Adrenomedullin Levels Research Articles

The role of adrenomedullin and galanin in recurrent vasovagal syncope: a case control study

Orthostatic stimuli are known to elicit changes in vasoactive peptide levels. The hypothesis of no difference in adrenomedullin and/or galanin levels in patients with recurrent vasovagal syncope and healthy controls was tested in a passive 35-min head-up tilt test (HUTT). Twenty eight persons (14 patients and 14 healthy controls) were tested in a 35-min/60° head-up tilt test with telemetry monitoring. Three blood samples were evaluated for each person during the HUTT. Plasma levels of adrenomedullin and galanin were analysed by the Kruskal-Wallis test for all sampling periods. Vagal influence was indirectly assessed by the break index. There were no significant differences between groups in median values for either adrenomedullin or galanin plasma levels (all 6 p-values were greater than 0.4). For adrenomedullin, no significant difference between groups was found. For galanin, the rate of change between the 1st and 2nd measurement was significantly greater for patients (P=0.04), regardless of HUTT result but between the 2(nd) and 3(rd) measurement it was insignificant (P=0.36). In the group of positive cases, the break index increased significantly (P=0.02). We confirmed that there is a different galanin secretion pattern during orthostatic provocation in patients with recurrent vasovagal syncope than healthy individuals. For adrenomedullin, no significant difference was found. Asignificant increment of the break index confirmed increased vagal influence in the subgroup of positive cases.

Adrenomedullins: Therapeutic Potential in Cardiovascular Disease

Cardiovascular disease is a leading cause of death and disability and despite advances in treatment there remains an ongoing need to develop new therapeutic interventions. Accumulating evidence points towards an important role for the adrenomedullin (AM) family of peptides in pressure/volume homeostasis and indicate potential as therapeutic agents in a variety of clinical settings including cardiovascular disease. Plasma levels of AM are raised in cardiovascular disease in proportion to severity of cardiac dysfunction and are useful prognostic indicators of outcome. AM administration in both experimental and human heart failure induces a beneficial spectrum of biological action including reduced arterial and atrial pressures, improved cardiac output, inhibition of plasma aldosterone and preservation or augmentation of urinary sodium excretion. Experimental data also supports a role for AM in cardioprotection in cardiac ischemia/reperfusion injury and in the progression of heart failure following myocardial infarction. Thus, strategies to manipulate the AM system may prove beneficial as adjunctive therapy in cardiovascular disease. Keywords: Adrenomedullin, cardiovascular disease, heart failure, myocardial infarction, plasma levels, prognosis, homeostasis, renin-angiotensin-aldosteron system

Adrenomedullin in Heart Failure: Molecular Mechanism and Therapeutic Implication

Many neurohumoral factors play an important role in regulation of the cardiovascular system and in the pathophysiology of heart failure. Adrenomedullin (AM) is a potent long-lasting vasodilatory peptide that was discovered in acid extracts of human pheochromocytoma tissues. Both AM and its gene expression are widely distributed in the cardiovascular system, including the heart, vessels, and kidneys. AM co-localizes with its receptor components such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the heart, vessels and kidneys, suggesting that it plays an important role in the regulation of cardiovascular function through an autocrine and/or paracrine mechanism. AM has inotropic action in vitro and in vivo and inhibits cardiac hypertrophy in myocytes as well as proliferation and collagen production in cardiac fibroblasts. These results suggest that AM functions as an antifibrotic, antihypertrophic and positive inotropic factor in the failing heart. In addition, AM has anti-apoptotic, angiogenic, anti-inflammatory and anti-oxidant effects. Several mechanisms such as cAMP/PKA, NO/cGMP, PI-3K/Akt and/or ERK are thought to mediate cellular AM signaling, suggesting that increased AM levels play a protective role in heart failure. Indeed, acute AM administration exerts beneficial vasodilatory, diuretic, natriuretic and inotropic effects on experimental and human heart failure. A recent pilot study has shown that AM has potential as a therapeutic drug in the clinical setting of acute decompensated heart failure. Keywords: Adrenomedullin, heart failure, antifibrotic effects, cardiovascular diseases, neurohumoral factors, cAMP response

Ethanol Consumption Alters the Expression and Reactivity of Adrenomedullin in the Rat Mesenteric Arterial Bed

Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on arterial blood pressure, vascular reactivity to AM and the expression of AM system components in the rat mesenteric arterial bed (MAB). Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Systolic, diastolic and mean arterial blood pressure were monitored in conscious rats. Vascular reactivity experiments were performed on isolated rat MAB. Matrix metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation were measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, CRLR (calcitonin receptor-like receptor) and RAMP1, 2 and 3 (receptor activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively. Ethanol consumption induced hypertension and decreased the relaxation induced by AM and acetylcholine in endothelium-intact rat MAB. Phenylephrine-induced contraction was increased in endothelium-intact MAB from ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 or the net MMP activity in the rat MAB. Ethanol consumption increased mRNA levels of pre-pro-AM and protein levels of AM in the rat MAB. Finally, no differences in protein levels or mRNA of CRLR and RAMP1, 2 and 3 were observed after treatment with ethanol. Our study demonstrates that ethanol consumption increases blood pressure and the expression of AM in the vasculature and reduces the relaxation induced by this peptide in the rat MAB.

Biomarkers of Left Ventricular Hypertrophy and Remodeling in Blacks

Left ventricular (LV) hypertrophy, a marker for adverse cardiovascular events, is more common in blacks than in non-Hispanic whites. Mechanisms leading to LV hypertrophy and mediating its clinical sequelae in blacks are not fully understood. We investigated the associations of 39 candidate biomarkers in distinct biological pathways with LV mass and geometry in blacks. Participants included 1193 blacks (63±9 years of age; 72% women; 78% hypertensive) belonging to hypertensive sibships. LV mass was measured by transthoracic echocardiography and indexed to height.(2.7) LV geometry was categorized as normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Generalized estimating equations were used to assess associations of the 39 biomarkers with LV mass index after adjustment for age, sex, and conventional risk factors. After adjustment for potential confounders, log-transformed levels of the following biomarkers were independently associated with LV mass index: N-terminal pro-brain natriuretic peptide (β±SE=0.07±0.01 pg/mL; P<0.0001), mid-regional pro-atrial natriuretic peptide (β±SE=0.08±0.02 pmol/L; P<0.0001), mid-regional pro-adrenomedullin (β±SE=0.09±0.03 nmol/L; P=0.0006), C-terminal pro-endothelin (β± SE=0.05±0.02 pmol/L; P=0.0009), and osteoprotegerin (β±SE=0.07±0.02 pg/mL; P=0.0005) (β is for 1 log increase in biomarker level). The associations of these biomarkers with LV mass index were mainly due to their association with eccentric hypertrophy. Higher circulating levels of natriuretic peptides, adrenomedullin, endothelin, and osteoprotegerin were associated with increased LV mass index, providing insights into the pathophysiology of LV hypertrophy in blacks.

Epicardial adipose tissue and its association to plasma adrenomedullin levels in patients with metabolic syndrome

ObjectiveTo assess the association between epicardial adipose tissue (EAT) thickness and plasma adrenomedullin plasma levels in patients with metabolic syndrome (MS). MethodsTwenty-one patients (12 females and 9 males) with MS according to the International Diabetes Federation guidelines, aged 22–58 years, were enrolled into the study and compared to 19 age-matched control subjects without MS. Plasma glucose, lipid, and adrenomedullin levels were assessed. EAT, left ventricular mass, and carotid intima–media thickness were evaluated by transthoracic two-dimensional echocardiography. ResultsNo statistically significant differences were found between the groups in age, sex, and height. Body weight, abdominal circumference (AC), body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly higher (p=0.0001) in MS patients; this group also showed significantly higher glucose (p=0.001), total cholesterol (p=0.01), LDL-C (p=0.03), VLDL-C (p=0.005), triglyceride (p=0.002), Tg/HDL ratio (p=0.0001), and plasma adrenomedullin (3.49±1.21 vs 1.69±0.92ng/mL; p=0.0001) levels and lower HDL-C (p=0.02) levels as compared to the control group. EAT was significantly thicker in MS patients compared to the control group (8.45±3.14 vs 5.43±0.96; p=0.0001), showed a positive correlation to BMI (r=0.347; p=0.02), AC (r=0.350; p=0.02), DBP (r=0.346; p=0.02), and adrenomedullin levels (r=0.741; p=0.0001). In multiple linear regression analysis, adrenomedullin was the only parameter associated to EAT (R2=0.550; p=0.0001). ConclusionIn this small patient group, a statistically significant association was found between EAT and plasma adrenomedullin levels, which may be considered as a potential biomarker of MS.

The relationship of adrenomedullin and left ventricular remodeling in older patients with essential hypertension

ObjectiveTo investigate the relationship of adrenomedullin (ADM) and left ventricular remodeling in older patients with essential hypertension.Methods77 essential hypertension patients were divided into normal left ventricular group (normal group), left...

Changes in Adrenomedullin in Patients with Proliferative Diabetic Retinopathy

Purpose: To measure adrenomedullin (ADM) levels in the blood, vitreous fluid and fibrous membrane in patients with proliferative diabetic retinopathy (PDR) and study its changes in different pathological conditions.Methods: We used radioimmunoassay technique to determine immunoreactive- adrenomedullin (IR-ADM) concentrations in the plasma, vitreous samples and fibrous membrane obtained from 9 control subjects with idiopathic macular hole and 23 patients with PDR undergoing vitrectomy.Results: IR-ADM levels in the plasma, vitreous samples and fibrous membrane tissues (16.1 ± 2.91fmol/ml, 9.80 ± 2.51fmol/ml and 34.8 ± 5.22fmol/mg) were all significantly elevated in patients with PDR compared with control subjects (11.6 ± 2.38 fmol/ml, 5.8 ± 1.64 fmol/ml and 22.4 ± 1.72 fmol/mg). The levels of ADM in vitreous were also significantly higher in PDR patients with diabetic macular edema (DME) (11.2 ± 2.36 fmol/ml) than those of patients without DME (8.0 ± 1.11 fmol/ml) and controls (5.8 ± 1.64 fmol/ml).Conclusions: These findings suggest that ADM may be produced locally in the eyes and may correlate with the severity and proliferative reactions of diabetic retinopathy.

Plasma adrenomedullin levels in children with asthma: Any relation with atopic dermatitis?

BackgroundAsthma is a chronic, inflammatory disease of the airway, and adrenomedullin (ADM) may have some effects against bronchoconstriction. However, the role(s) of ADM in asthmatic children have not been evaluated yet. The aims of this study were to determine if there are any changes in plasma ADM levels during acute asthma attack, and to search for any association between allergen sensitivity and ADM level in asthmatic children. MethodsTwenty-seven children with acute asthma attack, ranging in age from 5 to 15 years were investigated and compared with 20 controls. Plasma ADM levels (ng/mL) were measured by ELISA method. ResultsNo significant difference was found in ADM levels between the controls and patients in either the acute attack or remission period. Plasma ADM levels were significantly higher in the acute attack (p=0.043) compared to the remission period in patients who were considered as having a “severe attack” according to GINA (Global Initiative for Asthma) classification. There were statistically significant correlations between the patients’ AlaTOP and Food Panel 7 levels and plasma ADM levels in the acute attack period (p=0.010, p=0.001, respectively). The ADM levels in patients with a history of atopic dermatitis were significantly higher in the acute attack period compared to those without a history of atopic dermatitis (p=0.007). ConclusionWe speculate that ADM may have a role in children with atopic dermatitis, and may also have a role in the immuno-inflammatory process of asthma.

Nitric oxide mediated activation of adrenomedullin and matrix metalloproteinases-2 and -9 in women with endometriosis undergoing IVF

Adrenomedullin (ADM), a vasodilator peptide, is reported to participate in the growth and differentiation of the endometrium. Its function is mediated at least partly by nitric oxide (NO). Association of intrafollicular concentration of ADM in women with endometriosis undergoing IVF is not reported so far. The aim of the present study is to examine NO mediated activation of ADM and matrix metalloproteinases (MMP) -2 and -9 in women with endometriosis undergoing IVF. Follicular fluid (FF) was collected from 80 women with endometriosis and 50 normal ovulating women with tubal factor infertility (controls) at the time of oocyte retrieval. These women were reporting to the Institute of Reproductive Medicine, Kolkata, India for IVF treatment. All women were of age between 26 and 38 years. Expression of ADM, MMP-2 and -9 in FF was assessed using Western blot and their quantitative analysis done by ELISA. Total nitrite level, measured as an index of NO, was measured using spectrophotometry. Intrafollicular levels of NO, ADM, MMP-2 and MMP-9 were found to be significantly higher in endometriosis as compared to controls. A significant positive correlation was observed between NO level and expression of ADM (r = 0.491, P<0.0001), MMP-2 (r = 0.602, P<0.0001) and MMP-9 (r = 0.758, P<0.0001), respectively. In addition, IVF outcome parameters were adversely affected in endometriosis compared with controls. The findings suggest that increased NO level in endometriosis activates the production of ADM and MMPs which promote angiogenesis and excessive matrix degradation, respectively. While NO, MMP-2 and -9 correlated well with IVF outcome, no relationship existed between FF concentrations of ADM and IVF success rate. Drug induced regulation of NO may be considered as a potential option for improving IVF outcome in endometriosis.

Adrenomedullin in rat follicles and corpora lutea: expression, functions and interaction with endothelin-1

BackgroundAdrenomedullin (ADM), a novel vasorelaxant peptide, was found in human/rat ovaries. The present study investigated the interaction of ADM and endothelin-1 (ET-1) in follicles and newly formed corpora lutea (CL) and the actions of ADM on progesterone production in CL during pregnancy.MethodsThe peptide and gene expression level of adrenomedullin in small antral follicles, large antral follicles and CL was studied by real-time RT-PCR and EIA. The effect of ADM treatment on oestradiol production in 5-day follicular culture and on progesterone production from CL of different pregnant stages was measured by EIA. The interaction of ADM and ET-1 in follicles and CL at their gene expression level was studied by real-time RT-PCR.ResultsIn the rat ovary, the gene expression of Adm increased during development from small antral follicles to large antral follicles and CL. In vitro treatment of preantral follicular culture for 5 days with ADM increased oestradiol production but did not affect follicular growth or ovulation rate. The regulation of progesterone production by ADM in CL in culture was pregnancy-stage dependent, inhibitory at early and late pregnancy but stimulatory at mid-pregnancy, which might contribute to the high progesterone production rate of the CL at mid-pregnancy. Moreover, the interaction between ADM and ET-1 at both the production and functional levels indicates that these two vasoactive peptides may form an important local, fine-tuning regulatory system together with LH and prolactin for progesterone production in rat CL.ConclusionsAs the CL is the major source of progesterone production even after the formation of placenta in rats, ADM may be an important regulator in progesterone production to meet the requirement of pregnancy.

Chronic ethanol consumption reduces adrenomedullin-induced relaxation in the isolated rat aorta

Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on vascular reactivity to AM and the expression of AM system components in the rat aorta. Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Vascular reactivity experiments were performed in the isolated rat aorta. Metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation was measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, calcitonin receptor-like receptor (CRLR) and RAMP1, 2, and 3 (receptor-activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively. Ethanol intake reduced AM-induced relaxation in endothelium-intact rat aortas, whereas calcitonin gene-related peptide-, acetylcholine-, and sodium nitroprusside-induced relaxation were not affected by ethanol intake. N G-nitro- l-arginine-methyl-ester ( l-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and tetraethylammonium reduced AM-induced relaxation in aortic rings from both control and ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 in the rat aorta. Ethanol consumption increased mRNA levels of pre-pro-AM and RAMP1. Protein levels of AM, CRLR, and RAMP1, 2, and 3 were not affected by ethanol consumption. The major findings of the present study are that ethanol consumption reduces the vascular relaxation induced by AM and changes the mRNA expression of the components of the AM system in the vasculature. This response could be one of the mechanisms by which ethanol predisposes individuals to vascular dysfunction and hypertension.

Daikenchuto (TU-100) ameliorates colon microvascular dysfunction via endogenous adrenomedullin in Crohn’s disease rat model

Daikenchuto (TU-100), a traditional Japanese medicine, has been reported to up-regulate the adrenomedullin (ADM)/calcitonin gene-related peptide (CGRP) system, which is involved in intestinal vasodilatation. The microvascular dysfunction of the intestine in Crohn's disease (CD), due to down-regulation of the ADM/CGRP system, is etiologically related to the recurrence of CD. Therefore, we investigated the vasodilatory effect of TU-100 in a CD rat model. Colitis was induced by the rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. Laser Doppler blood flowmetry was used to measure colonic blood flow. ADM, CGRP, and their receptors in the ischemic colon were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme immunoassays. Additionally, we determined whether the intestinal epithelial cell line IEC-6 released ADM in response to TU-100. TU-100 increased blood flow in ischemic segments of the colon but not in hyperemic segments. Pretreatment with an antibody to ADM abolished the vasodilatory effect of TU-100. CGRP levels and βCGRP mRNA expression were decreased in the ischemic colon, while protein and mRNA levels of ADM were unchanged. Hydroxy α-sanshool, the main constituent of TU-100, was the most active component in improving blood flow. Additionally, both TU-100 and hydroxy α-sanshool enhanced the release of ADM from IEC-6 cells. In the ischemic colon, endogenous βCGRP, but not ADM, was decreased. Thus, it was concluded that TU-100 ameliorated microvascular dysfunction by the up-regulation of endogenous ADM in the CD rat model. TU-100 may be a possible therapeutic agent for gastrointestinal ischemia-related diseases including CD.

Plasma adrenomedullin level is related to a single nucleotide polymorphism in the adrenomedullin gene

Adrenomedullin (ADM) plays an important role in inflammation and is a marker of future cardiovascular events. We studied common single nucleotide polymorphisms (SNPs) in the gene encoding ADM and their relationship with the plasma levels of ADM and other inflammatory markers. Plasma ADM, interleukin 6 (IL6), fibrinogen, and C-reactive protein (CRP) were measured in 476 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study-2. Four tag SNPs in ADM were genotyped. Plasma ADM level increased with decreasing plasma IL6 level (β=-0.116, P=0.014). Plasma ADM level was not related to plasma levels of CRP and fibrinogen, and other clinical characteristics, except age (P=0.049). The four SNPs, rs3814700, rs11042725, rs34354539, and rs4910118, had minor allele frequencies of 31.1, 28.7, 33.8, and 23.4% respectively. Carriers of the minor allele of rs4910118 had a mean plasma ADM level that was 10.5% (95% confidential interval: 2.5-17.8%) lower than the non-carriers (β=-0.115, P=0.011). Haplotype analysis revealed a similar significant association with plasma ADM (P=0.040). In multivariate analysis, the presence of the minor allele of rs4910118, but not plasma IL6, was independently associated with plasma ADM (P=0.010). Plasma ADM correlates with plasma IL6 level, consistent with its role in inflammation. It is related to an SNP common in Chinese, independent of other covariates. ADM genotype should be included in future studies of cardiovascular risk prediction.

Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome.

The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

Stroke is a leading cause of death and the primary medical cause of acquired adult disability worldwide. The progressive brain injury after acute stroke is partly mediated by ischemia-elicited inflammatory responses. The vasoactive hormone adrenomedullin (AM), upregulated under various inflammatory conditions, counterbalances inflammatory responses. However, regulation of AM activity in ischemic stroke remains largely unknown. Recent studies have demonstrated the presence of a specific AM binding protein (that is, AMBP-1) in mammalian blood. AMBP-1 potentiates AM biological activities. Using a rat model of focal cerebral ischemia induced by permanent middle cerebral artery occlusion (MCAO), we found that plasma levels of AM increased significantly, whereas plasma levels of AMBP-1 decreased significantly after stroke. When given peripherally early after MCAO, exogenous human AM in combination with human AMBP-1 reduced brain infarct volume 24 and 72 h after MCAO, an effect not observed after the treatment by human AM or human AMBP-1 alone. Furthermore, treatment of human AM/AMBP-1 reduced neuron apoptosis and morphological damage, inhibited neutrophil infiltration in the brain and decreased serum levels of S100B and lactate. Thus, human AM/AMBP-1 has the ability to reduce stroke-induced brain injury in rats. AM/AMBP-1 can be developed as a novel therapeutic agent for patients with ischemic stroke.

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction

BackgroundIt is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. Methods20 men complaining vascular ED (mean IIEF5=12±6 and peak systolic velocity-PSV=24±2cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59±11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). ResultsPatients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r2=0.22; p<0.005). The proportion of patients with an IIEF5 score of ≥22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline. ConclusionsWe demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels.

Role of Biomarkers in Exacerbation of Chronic Obstructive Pulmonary Disease

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are the main actuators of disease-related costs, morbidity, and mortality. Early and adequate recognition of an acute exacerbation as well as an individualized treatment is important to minimize mortality, morbidity, and worsening of lung function. However, the distinction of day-to-day variation of symptoms from exacerbations remains a clinical challenge. Accordingly, the use of laboratory parameters to improve the diagnostic accuracy in AECOPD is an area of continuous interest. In this article, we review the most relevant literature concerning the value of biological circulating blood markers for the diagnosis, assessment of morbidity as well as short-term and long-term survival in patients with COPD exacerbations. Potentially useful biomarkers at exacerbation of COPD might reflect inflammation and infection (C-reactive protein, procalcitonin, interleukin-6, serum interferon-γ–inducible protein), cardiac stress (copeptin, brain natriuretic peptide, atrial natriuretic peptide, pro-adrenomedullin, pro-endothelin), and other pathophysiological mechanisms (leptin and adiponectin, fibrinogen, surfactant protein D). So far, no biomarker has been established to possess the required high sensitivity and specificity for the definite diagnosis of AECOPD. Evidence supports the use of procalcitonin for antibiotic guidance in patients with AECOPD. Re-hospitalization and death within 6 months were particularly common in patients with high copeptin levels at exacerbation. Brain natriuretic peptide identifies patients requiring intensive care. Pro-atrial natriuretic peptide and pro- adrenomedullin levels at exacerbation are associated with a poor long-term survival after exacerbation. Considering the predictive value of serum biomarkers for the assessment of disease severity and outcome, they potentially play a major role in the individualization of therapy in COPD.

Sulforaphane and Rebamipide Protect Small Intestinal Mucosa From Indomethacin-Induced Injury Through Different Mechanisms in Mice In Vivo

Background and Aims: Postoperative peritoneal adhesion formation frequently occurs and remains a major problem after abdominal surgery. Daikenchuto (TU-100), a traditional Japanese oral medicine, prevents peritoneal adhesion after abdominal surgery. However, the precise mechanism of action is still unclear. We recently reported that 6-shogaol (6SG) and hydroxy α-sanshool (HAS), the main ingredients in TU-100, are absorbed in humans and can enhance the endogenous anti-fibrotic and anti-inflammatory peptide, adrenomedullin (ADM). The peritoneal fibrinolytic system is crucial for peritoneal adhesion formation. The present study assessed the mechanism of ADM production and the fibrinolytic responses of mesothelial cells to inflammatory factors to determine the anti-adhesion mechanism of TU-100. Methods: Test samples were added to cultures of the rat mesothelial cell line 4/ 4RM-4. After 6 to 24 h, the levels of ADM, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) in the culture supernatants were measured by EIA and RT-PCR. The active ingredients of TU-100 in the blood of rats that were orally administered TU-100 were measured by LC-Ms/Ms. Results: ADM production by 4/4RM-4 cells was significantly increased upon the addition of 6SG and HAS, which were efficiently absorbed into the circulation within 30 minutes after oral administration. Because these compounds activate the transient receptor potential (TRP) V1 and A1 channels, the TRPA1 agonist allyl isothiocyanate (AITC) and TRPV1 agonist capsaicin (CAP) were evaluated in the ADM production test. AITC, but not CAP, was active and increased ADM production. This activity of 6SG, HAS and AITC was significantly abolished by also adding the TRPA1 antagonist HC-030031. RT-PCR analysis demonstrated that 4/4RM-4 cells expressed messenger RNA for TRPA1 but not TRPV1. Inflammatory mediators IL-6, TNFα, and lipopolysaccharide (LPS) upregulated PAI-1, but not tPA, production by 4/4RM-4 cells. Conversely, ADM downregulated PAI-1 without affecting tPA, and moreover inhibited IL-6 and TNFα production by immune cells. Conclusions: ADM can restore the imbalance in the fibrinolytic