Acute impact of drinking coffee on the cerebral and systemic vasculature.

Previous studies have suggested that the risk of ischemic stroke increases immediately after drinking coffee. Indeed, drinking coffee, that is, caffeine, acutely increases arterial stiffness as well as blood pressure and peripheral vascular resistance. On the other hand, it has been reported that arterial stiffening is associated with elevation in the pulsatility index (PI) of cerebral blood flow (CBF), which increases the risk of brain disease. However, the effect of drinking coffee on the PI of the CBF and its interaction with arterial stiffness remain unknown. Against this background, we hypothesized that an acute increase in arterial stiffness induced by drinking coffee augments cerebral pulsatile stress. To test this hypothesis, in 10 healthy young men we examined the effects of drinking coffee on the PI of middle cerebral artery blood velocity (MCAv) and brachial-ankle pulse wave velocity (baPWV) as indices of cerebral pulsatile stress and arterial stiffness, respectively. Mean arterial blood pressure and baPWV were higher (P < 0.01 and P = 0.02), whereas mean MCAV and mean cerebrovascular conductance index were lower upon drinking coffee (P = 0.02 and P < 0.01) compared with a placebo (decaffeinated coffee). However, there was no difference in the PI of MCAv between drinking coffee and the placebo condition. These findings suggest that drinking coffee does not increase cerebral pulsatile stress acutely despite an elevation in arterial stiffness in the systemic circulation.

Estradiol regulates GH-releasing peptide's interactions with GH-releasing hormone and somatostatin in postmenopausal women.

OBJECTIVE: Estrogen stimulates pulsatile secretion of GH, via mechanisms that are largely unknown. An untested hypothesis is that estradiol (E2) drives GH secretion by amplifying interactions among GH-releasing hormone (GHRH), somatostatin (SS), and GH-releasing peptide (GHRP). DESIGN: The design comprised double-blind randomized prospective administration of transdermal E2 vs placebo to healthy postmenopausal women (n=24) followed by pulsatile GHRH or SS infusions for 13 h overnight with or without continuous GHRP2 stimulation. METHODS: End points were mean concentrations, deconvolved secretion, and approximate entropy (ApEn; a regularity measure) of GH. RESULTS: By generalized ANOVA models, it was observed that E2 vs placebo supplementation: i) augmented mean (13-h) GH concentrations (P=0.023), GHRH-induced pulsatile GH secretion over the first 3 h (P=0.0085) and pulsatile GH secretion over the next 10 h (P=0.054); ii) increased GHRP-modulated (P=0.022) and SS-modulated (P<0.001) GH ApEn; and iii) did not amplify GHRH/GHRP synergy during pulsatile GH secretion. By linear regression, E2 concentrations were found to be positively correlated with GH secretion during GHRP2 infusion (P=0.022), whereas BMI was found to be negatively correlated with GH secretion during GHRH (P=0.006) and combined GHRH/GHRP (P=0.015) stimulation. E2 and BMI jointly determined triple (combined l-arginine, GHRH, and GHRP2) stimulation of GH secretion after saline (R²=0.44 and P=0.003) and pulsatile GHRH (R²=0.39 and P=0.013) infusions. CONCLUSION: In summary, in postmenopausal women, E2 supplementation augments the amount (mass) and alters the pattern (regularity) of GH secretion via interactions among GHRH, SS, GHRP, and BMI. These outcomes introduce a more complex model of E2 supplementation in coordinating GH secretion in aging women.

A randomised controlled trial evaluating the effect of potassium supplementation on vascular function and the renin-angiotensin-aldosterone system.

There is limited evidence on the effect of potassium supplementation on the vasculature in patients at increased cardiovascular risk. Potassium increases aldosterone and there is a strong association of hyperaldosteronism with poor cardiac outcomes. We aimed to determine whether potassium supplementation has a significant medium-term effect on aldosterone levels and, if so, what the overall effect of this is on vascular function in patients at moderate cardiovascular disease risk. Forty patients at moderate cardiovascular disease risk were included in a randomised placebo-controlled crossover study. Patients were assigned to 64 mmol potassium chloride or placebo for 6 weeks. Vascular function was assessed using pulse-wave analysis including the detection of a change in augmentation index to salbutamol and nitroglycerine-induced vasodilation. There was no change in augmentation index with potassium vs placebo (25.2±1.4 vs. 26.0±1.3%, respectively). Potassium improved brachial systolic blood pressure (131.8±2.2 vs. 137.1±2.4 mm Hg; P=0.013), central systolic blood pressure (123.2±2.3 vs. 128.4±2.3 mm Hg; P=0.011) and central diastolic blood pressure (80.3±1.3 vs. 83.7±1.4 mm Hg; P=0.019). Plasma renin activity and serum aldosterone both increased with potassium (P=0.001 and P=0.048 respectively). We found that potassium supplementation had no effect on endothelial function or pulse-wave analysis. It lowered brachial systolic and central blood pressure. It was associated with increased plasma renin activity and serum aldosterone.

Effect of vitamin D on aortic remodeling in streptozotocin-induced diabetes.

BACKGROUND: Diabetes mellitus is associated with micro- and macrovascular complications and increased cardiovascular risk. Elevated levels of serum asymmetric dimethylarginine (ADMA) may be responsible for endothelial dysfunction associated with diabetes-induced vascular impairment. Vitamin D may have potential protective effects against arterial stiffening. This study aimed to examine both the effects of diabetes on the functional/structural properties of the aorta and the endothelial function and the effects of vitamin D supplementation. METHODS: Male Wistar rats (n = 30) were randomly assigned to control untreated, diabetic untreated, and diabetic + cholecalciferol groups. Diabetes was induced by intraperitoneal injection of streptozotocin, followed by oral administration of cholecalciferol (500 IU/kg) for 10 weeks in the treatment group. Aortic pulse wave velocity (PWV) was recorded over a mean arterial pressure (MAP) range of 50 to 200 mmHg using a dual pressure sensor catheter. Intravenous infusion of phenylephrine and nitroglycerine was used to increase and decrease MAP, respectively. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured using a radioimmune assay. ADMA levels in serum were measured by enzyme-linked immunoassay. Aortic samples were collected for histomorphometrical analysis. RESULTS: PWV up to MAP 170 mmHg did not reveal any significant differences between all groups, but in diabetic rats, PWV was significantly elevated across MAP range between 170 and 200 mmHg. Isobaric PWV was similar between the treated and untreated diabetic groups, despite significant differences in the levels of serum 25(OH)D (493 ± 125 nmol/L vs 108 ± 38 nmol/L, respectively). Serum levels of ADMA were similarly increased in the treated and untreated diabetic groups, compared to the control group. The concentration and integrity of the elastic lamellae in the medial layer of the aorta was impaired in untreated diabetic rats and improved by vitamin D supplementation. CONCLUSION: PWV profile determined under isobaric conditions demonstrated differential effects of uncontrolled diabetes on aortic stiffness. Diabetes was also associated with elevated serum levels of ADMA. Vitamin D supplementation did not improve the functional indices of aortic stiffness or endothelial function, but prevented the fragmentation of elastic fibers in the aortic media.

Effect of Omega-3 fatty acid supplementation on markers of platelet and endothelial function in patients with peripheral arterial disease.

OBJECTIVE: Omega-3 fatty acids have been shown to reduce platelet and endothelial activation in patients with or at risk of cardiac disease. We aimed to determine if Omega-3 fatty acid supplementation in addition to best medical therapy can reduce the increased platelet and endothelial activity that is present in patients with intermittent claudication. METHODS: One hundred and fifty patients who were receiving aspirin and statin therapy were recruited into a randomised cross-over double blind study involving 6 week supplementation with OMACOR fish oil (850-882 mg eicosapentaenoic and docosahexaenoic acid) versus placebo. A 12 week washout period occurred between treatments. Patients with diabetes were excluded. For each outcome a random effects model was fitted in which treatment and period were fixed effects and patients were random effects. RESULTS: Omega-3 supplementation had no effect on the primary outcome measure von Willebrand factor. Similarly Omega-3 supplementation resulted in no change in unstimulated or stimulated P-selectin expression and fibrinogen binding, or platelet aggregation (Ultegra point of care). Pulse wave velocity was also unchanged. High-sensitivity C-reactive protein, s-ICAM and IL-6 were also unchanged. CONCLUSION: Supplementation with Omega-3 fatty acids had no affect on platelet and endothelial activation or markers of inflammation in patients with peripheral arterial disease.

Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men.

BACKGROUND: Nitric oxide (NO) plays a key role in the maintenance of vascular tone, contributing to the functional regulation of arterial stiffness. Although oral L-citrulline could become the effective precursor of L-arginine (substrate for endothelial NO synthase) via the L-citrulline/ L-arginine pathway, little is known about the efficacy of L-citrulline application on arterial stiffness. OBJECTIVE: We examined the short-term effects of L-citrulline supplementation on arterial stiffness in humans. METHODS: In a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (baPWV; index of arterial stiffness >1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days. baPWV and various clinical parameters were measured before (baseline) and after oral supplementation of L-citrulline or placebo. RESULTS: Compared with the placebo group, baPWV was significantly reduced in the L-citrulline group (p<0.01). No significant differences in blood pressure (BP) were found between the two groups, and no correlation was observed between BP and baPWV. The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group (p<0.05). Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group (p<0.05, p<0.01, p<0.05, respectively). Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (r=-0.553, p<0.05). CONCLUSION: These findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans.

Aromatase inhibition causes increased amplitude, but not frequency, of hypothalamic-pituitary output in normal women.

OBJECTIVE: To better understand the site and mode of action of aromatase inhibitors. DESIGN: Prospective study. SETTING: Academic research environment. PATIENT(S): Five eumenorrheic (without polycystic ovary syndrome), early follicular phase women with a normal body mass index (mean: 20.47±0.68 kg/m2), and 12 normal weight, midreproductive aged, early follicular phase women with a normal body mass index (mean: 20.8±1.7 kg/m2) as historical controls. INTERVENTION(S): 2.5 mg letrozole daily for 7 days, with daily urine collection (first morning void), thrice weekly blood sampling, and 4 hours of blood sampling every 10 minutes. MAIN OUTCOME MEASURE(S): Serum luteinizing hormone (LH) measured by a well-characterized immunofluorometric assay with LH pulse characteristics compared between treated and control groups using t tests. RESULT(S): Mean LH and LH pulse amplitude more than doubled in the women who had taken letrozole compared with the controls, but the LH pulse frequency did not differ between the women taking letrozole and the controls. CONCLUSION(S): These results indicate that the release of negative feedback inhibition of estradiol on the hypothalamic-pituitary axis in normal women by aromatase inhibitors creates an amplitude-related increase in endogenous hypothalamic-pituitary drive. The finding that the mean LH and LH pulse amplitude, but not the frequency, increased after letrozole suggests a possible pituitary site of action.

Cinacalcet may reduce arterial stiffness in patients with chronic renal disease and secondary hyperparathyroidism - results of a small-scale, prospective, observational study.

AIMS: This study evaluated the impact of cinacalcet on arterial stiffness, determined by pulse wave velocity (PWV), in patients with chronic renal disease and secondary hyperparathyroidism (SHPT). PATIENTS AND METHODS: This prospective, observational study included, SHPT patients with chronic renal disease on dialysis undergoing cinacalcet treatment with a follow-up of 12 months. RESULTS: 21 patients, 62% males, with a mean age of 51.3 years (± 18.0) were included. Cinacalcet was given for at least a year with a mean daily dose of 35 mg (range 30-60 mg). Aortic PWV significantly decreased after 12 months of cinacalcet treatment (9.35 ± 1.83 m/sg vs. 8.66 ± 1.86 m/sg; p = 0.030). Additionally, there was a notable reduction trend in the left ventricular mass index (166.6 ± 39.4 g/m² vs. 156.1 ± 31.8 g/m²), although it did not achieve statistical significance (p = 0.063). Alkaline phosphatase and PTH were significantly decreased during the study. However, serum calcium, phosphorus and blood pressure remained stable. CONCLUSION: The results of this study support the possibility that cinacalcet reduces arterial stiffness of SHPT patients with chronic renal disease after 12 months of treatment. Prospective, randomized clinical trials are needed to confirm these preliminary findings.

Effects of safflower seed extract on arterial stiffness.

Safflower seed extract (SSE) contains characteristic polyphenols and serotonin derivatives (N-( p-coumaroyl) serotonin and N-feruloylserotonin), which are reported to inhibit oxidation of low-density lipoprotein (LDL), formation of atherosclerotic plaques, and improve arterial stiffness as assessed by pulse wave analysis in animal models. The effects of long-term supplementation with SSE on arterial stiffness in human subjects were evaluated. This doubleblind, placebo-controlled study was conducted in 77 males (35-65 years) and 15 postmenopausal females (55-65 years) with high-normal blood pressure or mild hypertension who were not undergoing treatment. Subjects received SSE (70 mg/day as serotonin derivatives) or placebo for 12 weeks, and pulse wave measurements, ie, second derivative of photoplethysmogram (SDPTG), augmentation index, and brachial-ankle pulse wave velocity (baPWV) were conducted at baseline, and at weeks 4, 8, and 12. Vascular age estimated by SDPTG aging index improved in the SSE-supplemented group when compared with the placebo group at four (P = 0.0368) and 12 weeks (P = 0.0927). The trend of augmentation index reduction (P = 0.072 versus baseline) was observed in the SSE-supplemented group, but reduction of baPWV by SSE supplementation was not observed. The SSE-supplemented group also showed a trend towards a lower malondialdehyde-modified-LDL autoantibody titer at 12 weeks from baseline. These results suggest long-term ingestion of SSE in humans could help to improve arterial stiffness.

Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.

To determine the effects of potassium supplementation on endothelial function, cardiovascular risk factors, and bone turnover and to compare potassium chloride with potassium bicarbonate, we carried out a 12-week randomized, double-blind, placebo-controlled crossover trial in 42 individuals with untreated mildly raised blood pressure. Urinary potassium was 77+/-16, 122+/-25, and 125+/-27 mmol/24 hours after 4 weeks on placebo, potassium chloride, and potassium bicarbonate, respectively. There were no significant differences in office blood pressure among the 3 treatment periods, and only 24-hour and daytime systolic blood pressures were slightly lower with potassium chloride. Compared with placebo, both potassium chloride and potassium bicarbonate significantly improved endothelial function as measured by brachial artery flow-mediated dilatation, increased arterial compliance as assessed by carotid-femoral pulse wave velocity, decreased left ventricular mass, and improved left ventricular diastolic function. There was no significant difference between the 2 potassium salts in these measurements. The study also showed that potassium chloride reduced 24-hour urinary albumin and albumin:creatinine ratio, and potassium bicarbonate decreased 24-hour urinary calcium, calcium:creatinine ratio, and plasma C-terminal cross-linking telopeptide of type 1 collagen significantly. These results demonstrated that an increase in potassium intake had beneficial effects on the cardiovascular system, and potassium bicarbonate may improve bone health. Importantly, these effects were found in individuals who already had a relatively low-salt and high-potassium intake.

The herbal medicine Daikenchuto increases blood flow in the superior mesenteric artery.

Daikenchuto is a traditional herbal medicine that is used for the treatment of cold feeling in the abdomen, while Orengedokuto, also a traditional herbal medicine, is used for treating inflammatory and ulcerative diseases affecting internal organs. However, the effects of these herbal medicines on cardiac output (CO) and intestinal blood flow have never been investigated. This examiner-blinded randomized crossover study intended to clarify the influence of Daikenchuto and Orengedokuto on CO and blood flow volume in the superior mesenteric artery (SMA). Fourteen healthy men (35 +/- 7 years old) were randomly assigned to two groups: group A and group B. Initially, all subjects were given 50 ml of water orally. After 7 days, subjects in group A were given 5.0 g of Daikenchuto, and 7 days later they were given 2.5 g of Orengedokuto. These herbal medicines were given to group B subjects in the reverse order. CO and SMA blood flow volume were measured from rest to 90 min after the administration of water or each medicine. There was a significant increase in SMA blood flow volume after the administration of Daikenchuto, compared to water alone (p < 0.05) and Orengedokuto (p < 0.05). SMA blood flow volume was significantly increased between 5 and 90 min after administration of Daikenchuto (p < 0.01) compared to the resting state. However, there was no significant change in CO after the administration of either agent. The present study indicates that Daikenchuto increases SMA blood flow volume without increasing CO.

Atrazine inhibits pulsatile luteinizing hormone release without altering pituitary sensitivity to a gonadotropin-releasing hormone receptor agonist in female Wistar rats.

Atrazine [2-chloro-4-(ethylamino)-6-(isopropylamino)-s-tri-azine] is one of the most commonly used herbicides in the United States. Atrazine has been shown to suppress luteinizing hormone (LH) release and can lead to a prolongation of the estrous cycle in the rat. The objectives of this study were to examine the effects of atrazine on normal tonic release of LH and to elucidate the site of action of atrazine in the hypothalamic-pituitary-gonadal axis. Episodic release of gonadotropin-releasing hormone (GnRH) and the corresponding release of LH from the anterior pituitary gland are required for normal reproductive function. To determine if atrazine affects pulsatile LH release, ovariectomized adult female Wistar rats were administered atrazine (50, 100, or 200 mg/kg of body weight daily by gavage) or vehicle control for 4 days. On the final day of atrazine treatment, blood samples were obtained using an indwelling right atrial cannula. In the group receiving 200 mg/kg, there was a significant reduction in LH pulse frequency and a concomitant increase in pulse amplitude. To determine if the effects of atrazine on LH release were due to changes at the level of the pituitary, animals were passively immunized against endogenous GnRH, treated with atrazine, and challenged with a GnRH receptor agonist. Atrazine failed to alter pituitary sensitivity to the GnRH receptor agonist at any dose used. Taken together, these findings demonstrate that high doses of atrazine affect the GnRH pulse generator in the brain and not at the level of gonadotrophs in the pituitary.

Organizational actions of postnatal estradiol in female sheep treated prenatally with testosterone: programming of prepubertal neuroendocrine function and the onset of puberty.

Prenatal testosterone (T) exposure defeminizes reproductive neuroendocrine function in female sheep, although the LH surge dysfunctions are initially less severe in gonadally intact females than in females subject to neonatal ovariectomy and estradiol (E) replacement. Because prepubertal ovarian production of E differs quantitatively and qualitatively from chronic E replacement, we tested the hypothesis that postnatal E exacerbates the consequences of prenatal T on the positive, but not the negative, steroid feedback controls of GnRH secretion. Our approach was to characterize prepubertal sensitivity to E negative feedback, the onset and maintenance of progestagenic cycles, and the LH surge response in ovary intact, prenatally untreated (control), and T-treated (T) sheep that were exposed postnatally to only endogenous E, or exposed to excess E by s.c. implant. Sensitivity to E negative feedback was reduced in T females, but excess postnatal E did not further increase LH pulse frequency. Excess E prevented ovarian cycles in several control females, and increased cycle irregularity in T females. However, the LH surge mechanism was functional in all control females (regardless of postnatal E exposure) and in some T females without excess E, but nonfunctional in T females with excess E. These findings suggest that postnatal E does not program increased resistance to E negative feedback, but excess postnatal E does disrupt other mechanisms required for ovarian cyclicity. We conclude that in this precocial species, prenatal steroids are sufficient to program controls of tonic LH secretion, but the LH surge mechanism is susceptible to further programming by postnatal E.

Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a meta-analysis of randomized controlled trials.

BACKGROUND: Previous trials suggest that oral l-arginine administration affects endothelial function. However, most of these studies were small, the conclusions were inconsistent, and the precise effects are therefore debatable. OBJECTIVE: The objective was to assess the effect of oral l-arginine supplementation on endothelial function, as measured with the use of fasting flow-mediated dilation (FMD). DESIGN: We conducted a meta-analysis of randomized, placebo-controlled l-arginine supplementation trials that evaluated endothelial function. Trials were identified in PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant papers. The weighted mean difference (WMD) was calculated for net changes in FMD by using random-effect models. Previously defined subgroup analyses and meta-regression analyses were performed to explore the influence of study characteristics. RESULTS: Thirteen trials were included and evaluated. Because there was only one long-term study, we focused on short-term effects of l-arginine (12 studies, 492 participants). In an overall pooled estimate, l-arginine significantly increased FMD (WMD: 1.98%; 95% CI: 0.47, 3.48; P = 0.01). Meta-regression analysis indicated that the baseline FMD was inversely related to effect size (regression coefficient = -0.55; 95% CI: -1.00, -0.1; P = 0.016). A subgroup analysis suggested that l-arginine supplementation significantly increased FMD when the baseline FMD levels were <7% (WMD: 2.56%; 95% CI: 0.87, 4.25; P = 0.003), but had no effect on FMD when baseline FMD was >7% (WMD: -0.27%; 95% CI: -1.52, 0.97; P = 0.67). CONCLUSION: Short-term oral l-arginine is effective at improving the fasting vascular endothelial function when the baseline FMD is low.

Astaxanthin vs placebo on arterial stiffness, oxidative stress and inflammation in renal transplant patients (Xanthin): a randomised controlled trial.

BACKGROUND: There is evidence that renal transplant recipients have accelerated atherosclerosis manifest by increased cardiovascular morbidity and mortality. The high incidence of atherosclerosis is, in part, related to increased arterial stiffness, vascular dysfunction, elevated oxidative stress and inflammation associated with immunosuppressive therapy. The dietary supplement astaxanthin has shown promise as an antioxidant and anti-inflammatory therapeutic agent in cardiovascular disease. The aim of this trial is to investigate the effects of astaxanthin supplementation on arterial stiffness, oxidative stress and inflammation in renal transplant patients. METHOD AND DESIGN: This is a randomised, placebo controlled clinical trial. A total of 66 renal transplant recipients will be enrolled and allocated to receive either 12 mg/day of astaxanthin or an identical placebo for one-year. Patients will be stratified into four groups according to the type of immunosuppressant therapy they receive: 1) cyclosporine, 2) sirolimus, 3) tacrolimus or 4) prednisolone+/-azathioprine, mycophenolate mofetil or mycophenolate sodium. Primary outcome measures will be changes in 1) arterial stiffness measured by aortic pulse wave velocity (PWV), 2) oxidative stress assessed by plasma isoprostanes and 3) inflammation by plasma pentraxin 3. Secondary outcomes will include changes in vascular function assessed using the brachial artery reactivity (BAR) technique, carotid artery intimal medial thickness (CIMT), augmentation index (AIx), left ventricular afterload and additional measures of oxidative stress and inflammation. Patients will undergo these measures at baseline, six and 12 months. DISCUSSION: The results of this study will help determine the efficacy of astaxanthin on vascular structure, oxidative stress and inflammation in renal transplant patients. This may lead to a larger intervention trial assessing cardiovascular morbidity and mortality. TRIAL REGISTRATION: ACTRN12608000159358.

Black cohosh has central opioid activity in postmenopausal women: evidence from naloxone blockade and positron emission tomography neuroimaging.

OBJECTIVE: To test whether black cohosh (BC) exhibits an action on the central endogenous opioid system in postmenopausal women. DESIGN: This was a mechanistic study conducted in the same individuals of luteinizing hormone pulsatility with a saline/naloxone challenge (n = 6) and positron emission tomography with [C]carfentanil, a selective micro-opioid receptor radioligand (n = 5), before and after 12 weeks of unblinded treatment with a popular BC daily supplement. RESULTS: BC treatment for 12 weeks at a standard dose (Remifemin, 40 mg/day) had no effect on spontaneous luteinizing hormone pulsatility or estrogen concentrations. With naloxone blockade, there was an unexpected suppression of mean luteinizing hormone pulse frequency (saline vs naloxone = 9.0 +/- 0.6 vs 6.0 +/- 0.7 pulses/16 h; P = 0.056), especially during sleep when the mean interpulse interval was prolonged by approximately 90 minutes (saline night interpulse interval = 103 +/- 9 min vs naloxone night interpulse interval = 191 +/- 31 min, P = 0.03). There were significant increases in mu-opioid receptor binding potential in the posterior and subgenual cingulate, temporal and orbitofrontal cortex, thalamus, and nucleus accumbens ranging from 10% to 61% across brain regions involved in emotional and cognitive function. In contrast, binding potential reductions of lesser magnitude were observed in regions known to be involved in the placebo response (anterior cingulate and anterior insular cortex). CONCLUSIONS: Using two different challenge paradigms for the examination of central opioid function, a neuropharmacologic action of BC treatment was demonstrated in postmenopausal women.

Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation.

OBJECTIVE: Equol, a gut bacterial metabolite of isoflavone daidzein, may improve health through changes in vascular function and in estrogen metabolism. Tibolone, a synthetic steroid alternative for the treatment of postmenopausal symptoms, causes a different estrogenic milieu than estrogen and may affect vascular health. We studied the effects of equol production and soy supplementation on vascular function in postmenopausal women under long-term tibolone use. METHODS: We screened 110 women using tibolone for 3-60 months for high equol production capacity with a one-week soy challenge. Twenty women with high equol production capacity (4-fold elevation in equol level) and 20 comparable control women without this capacity were treated in a randomized placebo-controlled cross-over trial with a soy drink (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Arterial stiffness and endothelial function were assessed before and after soy and placebo supplementation with pulse-wave analysis. RESULTS: Prior to soy supplementation arterial stiffness, expressed as augmentation index, was lower (p=0.01) in equol producers (25.9+/-1.1%) than non-equol producers (29.6+/-0.9%). Similarly, endothelial function index was better at baseline (p=0.009) in these women (72.3+/-5.3%) compared to women lacking equol production capacity (55.2+/-3.8%). Soy supplementation had no effect on arterial stiffness or endothelial function in either group. CONCLUSION: In postmenopausal tibolone users, endogenous equol production capability is associated with favorable vascular function. This phenomenon was not affected by soy and thus, equol producing capacity may be an independent vascular health marker, at least in postmenopausal women using tibolone.

The effect of curcumin on ethanol induced changes in suprachiasmatic nucleus (SCN) and pineal.

(1) Circadian clocks have been localized to discrete sites within the nervous system of several organisms and in mammals to the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN controls and regulates the production and discharge of melatonin (hormonal message of darkness) from the pineal gland via a multisynaptic efferent pathway. The nocturnal rise in melatonin production from serotonin results due to an increased activity of serotonin N-acetyl transferase (NAT). (2) The complex interaction between alcohol and biological clock need to be understood as alcoholism results in various clock linked neuronal disorders especially loss of memory and amnesia like state of consciousness, sleep disorders, insomnia, dementia etc. (3) Serotonin, 5-Hydroxy-tryptamine (5-HT) plays an important role in mediating alcohol's effects on the brain. Understanding the impact of alcohol consumption on circadian system is a pre-requisite to help in treatment of alcohol induced neurological disorders. We, therefore, studied the effect of ethanol drinking and ethanol withdrawal on daily rhythms of serotonin and its metabolite, 5-hydroxy-indole acetic acid (5-HIAA) in SCN and Pineal of adult male Wistar rats maintained under light-dark (LD, 12:12) conditions. (4) Curcumin is well known for its protective properties such as antioxidant, anti-carcinogenic, anti-viral and anti-infectious etc. Hence, we studied the effect of curcumin on ethanol induced changes on 5-HT and 5-HIAA levels and rhythms in SCN and Pineal. (5) Ethanol withdrawal could not restore either rhythmicity or phases or levels of 5-HT and 5-HIAA. Curcumin administration resulted in partial restoration of daily 5-HT/5-HIAA ratio, with phase shifts in SCN and in Pineal. Understanding the impact of alcohol consumption on circadian system and the role of herbal medication on alcohol withdrawal will help in treatment of alcohol induced neurological disorders.

Drug effects on the mechanical properties of large arteries in humans.

1. Arteries become stiffer with increasing age and various disease states. A complete description of arterial mechanical properties in vivo is not possible, although a number of methods have been used. 2. Detailed discussion in the present review is limited to pulse wave velocity and estimates of central waveform morphology derived by the application of a generalized arterial transfer function. 3. Many drugs affect these parameters, either increasing or decreasing apparent stiffness. However, the extent to which changes reflect changes in blood pressure rather than more fundamental vessel wall properties remains unclear. Similarly, it is as yet unknown whether determining the need for, or assessing the effectiveness of, drug treatment by the assessment of arterial mechanical properties will offer any advantage and the usefulness of these techniques as routine clinical tools remains to be established.