Menopausal vasomotor symptoms and adiponectin among midlife women.

OBJECTIVE: Vasomotor symptoms (VMS) are prevalent symptoms that can have a negative impact on quality of life. VMS have also been linked to cardiovascular disease risk, yet the mechanisms underlying these associations have not been elucidated. Some initial works link VMS to adverse adipokine profiles or cytokines produced by adipose tissue. However, results are not entirely consistent and are based entirely on self-report VMS, which is influenced by a range of memory and reporting biases. The aim of this work was to test whether physiologically assessed VMS are associated with lower adiponectin, the most abundant adipokine in the body, controlling for confounding factors. We also consider whether adiponectin explains previously documented relationships between VMS and carotid atherosclerosis. METHODS: A total of 300 peri- and postmenopausal nonsmoking women aged 40 to 60 years enrolled in the MsHeart study comprised the analytic sample. Women were free of hormone therapy or other medications impacting VMS, insulin-dependent diabetes, and cardiovascular disease. Participants underwent ambulatory physiologic VMS monitoring, physical measures, a carotid ultrasound, and fasting phlebotomy. RESULTS: More frequent physiologically assessed VMS were associated with lower adiponectin ( B [SE] = -0.081 [0.028], P = 0.004; or 0.081 lower µg/mL in adiponectin for each additional VMS over 24 hours), controlling for age, race/ethnicity, education, insulin resistance, and waist circumference. Associations were not explained by endogenous estradiol. Adiponectin did not explain associations between VMS and carotid atherosclerosis. CONCLUSIONS: Physiologic VMS were associated with lower adiponectin after considering potential confounders. The role of adipokines in VMS and in links between VMS and health warrants further attention.

Menopause.

This review focuses on the diagnosis and management of menopause, highlighting both hormonal and nonhormonal treatment options. In particular, the article focuses on recent data on the risks and benefits of hormone therapy to help clinicians better counsel their patients about decision making with regard to understanding and treating menopause symptoms.

The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications.

Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65-75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.

Altered Nocturnal Cardiovascular Control in Children With Sleep-Disordered Breathing.

Study objectives: To assess cardiovascular control during sleep in children with sleep-disordered breathing (SDB) and the effect of adenotonsillectomy in comparison to healthy nonsnoring children. Methods: Cardiorespiratory signals obtained from overnight polysomnographic recordings of 28 children with SDB and 34 healthy nonsnoring children were analyzed. We employed an autoregressive closed-loop model with heart period (RR) and pulse transit time (PTT) as outputs and respiration as an external input to obtain estimates of respiratory gain and baroreflex gain. Results: Mean and variability of PTT were increased in children with SDB across all stages of sleep. Low frequency power of RR and PTT were attenuated during non-rapid eye movement (REM) sleep. Baroreflex sensitivity was reduced in children with SDB in stage 2 sleep, while respiratory gain was increased in slow wave sleep. After adenotonsillectomy, these indices normalized in the SDB group attaining values comparable to those of healthy children. Conclusions: In children with mild-to-moderate SDB, vasomotor activity is increased and baroreflex sensitivity decreased during quiet, event-free non-REM sleep. Adenotonsillectomy appears to reverse this effect.

Xanthine oxidase inhibition protects against Western diet-induced aortic stiffness and impaired vasorelaxation in female mice.

Consumption of a high-fat, high-fructose diet [Western diet (WD)] promotes vascular stiffness, a critical factor in the development of cardiovascular disease (CVD). Obese and diabetic women exhibit greater arterial stiffness than men, which contributes to the increased incidence of CVD in these women. Furthermore, high-fructose diets result in elevated plasma concentrations of uric acid via xanthine oxidase (XO) activation, and uric acid elevation is also associated with increased vascular stiffness. However, the mechanisms by which increased xanthine oxidase activity and uric acid contribute to vascular stiffness in obese females remain to be fully uncovered. Accordingly, we examined the impact of XO inhibition on endothelial function and vascular stiffness in female C57BL/6J mice fed a WD or regular chow for 16 wk. WD feeding resulted in increased arterial stiffness, measured by atomic force microscopy in aortic explants (16.19 ± 1.72 vs. 5.21 ± 0.54 kPa, P < 0.05), as well as abnormal aortic endothelium-dependent and -independent vasorelaxation. XO inhibition with allopurinol (widely utilized in the clinical setting) substantially improved vascular relaxation and attenuated stiffness (16.9 ± 0.50 vs. 3.44 ± 0.50 kPa, P < 0.05) while simultaneously lowering serum uric acid levels (0.55 ± 0.98 vs. 0.21 ± 0.04 mg/dL, P < 0.05). In addition, allopurinol improved WD-induced markers of fibrosis and oxidative stress in aortic tissue, as analyzed by immunohistochemistry and transmission electronic microscopy. Collectively, these results demonstrate that XO inhibition protects against WD-induced vascular oxidative stress, fibrosis, impaired vasorelaxation, and aortic stiffness in females. Furthermore, excessive oxidative stress resulting from XO activation appears to play a key role in mediating vascular dysfunction induced by chronic exposure to WD consumption in females.

New options for menopausal symptoms after 15 years of WHI Study.

Menopausal symptoms include vasomotor symptoms (VMS), vulvar-vaginal atrophy, and loss of bone mass associated with an increased risk of fracture. Treatment of VMS consists of lifestyle changes, hormone treatment (estrogens with and without progestogens, tissue selective estrogens complex or conjugated estrogens and bazedoxifene [CE/BZA], progestogens, and tibolone), and nonhormonal treatments. Genitourinary symptoms due to vulvar-vaginal atrophy are treated with systemic and local hormones, moisturizer creams and gels, CE/BZA, and a selective estrogen receptor modulator (ospemifene). In addition to lifestyle changes, treatments for the risk of fragility fracture include calcium and vitamin D, hormone treatment, selective estrogen receptor modulators (raloxifene, BZA), bisphosphonates, strontium ranelate, denosumab, and teriparatide. This article reviews treatment options and provides treatment algorithms for women with menopausal symptoms.

Effects of low doses of esmolol on cardiac and vascular function in experimental septic shock.

BACKGROUND: Administration of a selective ß1-blocker, such as esmolol, in human septic shock has demonstrated cardiovascular protective effects related to heart rate reduction. Certain experimental data also indicate that esmolol exerts systemic anti-inflammatory and beneficial effects on vascular tone. Thus, the present study aimed to determine whether a non-chronotropic dose of esmolol maintains its protective cardiovascular and anti-inflammatory effects in experimental septic shock. METHODS: Four hours after cecal ligation and puncture (CLP), Wistar male rats were randomly allocated to the following groups (n = 8): CLP, CLP + E-1 (esmolol: 1 mg.kg-1.h-1), CLP + E-5 (esmolol: 5 mg.kg-1.h-1), CLP + E-18 (esmolol: 18 mg.kg-1.h-1). An additional eight rats underwent sham operation. All rats received a continuous infusion of saline, analgesic and antibiotics 4 hours after the surgery. Assessment at 18 hours included in vivo cardiac function assessed by echocardiography and ex vivo vasoreactivity assessed by myography. Circulating cytokine levels (IL-6 and IL-10) were measured by ELISA. Cardiac and vascular protein expressions of p-NF-κB, IκBα, iNOS, p-AKT/AKT and p-eNOS/eNOS were assessed by western blotting. RESULTS: CLP induced tachycardia, hypotension, cardiac output reduction, hyperlactatemia and vascular hypo-responsiveness to vasopressors. Compared to CLP animals, heart rate was unchanged in CLP + E-1 and CLP + E-5 but was reduced in CLP + E-18. Stroke volume, cardiac output, mean arterial pressure and lactatemia were improved in CLP + E-1 and CLP + E-5, while vascular responsiveness to phenylephrine was only improved in CLP + E-5 and CLP + E-18. Plasma IL-6 levels were decreased in all esmolol groups. p-NF-κB was decreased in both cardiac and vascular tissues in CLP + E-5 and CLP + E-18. CONCLUSION: In experimental septic shock, low doses of esmolol still improved cardiac function and vasoreactivity. These benefits appear to be associated with a modulation of inflammatory pathways.

Managing the menopause: An update.

Vasomotor symptoms (VMS), genito-urinary syndrome of menopause (GSM), sleep disturbance, sexual dysfunction and mood disturbance are common during the menopause transition. The degree of "bother" from symptoms should guide discussions about treatment. Moderate dose estrogen-containing hormone therapy (HT) is currently the most effective treatment for VMS and also improves vaginal dryness. The indication for HT is moderate to severe VMS in women without contraindications. It should not be prescribed or continued for the treatment of chronic disease. GSM can effectively be treated with vaginal (topical) estrogens. The dose, delivery system and duration of treatment for HT should be individualised to relieve symptoms. For most healthy women aged 50-59 years, the risks of HT are low. Several widely available non-hormonal agents can treat VMS for those who should avoid or do not wish to take estrogen. These include selected antidepressants and gaba-agonists.

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. METHODS: Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. RESULTS: We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. CONCLUSIONS: Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.

AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle.

The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels.

Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis.

OBJECTIVES: The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis. BACKGROUND: Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD). METHODS: Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product. RESULTS: Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p < 0.0001), and CFR (1.19 ± 0.38 vs. 2.23 ± 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function. CONCLUSIONS: Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.

Novel ligands balance estrogen receptor ß and α agonism for safe and effective suppression of the vasomotor response in the ovariectomized female rat model of menopause.

Vasomotor thermo-dysregulation (hot flashes) are an often debilitating symptom of menopause. Effective treatment is achieved primarily through activation of the estrogen receptor (ER)α with estrogens but is also associated with increased risk for breast and uterine cancer. In this study, we have tested novel compounds lacking the B ring of 17-hydroxy-ß-estradiol (E2) (A-CD compounds) with differing ratios of ERα:ERß binding affinities for the ability to reduce diurnal/nocturnal tail-skin temperatures (TSTs) in the ovariectomized female rat menopausal hot flash model. Normal mammary tissue expresses the predominantly antiproliferative ERß. Therefore, we hypothesized that a preferential ERß agonist with fractional ERα activity would safely reduce TSTs. The A-CD compound, L17, is a preferential ERß agonist that has a ratio of ERß:ERα binding affinity relative to E2 of 9.3 (where ERß:ERα for E2, 1.0). In the ovariectomized rat, daily administration of low doses (1 mg/kg) of the A-CD compound TD81 (ERα:ERß relative affinity, 15.2) was ineffective in temperature regulation, whereas L17 showed a trend toward TST reduction. Both E2 and the A-CD compound, TD3 (ERß:ERα relative affinity, 5.0), also reduced TSTs but had marked proliferative effects on mammary and uterine tissues. At 2 mg/kg, L17 strongly reduced TSTs even more effectively than E2 but, importantly, had only minimal effect on uterine weight and mammary tissues. Both E2- and L17-treated rats showed similar weight reduction over the treatment period. E2 is rapidly metabolized to highly reactive quinones, and we show that L17 has 2-fold greater metabolic stability than E2. Finally, L17 and E2 similarly mediated induction of c-fos expression in neurons within the rat thermoregulatory hypothalamic median preoptic nucleus. Thus, the A-CD compound, L17, may represent a safe and effective approach to the treatment of menopausal hot flashes.

Pathophysiology of coronary collaterals.

While the existence of structural adaptation of coronary anastomoses is undisputed, the potential of coronary collaterals to be capable of functional adaptation has been questioned. For many years, collateral vessels were thought to be rigid tubes allowing only limited blood flow governed by the pressure gradient across them. This concept was consistent with the notion that although collaterals could provide adequate blood flow to maintain resting levels, they would be unable to increase blood flow sufficiently in situations of increased myocardial oxygen demand. However, more recent studies have demonstrated the capability of the collateral circulation to deliver sufficient blood flow even during exertion or pharmacologic stress. Moreover, it has been shown that increases in collateral flow could be attributed directly to collateral vasomotion. This review summarizes the pathophysiology of the coronary collateral circulation, ie the functional adapation of coronary collaterals to acute alterations in the coronary circulation.

Impaired coronary microvascular reactivity in women with apical ballooning syndrome (Takotsubo/stress cardiomyopathy).

AIMS: The pathophysiology of apical ballooning syndrome (ABS) remains to be elucidated. The aim of this study was to evaluate the coronary vascular reactivity of patients who were previously diagnosed with ABS. METHODS AND RESULTS: A total of 228 cases of ABS were prospectively identified, and of these, 10 patients (median age 61 years (IQR 48-75); all females) who underwent coronary vasomotion testing were included in the study. Coronary epicardial and microvascular responses to intracoronary acetylcholine (ACH; % change in diameter and % change in blood flow at doses of 10(-6)-10(-4) mol/l), nitroglycerin (200-300 mg), and adenosine (36-60 µg) were evaluated. The median change in diameter with ACH was -9.3% (IQR -36.4, 3.2) with six patients (60%) demonstrating epicardial coronary constriction. The median increase in peak coronary blood flow in response to ACH was 13.1% (IQR -18.6, 55.0). This was markedly lower than the blood flow response seen in a reference group of 211 women from our laboratory (mean age 60 years) with normal microvascular responses to ACH: 103% (IQR 75, 149). Seven (70%) patients had <50% increase in coronary blood flow indicating abnormal microvascular response to ACH. 70% had either abnormal epicardial or microvascular response to ACH. Median coronary flow reserve was abnormal at 2.2% (IQR 2.0, 3.4; normal >2.5), and 90% had at least one abnormal measure of microvascular vasomotion. CONCLUSION: The novel observation is that coronary microvascular dysfunction is highly prevalent in patients with ABS. Thus, chronically impaired coronary vascular reactivity, especially involving the microcirculation, may be a central feature of the pathophysiology of ABS.

Menopause could be involved in the pathogenesis of muscle and joint aches in mid-aged women.

BACKGROUND: Muscle and joint aches (MJA) are frequently observed among menopausal women. They impair quality of life and are a burden to the healthcare system. OBJECTIVE: To analyze the relation between MJA and several variables related to the menopause. METHODS: In this cross-sectional study, 8373 healthy women aged 40-59 years, accompanying patients to healthcare centers in 18 cities of 12 Latin American countries, were asked to fill out the Menopause Rating Scale (MRS) and a questionnaire containing personal data. RESULTS: Mean age of the whole sample was 49.1±5.7 years, 48.6% were postmenopausal and 14.7% used hormone therapy (HT). A 63.0% of them presented MJA, with a 15.6% being scored as severe to very severe according to the MRS (scores 3 or 4). Logistic regression model determined that vasomotor symptoms (OR: 6.16; 95% CI, 5.25-7.24), premature menopause (OR: 1.58; 95% CI, 1.02-2.45), postmenopausal status (OR: 1.43; 95% CI, 1.20-1.69), psychiatric consultation (OR: 1.93; 95% CI, 1.60-2.32) and the use of psychotropic drugs (OR: 1.35; 95% CI, 1.08-1.69) were significantly related to the presence of severe-very severe MJA. Other significant variables included: age, tobacco consumption and lower education. Self perception of healthiness (OR: 0.49; 95% CI, 0.41-0.59), private healthcare access (OR: 0.77; 95% CI, 0.67-0.88) and HT use (OR: 0.75; 95% CI, 0.62-0.91) were significantly related to a lower risk for the presence of severe-very severe MJA. CONCLUSION: In this large mid-aged sample the prevalence of MJA was high, which was significantly associated to menopausal variables, especially vasomotor symptoms. This association may suggest a potential role of mid-life female hormonal changes in the pathogenesis of MJA.

Impaired vasomotor function induced by the combination of hypertension and hypercholesterolemia.

Although it is well known that endothelial function is compromised in the presence of either hypertension (HTN) or hypercholesterolemia (HCh), less is known about whether and how the combination of these risk factors (HTN+HCh) results in impaired endothelium-dependent dilation (EDD). The aims of this study were to evaluate the influence of HTN+HCh on vasomotor function and to identify the mechanisms that underlie the altered vascular reactivity elicited by HTN+HCh. Endothelium-dependent and -independent vasomotor responses of aortic vessels were studied in mice with diet-induced HCh and/or HTN induced by chronic administration of either angiotensin II (AngII) or deoxycorticosterone acetate-salt. HTN+HCh elicited an impairment of EDD that appeared between each risk factor alone. Incubation with catalase resulted in more severe EDD impairment. Each risk factor enhanced vascular H2O2 production, but a larger response was noted with HTN+HCh. An attenuated EDD was not observed in AngII type 1a receptor deficient (AT1r(-/-)) mice, but AT1r(-/-) bone marrow chimeras exhibited more profound impairment compared with wild-type. HTN+HCh does not exert an additive effect of vasomotor dysfunction compared with either risk factor alone, and both H2O2 and blood cell-associated AT1r contribute to the impaired EDD responses in mice with HTN+HCh.

Prevalence of vasomotor, psychological, psychosomatic and sexual symptoms in perimenopausal and recently postmenopausal Greek women: association with demographic, life-style and hormonal factors.

AIM: To assess the prevalence of climacteric symptoms and their association with demographic, life-style and hormonal parameters in Greek peri- and recently postmenopausal women. METHODS: 1025 Greek women who were either perimenopausal or within their first 5 postmenopausal years participated in this cross-sectional observational study. Menopausal symptoms were assessed by the Greene Climacteric Scale and were tested for associations with demographic, anthropometric, life-style and hormonal parameters. RESULTS: 29.8% Of the women reported moderate to severe menopausal symptoms. More specifically, 39.2% reported vasomotor, 21.3% psychological, 6.3% psychosomatic and 34.5% sexual symptoms. Years since menopause (r = 0.13, p < 0.01), waist circumference (r = 0.11, p < 0.05) as well as serum FSH, LH and estradiol (r = 0.15, r = 0.118, r = -0.157; p < 0.01) correlated with the intensity of menopausal symptoms. In the multivariate analysis years since menopause and serum estradiol were the only significant predictors of menopausal symptoms (b = -0.158 and b = -0.198, p < 0.001, respectively), explaining though only 4.8% of the variance. CONCLUSION: One out of three Greek women has moderate to severe climacteric symptoms during the menopause transition or the first postmenopausal years. This frequency is comparable to other White populations. Menopausal age and endogenous estrogens are significant predictors of climacteric symptoms.

Peripheral autonomic nerves of human pineal organ terminate on vessels, their supposed role in the periodic secretion of pineal melatonin.

Nonvisual pineal and retinal photoreceptors are synchronizing circadian and circannual periodicity to the environmental light periods in the function of various organs. Melatonin of the pineal organ is secreted at night and represents an important factor of this periodic regulation. Night illumination suppressing melatonin secretion may result in pathological events like breast and colorectal cancer. Experimental works demonstrated the role of autonomic nerves in the pineal melatonin secretion. It was supposed that mammalian pineals have lost their photoreceptor capacity that is present in submammalians, and sympathetic fibers would mediate light information from the retina to regulate melatonin secretion. Retinal afferentation may reach the organ by central nerve fibers via the pineal habenulae as well. In our earlier works we have found that the pineal organ developing from lobular evaginations of the epithalamus differs from peripheral endocrine glands and is composed of a retina-like central nervous tissue that is comprised of cone-like pinealocytes, secondary pineal neurons and glial cells. Their autonomic nerves in submammalians as well as in mammalian animals do not terminate on pineal cells, rather, they run in the meningeal septa among pineal lobules and form vasomotor nerve endings. Concerning the adult human pineal there are no detailed fine structural data about the termination of autonomic fibers, therefore, in the present work we investigated the ultrastructure of the human pineal peripheral autonomic nerve fibers. It was found, that similarly to other parts of the brain, autonomic nerves do not enter the human pineal nervous tissue itself but separated by glial limiting membranes take their course in the meningeal septa of the organ and terminate on vessels by vasomotor endings. We suppose that these autonomic vasomotor nerves serve the regulation of the pineal blood supply according to the circadian and circannual changes of the metabolic activity of the organ and support by this effect the secretion of pineal neurohormones including melatonin.

Vasomotor symptoms and lipid profiles in women transitioning through menopause.

OBJECTIVE: To examine associations between vasomotor symptoms and lipids over 8 years, controlling for other cardiovascular risk factors, estradiol, and follicle-stimulating hormone. METHODS: Study of Women's Health Across the Nation participants (N=3,201), aged 42-52 years at entry, completed interviews on frequency of hot flushes and night sweats (none, 1-5 days, 6 days or more, in the past 2 weeks) physical measures (blood pressure, height, weight), and blood draws (low-density lipoprotein [LDL], high-density lipoprotein [HDL], apolipoprotein A-1, apolipoprotein B, lipoprotein[a], triglycerides, serum estradiol, follicle-stimulating hormone) yearly for 8 years. Relations between symptoms and lipids were examined in linear mixed models adjusting for cardiovascular risk factors, medications, and hormones. RESULTS: Compared with no flushes, experiencing hot flushes was associated with significantly higher LDL (1-5 days: ß [standard error]=1.48 [0.47], P<.01; 6 days or more: ß [standard error]=2.13 [0.62], P<.001), HDL (1-5 days: ß [standard error]=0.30 [0.18]; 6 days or more: ß [standard error]=0.77 [0.24], P<.01), apolipoprotein A-1 (1-5 days: ß [standard error]=0.92 [0.47], P<.10; 6 days or more: ß [standard error]=1.97 [0.62], P<.01), apolipoprotein B (1-5 days: ß [standard error]=1.41 [0.41], P<.001; 6 days or more: ß [standard error]=2.51 [0.54], P<.001), and triglycerides (1-5 days: percent change [95% confidence interval]=2.91 [1.41-4.43], P<.001; 6 days or more: percent change [95% confidence interval[=5.90 [3.86-7.97], P<.001) in multivariable models. Findings largely persisted adjusting for hormones. Estimated mean differences in lipid levels between hot flushes 6 days or more compared with no days ranged from less than 1 (for HDL) to 10 mg/dL (for triglycerides). Night sweats were similar. Associations were strongest for lean women. CONCLUSION: Vasomotor symptoms were associated with higher LDL, HDL, apolipoprotein A-1, apolipoprotein B, and triglycerides. Lipids should be considered in links between hot flushes and cardiovascular risk. LEVEL OF EVIDENCE: II.

K(ATP) channel action in vascular tone regulation: from genetics to diseases.

ATP-sensitive potassium (K(ATP)) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The K(ATP) channels consist of 4 pore-forming inward rectifier K(+) channel (Kir) subunits and 4 regulatory sulfonylurea receptors (SUR). The major vascular isoform of K(ATP) channels is composed of Kir6.1/SUR2B, although low levels of other subunits are also present in vascular beds. The observation from transgenic mice and humans carrying Kir6.1/SUR2B channel mutations strongly supports that normal activity of the Kir6.1/SUR2B channel is critical for cardiovascular function. The Kir6.1/SUR2B channel is regulated by intracellular ATP and ADP. The channel is a common target of several vasodilators and vasoconstrictors. Endogenous vasopressors such as arginine vasopressin and α-adrenoceptor agonists stimulate protein kinase C (PKC) and inhibit the K(ATP) channels, while vasodilators such as ß-adrenoceptor agonists and vasoactive intestinal polypeptide increase K(ATP) channel activity by activating the adenylate cyclase-cAMP-protein kinase A (PKA) pathway. PKC phosphorylates a cluster of 4 serine residues at C-terminus of Kir6.1, whereas PKA acts on Ser1387 in the nucleotide binding domain 2 of SUR2B. The Kir6.1/SUR2B channel is also inhibited by oxidants including reactive oxygen species allowing vascular regulation in oxidative stress. The molecular basis underlying such a channel inhibition is likely to be mediated by S-glutathionylation at a few cysteine residues, especially Cys176, in Kir6.1. Furthermore, the channel activity is augmented in endotoxemia or septic shock, as a result of the upregulation of Kir6.1/SUR2B expression. Activation of the nuclear factor-κB dependent transcriptional mechanism contributes to the Kir6.1/SUR2B channel upregulation by lipopolysaccharides and perhaps other toll-like receptor ligands as well. In this review, we summarize the vascular K(ATP) channel regulation under physiological and pathophysiological conditions, and discuss the importance of K(ATP) channel as a potentially useful target in the treatment and prevention of cardiovascular diseases.