estradiol). After 55 days of treatment, evidence of social recognition memory, measured by 24-h habituation, was found only in mice receiving the 0.72-mg pellet. This result is remarkable as previous reports indicate that individually-housed untreated rats and mice do not show habituation beyond 2 h. Our study further revealed that estrogen also increased frequencies of baseline social investigation without affecting general activity levels and decreased delayed post-swim-stress serum corticosterone concentration. Thus, these results suggest that long-term estrogen replacement increased the interest in social interaction as well as decreased stress responses. It is likely that the 24-h habituation observed in the estrogen replacement group is mediated jointly by the non-mnemonic effects of estrogen on the behavior displayed during the stage of memory encoding as well as mnemonic effects during the stage of memory consolidation.     

Intramuscular pressure, force and blood flow in rabbit tibialis anterior muscles during single and repetitive contractions

The elevated intramuscular pressure (IMP) associated with sustained muscle contraction can affect blood flow, and could influence the long-term viability of functional skeletal muscle grafts. We therefore examined the relationship between force, peak IMP and blood flow in the tibialis anterior muscle of the anaesthetized rabbit. During isometric contractions, IMP was related linearly to force, and only the slope of the relationship varied between animals. During isotonic contractions, however, the highest values of IMP were found at the lowest force levels, and IMP appeared to be related to the amount and speed of shortening. During repeated isometric contractions, the ratio of IMP to force varied with time, stimulation pattern and subject. Mean blood flow did not differ appreciably between␣repetitive isometric contractions at duty cycles of 10–40%, and was unrelated to integrated pressure, integrated force, or depth from the surface. We conclude: (1) that IMP is unlikely to affect mean blood flow during cyclic activity that has a duty cycle less than 40%; and (2) that the clinical use of IMP as a predictor of muscle force appears to be justified only for single isometric contractions, and needs to be interpreted cautiously when contractions involve shortening or fatigue. Accepted: 17 November 1997     

Effects of daily activities on ambulatory blood pressure during menstrual cycle in normotensive women

The purpose of this study was to determine whether (1) there is a menstrual phase effect on blood pressure (BP) and heart rate (HR), and (2) the effects of physical effort, posture, or moods on BP and HR is mediated by the menstrual phase. Twelve normotensive women, aged between 28 and 50, with normal menstrual cycles were studied. BP was measured at 30- to 60-min intervals during a 24-hr period using an ambulatory BP monitor on Days 1, 8, 15, and 22 of the menstrual cycle. Participants were asked to report their posture, physical effort, and mood (annoyed, tense, and happy) on 5-point Likert-type scales each time the ambulatory BP monitor took measurements. Systolic BP (SBP) was lower on Day 8 of the cycle. Diastolic BP (DBP) and HR were lower on Days 1 and 8. Daytime SBP was affected by the time of the day and posture, but not by moods, whereas daytime DBP was affected by posture and levels of tenseness. The level of physical effort only affected HR, not BP. The average daytime physical and emotional variables had little influence over the average daytime BP. In 1 normotensive women with a normal menstrual cycle, SBP was lower during the follicular phase and DBP and HR were lower during the follicular phase and menstruation even after controlling the effects of other factors. Physical activity or moods had only momentary effects on BP or HR. A cross-validation statistical method used is suggested to study how individuals are affected by various factors. With the use of this method, the inclusion of menstrual phase in the model improved the prediction of SBP for 5 out of the 12 women studied.     

Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women.

The effects of estrogen replacement therapy on lipid and glucose metabolism as related to abdominal fat distribution were investigated in fifty-one healthy postmenopausal women aged 52-53 years. They were randomized to treatment with either estradiol 2 mg or placebo daily for three months in a double-blind design. Forty-six women continued with estradiol for another nine months in an open design with the addition of medroxyprogesterone for ten days every three months. Intra-abdominal and subcutaneous abdominal fat, and intrapelvic and subcutaneous pelvic fat was estimated by computed tomography before and after one year of estrogen treatment. Euglycemic hyperinsulinemic clamp, oral glucose tolerance test and analyses of blood lipids were performed after 3 and 12 months of treatment. Estrogen replacement therapy decreased body fat mass as well as intra-abdominal and intrapelvic fat, but not the subcutaneous fat compartments. LDL cholesterol decreased and HDL cholesterol increased, whereas triglycerides were not changed by one year of estrogen treatment. Insulin sensitivity and glucose tolerance were not affected by estrogen treatment. In postmenopausal women estrogen treatment for one year decreased intra-abdominal and intrapelvic fat compartments, but this was not related to changes in plasma lipid levels. Insulin sensitivity and plasma triglycerides were not affected by estrogen treatment.     

Reduction in extracellular muscle volume increases heart rate and blood pressure response to isometric exercise

To investigate the effect of local dehydration on heart rate and blood pressure during static exercise, six healthy male subjects performed exercise of the calf muscles with different extracellular volumes of the working muscles. Exercise consisted of 5 min of static calf muscle contractions at about 10% of maximal voluntary contraction. The body position during exercise was identical in all tests, i.e. supine with the knee joint 90 degrees flexed. During a 25-min pre-exercise period three different protocols were employed to manipulate the calf volume. In test A the subjects rested in the exercise position; in test B the body position was the same as in A but calf volumes were increased by venous congestion [cuffs inflated to 10.67 kPa (80 mmHg)]; in test C the calf volumes were decreased by lifting the calves about 40 cm above heart level with the subjects supine. To clamp the changed calf volumes in tests B and C, cuffs were inflated to 300 mmHg 5 min before the onset of exercise. This occlusion was maintained for 1 min after the termination of exercise. Compared to tests A and B, the reduced volume of test C led to significant increases in heart rate and blood pressure during exercise. Oxygen uptake did not exceed resting levels in tests B and C until the cuffs were deflated, indicating that only calf muscles contributed to the neurogenic peripheral drive. It is concluded that extracellular muscle volume plays a significant role in adjusting heart rate and blood pressure during static exercise.     

Effect of tryptophan and 5-hydroxytryptophan on the blood pressure of patients with mild to moderate hypertension

Summary Chronic treatment with L-tryptophan (4 g/day) reduced mean blood pressure in 8 of 9 patients with mild to moderate essential hypertension. No significant side effects of treatment were observed. An additional group of 8 patients was treated chronically with L-5-hydroxytryptophan (800 mg/day), the immediate precursor of serotonin. Five of the 8 patients had a significant reduction in mean arterial pressure. No significant side effects of treatment were observed. The reduction of blood pressure accompanying treatment with L-5-hydroxytryptophan suggests that at least a portion of the antihypertensive effect of L-tryptophan is mediated via serotonin.     

Estrogen treatment effects on cognition, memory and mood in male-to-female transsexuals

Gonadal hormones, particularly estrogens, have been suggested to influence memory and cognitive tasks that show sex differences. Previously, we reported that male-to-female (M-F) transsexuals undergoing estrogen treatment for sex re-assignment scored higher on verbal Paired Associate Learning (PAL) than a transsexual control group awaiting estrogen treatment. The present study used a more robust design to examine further associations between estrogen and cognition. We assessed additional aspects of memory, including visual, spatial, object and location memory, other cognitive abilities that show reliable sex differences, including verbal and visual-spatial abilities, and mood variables that could mediate associations between estrogen and cognition. In addition to comparing groups of individuals on and off estrogen, we used two repeated measures designs (AB and BA). The AB group was tested prior to hormone treatment and then again after treatment had begun; the BA group was tested while on estrogen treatment and then again when hormones had been withdrawn prior to surgery. Few changes in memory or cognition were observed, and changes that were observed were not consistent across study designs. The lack of significant effects did not relate to mood changes or to the sexual orientation of participants. These findings suggest that estrogen treatment associated with sex change for M-F transsexuals has little or no influence on sex-typed aspects of cognition or memory.     

The increase in systolic and diastolic blood pressure after exposure to cryogenic temperatures in normotensive men as a contraindication for whole-body cryostimulation

1.

The changes which occur in a human body subjected to cryogenic temperatures are still not completely understood. Thus the aim of this study was to evaluate changes in blood circulation induced by a single exposure to very low temperature during whole-body cryostimulation of young and clinically healthy male subjects. Prior to the study, candidates underwent a medical examination in order to eliminate individuals with contraindications towards cryostimulation.

2.

The study included 40 young men aged 22±0.7 years, average body weight 76.65±7.8 kg and height 175.5±7.2 cm. The participants were exposed to extremely low temperatures in a cryogenic chamber. Each session lasted for 3 min at −130 °C and was preceded by 30 s of adaptation in a vestibule at −60 °C. Blood pressure and heart rate were measured before entering the chamber, immediately after exiting, and 10 and 20 min after exiting.

3.

Our results showed a significant increase in systolic blood pressure after cryostimulation (by an average of 21 mmHg in comparison with the initial level before cryostimulation) and an increase in diastolic blood pressure after the cryostimulation (by 9 mmHg). The increase in systolic blood pressure was accompanied by a significant decrease in heart rate (by about 10 bpm). Cryostimulation of the whole body is a stress factor and a stimulus for the body which significantly increases systolic blood pressure, but the changes are temporary and not harmful for normotensive individuals.

     

Effect of alcohol on perceived exertion in relation to heart rate and blood lactate

The purpose of the study was to determine whether the perception of exertion is affected by alcohol during physical performance and whether altered self-rating of exertion is the result of an altered perception per se or of an altered physical capacity to perform work. Ten healthy men participated. Each subject was his own control and received an alcohol dose corresponding to 1 g.kg-1 body mass in 40% solution in the experimental session. The exercise test was performed on a cycle ergometer with an initial intensity of 50 W which was increased stepwise by 50 W at 4-min intervals up to near-maximal. The rating of perceived exertion (RPE) did not differ between alcohol and control sessions. Alcohol induced a significant increase in heart rate during exercise at 50 W (delta x = 8 beats.min-1) and at 100 W (delta x = 10 beats.min-1), while the change at higher intensities was insignificant. The systolic blood pressure and the blood lactate concentration were not significantly changed by alcohol. It is concluded that a moderate dose of alcohol does not alter RPE during physical exercise either per se or secondarily to an altered physical capacity to perform work.     

Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women

Prior studies of the effects of dehydroepiandrosterone (DHEA) on cognition have produced complex and inconsistent results. We hypothesize that these results may arise, in part, because of DHEA's metabolism into estrogens and androgens that produce opposing effects on cognition. Our study administered 50 mg of oral DHEA daily for 4 weeks in a placebo-controlled crossover design to six postmenopausal women. We measured blood levels of androgens (total testosterone, free testosterone, DHEA, DHEAS), estrogens (estradiol, estrone), and cognitive performance on recognition memory, perceptual identification, digit span memory, and visual attentional vigilance under both drug and placebo conditions. Multiple regression models incorporating the factors of age and body mass index (BMI) were used to ascertain the relation between sex steroids and cognitive performance. Our results demonstrated that estrogens produced a positive effect on recognition memory, while androgens produced a negative effect. This pattern reversed in perceptual identification with estrogens producing a negative effect and androgens producing a positive effect. In addition, BMI produced a negative effect on digit span memory, age produced a negative effect on perceptual identification, and androgens produced a negative effect on visual attentional vigilance. These results help, in part, to explain DHEA's complex effects on cognition. The diverse effects of sex steroids across tasks underscore the importance of identifying the specific cognitive mechanisms influenced by sex steroids and emphasizes that one should not expect sex steroids to produce homogeneous effects across cognitive tasks.     

Chronic effects of centrally administered adiponectin on appetite, metabolism and blood pressure regulation in normotensive and hypertensive rats

Acute studies suggest that adiponectin may reduce sympathetic activity and blood pressure (BP) via actions on the central nervous system (CNS). However, the chronic effects of adiponectin on energy expenditure and cardiovascular function are still poorly understood. We tested if chronic intracerebroventricular (ICV) infusion of adiponectin (1 or 7μg/day) in Sprague-Dawley rats fed a high fat diet (HFD) for 8 weeks and at the high dose (7μg/day) in spontaneously hypertensive rats (SHRs), a hypertensive model associated with sympathetic overactivity, evoked chronic reductions in BP and heart rate (HR). We also determined if chronic ICV adiponectin infusion alters appetite, whole body oxygen consumption (VO(2)), and insulin and leptin levels. Neither dose of adiponectin infused for 7 days significantly altered BP or HR in the HFD group (115±2 to 112±2mmHg and 384±6 to 379±6bpm at 1μg/day; 109±3 to 111±3mmHg and 366±5 and 367±5bpm at 7μg/day). The higher dose slightly reduced food intake (14±1 to 11±1g/day), whereas VO(2), insulin and leptin levels were not affected by the treatment. In SHRs, ICV adiponectin infusion reduced appetite (22±2 to 12±2g/day) and insulin levels (～55%), but did not alter BP (162±4 to 164±3mmHg) or HR (312±5 to 322±8bpm). These results suggest that adiponectin, acting via its direct actions on the CNS, has a small effect to reduce appetite and insulin levels, but it has no long-term action to reduce BP or HR, or to alter whole body metabolic rate.     

Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses

Background

L-theanine, an amino acid contained in green tea leaves, is known to block the binding of L-glutamic acid to glutamate receptors in the brain, and has been considered to cause anti-stress effects by inhibiting cortical neuron excitation. Both L-theanine and caffeine, which green tea contains, have been highlighted for their beneficial effects on cognition and mood.

Methods

In this study, we investigated the effects of orally administered L-theanine or caffeine on mental task performance and physiological activities under conditions of physical or psychological stress in humans. Fourteen participants each underwent three separate trials, in which they orally took either L-theanine + placebo, caffeine + placebo, or placebo only.

Results

The results after the mental tasks showed that L-theanine significantly inhibited the blood-pressure increases in a high-response group, which consisted of participants whose blood pressure increased more than average by a performance of a mental task after placebo intake. Caffeine tended to have a similar but smaller inhibition of the blood-pressure increases caused by the mental tasks. The result of the Profile of Mood States after the mental tasks also showed that L-theanine reduced the Tension-Anxiety scores as compared with placebo intake.

Conclusions

The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood-pressure increase in high-stress-response adults.     

Hydrostatic pressure is like high temperature and oxidative stress in the damage it causes to yeast

Abstract A comparison of barotolerance, thermotolerance and oxygen tolerance was made under different physiological conditions, such as heat shocked and recovered state, different growth phases and changes of physiological conditions by mutations. The three kinds of tolerance showed similar features under different physiological conditions. We suggest that the damage caused by hydrostatic pressure may be essentially the same as that due to high temperature and oxidative stress in yeast.     

Increase in the sensitivity of the vascular smooth muscle to constrictor factors after denervation and with a decrease in blood pressure

The effect of denervation on the contractile activity of the saphenous artery in normotensive rats and rats with regional hypotension was studied. Hypotension was caused by partial occlusion of the abdominal aorta distally from the renal arteries, and then, in four weeks, to denervate the saphenous artery, a portion of the femoral nerve in one of the limbs was resected. In two more weeks, the contractile responses of ring preparations of the saphenous artery (after removal of the endothelium and block of neuronal uptake and β-adrenoreceptors) were investigated under isometric conditions. In normotensive rats, the denervation led to an increase in the vascular sensitivity to norepinephrine, phenylephrine, serotonin, and KCl. Similar changes in contraction were caused by chronic hypotension; however, rats with hypotension exhibited no additional denervation-induced increase in the vascular sensitivity. After treatment with glyoxylic acid, the fluorescence intensity of the vascular adrenergic fibers adapted to a reduced pressure was lower than that in the norm. It was assumed that the vascular hypersensitivity in hypotension is caused by impairment of sympathetic innervation.     

Impact of tannic acid on blood pressure,oxidative stress and urinary parameters in L-NNA-induced hypertensive rats

Hypertension is a major health problem with increasing prevalence around the world. Tannic acid is water-soluble polyphenol that is present in tea, green tea, coffee, red wine, nuts, fruits and many plant foods. It has been reported to serve as an antioxidant or a pro-oxidant depending on the type of cells and its concentration. The purpose of our study was to evaluate the effect of tannic acid on systolic blood pressure, oxidative stress and some urinary parameters in the rat model of essential hypertension. Blood pressures of all rats were measured using the tail-cuff method. The nitric oxide synthase inhibitor N (omega)-nitro-L-arginine was administered orally at a dose of 0.5 g/l/day for 15 days to rats in order to create an animal model of hypertension. Tannic acid was intraperitoneally injected at a dose of 50 mg/kg for 15 days. Superoxide dismutase, catalase activity and the concentration of malondialdehyde (MDA) were determined in blood plasma and homogenates of heart, liver and kidney. In order to evaluate renal functions, urine pH, urine volume, urine creatine, uric acid, and urea nitrogen values were measured. Compared with the hypertension group, a decrease in MDA concentrations of heart tissue (p < 0.01), urea nitrogen values (p < 0.01) and urine volumes (p < 0.001) were established in hypertension + tannic acid group. There was also a decrease in blood pressure values (20th and 30th days) of this group, but there was no a statistical difference according to hypertension group. The findings of our research show the effect of tannic acid in lowering blood pressure in hypertensive rats.