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Current evidence suggests that testosterone therapy has numerous benefits and risks on cardiovascular health. Examples of this include published data that support improvements in insulin sensitivity and body composition which may reduce the risk of diabetes. On the other hand, testosterone therapy may offset such benefits by mild impairments in lipid parameters. Consequently, controversy on the effects of testosterone therapy on cardiovascular health remains. Studies are underway to clarify this important question for the benefit of men with hypogonadism.

Dysfunctional reactive oxygen species (ROS) signaling is considered an important disease mechanism. Therapeutically, non-selective scavenging of ROS by antioxidants, however, has failed in multiple clinical trials to provide patient benefit. Instead, pharmacological modulation of disease-relevant, enzymatic sources of ROS appears to be an alternative, more promising and meanwhile successfully validated approach. With respect to targets, the family of NADPH oxidases (NOX) stands out as main and dedicated ROS sources. Validation of the different NOX isoforms has been mainly through genetically modified rodent models and is lagging behind in other species. It is unclear whether the different NOX isoforms are sufficiently distinct to allow selective pharmacological modulation. Here we show for five widely used NOX inhibitors that isoform selectivity can be achieved, although individual compound specificity is as yet insufficient. NOX1 was most potently (IC50) targeted by ML171 (0.1 mu M); NOX2, by VAS2870 (0.7 mu M); NOX4, by M13 (0.01 mu M) and NOX5, by ML090 (0.01 mu M). In addition, some non-specific antioxidant and assay artefacts may limit the interpretation of data, which included, surprisingly, the clinically advanced NOX inhibitor, GKT136901. In a human ischemic blood-brain barrier hyperpermeability model where genetic target validation is not an option, we provide proof-of-principle that pharmacological target validation for different NOX isoforms is possible by applying an inhibitor panel at IC50 concentrations. Moreover, our findings encourage further lead optimization and development efforts for isoform-selective NOX inhibitors in different indications.

The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function. The Tal1cko mutant mice are hyperactive, impulsive, hypersensitive to reward, have learning deficits and a habituation defect in a novel environment. Only minor changes in their dopaminergic system were detected. Amphetamine induced striatal dopamine release and amphetamine induced place preference were normal in Tal1cko mice. Increased dopamine signaling failed to stimulate the locomotor activity of the Tal1cko mice, but instead alleviated their hyperactivity. Altogether, the Tal1cko mice recapitulate many features of the attention and hyperactivity disorders, suggesting a role for Tal1 regulated developmental pathways and neural structures in the control of motivation and movement.

Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis. Fil: de Kloet, J. E. R.. Leiden University; Países Bajos Fil: Meijer, Onno C.. Leiden University; Países Bajos Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: de Rijk, Roel H.. Leiden University; Países Bajos Fil: Joëls, Marian. University of Utrecht; Países Bajos. University of Groningen; Países Bajos

Adenosine A2A receptors (A2ARs) are highly expressed in the human striatum, and at lower densities in the cerebral cortex, the hippocampus, and cells of the immune system. Antagonists of these receptors are potentially useful for the treatment of motor fluctuations, epilepsy, postischemic brain damage, or cognitive impairment, and for the control of an immune checkpoint during immunotherapy of cancer. A2AR agonists may suppress transplant rejection and graft-versus-host disease; be used to treat inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis; be locally applied to promote wound healing and be employed in a strategy for transient opening of the blood–brain barrier (BBB) so that therapeutic drugs and monoclonal antibodies can enter the brain. Increasing A2AR signaling in adipose tissue is also a potential strategy to combat obesity. Several radioligands for positron emission tomography (PET) imaging of A2ARs have been developed in recent years. This review article presents a critical overview of the potential therapeutic applications of A2AR ligands, the use of A2AR imaging in drug development, and opportunities and limitations of PET imaging in future research.

Supplemental Digital Content is available in the text., CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb−/− rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb−/− rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and cardiac hypertrophy in the spontaneously hypertensive rat. In silico analysis of the human CFB locus revealed 2 cis-regulated expression quantitative trait loci for CFB expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for CFB in the development of spontaneously hypertensive rat metabolic syndrome phenotypes and of related traits in humans and indicate the potential for CFB as a novel target for treatment of cardiometabolic disease.

The impact of disease-related changes in the extracellular matrix (ECM) on the mechanical properties of human resistance arteries largely remains to be established. Resistance arteries from both pig and human parietal pericardium (PRA) display a different ECM microarchitecture compared with frequently used rodent mesenteric arteries. We hypothesized that the biaxial mechanics of PRA mirror pressure-induced changes in the ECM microarchitecture. This was tested using isolated pig PRA as a model system, integrating vital imaging, pressure myography, and mathematical modeling. Collagenase and elastase digestions were applied to evaluate the load-bearing roles of collagen and elastin, respectively. The incremental elastic modulus linearly related to the straightness of adventitial collagen fibers circumferentially and longitudinally (both R2 ≥ 0.99), whereas there was a nonlinear relationship to the internal elastic lamina elastin fiber branching angles. Mathematical modeling suggested a collagen recruitment strain (means ± SE) of 1.1 ± 0.2 circumferentially and 0.20 ± 0.01 longitudinally, corresponding to a pressure of ~40 mmHg, a finding supported by the vital imaging. The integrated method was tested on human PRA to confirm its validity. These showed limited circumferential distensibility and elongation and a collagen recruitment strain of 0.8 ± 0.1 circumferentially and 0.06 ± 0.02 longitudinally, reached at a distending pressure below 20 mmHg. This was confirmed by vital imaging showing negligible microarchitectural changes of elastin and collagen upon pressurization. In conclusion, we show here, for the first time in resistance arteries, a quantitative relationship between pressure-induced changes in the extracellular matrix and the arterial wall mechanics. The strength of the integrated methods invites for future detailed studies of microvascular pathologies. NEW & NOTEWORTHY This is the first study to quantitatively relate pressure-induced microstructural changes in resistance arteries to the mechanics of their wall. Principal findings using a pig model system were confirmed in human arteries. The combined methods provide a strong tool for future hypothesis-driven studies of microvascular pathologies.

Consumption of foods rich in ferulic acid (FA) such as wholegrain cereals, or FA precursors such as chlorogenic acids in coffee, is inversely correlated with risk of cardiovascular disease and type 2 diabetes. As a result of digestion and phase II metabolism in the gut and liver, FA is converted predominantly into ferulic acid-4-O-sulfate (FA-sul), an abundant plasma metabolite. Although FA-sul may be the main metabolite, very little has been reported regarding its bioactivities. We have therefore compared the ex vivo vasorelaxing effect of FA and FA-sul (10−7 - 3.10−5 M) on isolated mouse arteries mounted in tissue myographs. FA-sul, but not FA, elicited a concentration-dependent vasorelaxation of saphenous and femoral arteries and aortae. The FA-sul mediated vasorelaxation was blunted by 1H- [1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor. The role of sGC was confirmed in femoral arteries isolated from sGCα1(−/−) knockout mice. Furthermore, 4-aminopyridine, a specific inhibitor of voltage-dependent potassium channels, significantly decreased FA-sul mediated effects. In anesthetized mice, intravenous injection of FA-sul decreased mean arterial pressure, whereas FA had no effect, confirming the results obtained ex vivo. FA-sul is probably one of the major metabolites accounting for the blood pressure-lowering effects associated with FA consumption.

Klotho is an anti-ageing protein that functions in many pathways that govern ageing, like regulation of phosphate homeostasis, insulin signaling, and Wnt signaling. Klotho expression levels and levels in blood decline during ageing. The vascular phenotype of Klotho deficiency features medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension, and impaired angiogenesis and vasculogenesis, with characteristics similar to aged human arteries.Klotho-deficient phenotypes can be prevented and rescued by Klotho gene expression or protein supplementation. High phosphate levels are likely to be directly pathogenic and are a prerequisite for medial calcification, but more important determinants are pathways that regulate cellular senescence, suggesting that deficiency of Klotho renders cells susceptible to phosphate toxicity. Overexpression of Klotho is shown to ameliorate medial calcification, endothelial dysfunction, and hypertension.Endogenous vascular Klotho expression is a controversial subject and, currently, no compelling evidence exists that supports the existence of vascular membrane-bound Klotho expression, as expressed in kidney. In vitro, Klotho has been shown to decrease oxidative stress and apoptosis in both SMCs and ECs, to reduce SMC calcification, to maintain the contractile SMC phenotype, and to prevent mu-calpain overactivation in ECs.Klotho has many protective effects with regard to the vasculature and constitutes a very promising therapeutic target. The purpose of this review is to explore the etiology of the vascular phenotype of Klotho deficiency and the therapeutic potential of Klotho in vascular disease. (C) 2016 Elsevier B.V. All rights reserved.

Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 mu M L-NAME), blockade of ETA-and ETB-receptors (10 mu M bosentan) and stimulation of the endothelium with 0.001-10 mu M acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. L-NAME (1) increased arterial contractile responses to K+ (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 mu M) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of L-NAME during contractions induced by either 10 mu M PHE or 40 mM K+ were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.

Purpose of reviewAngiotensin II is a main regulator of kidney function. Renal actions mediated by the angiotensin AT(1) receptor have been well known for many years. In contrast, several details of angiotensin AT(2) receptor actions in kidney physiology and pathophysiology were only described very recently. These findings are reviewed in this article.Recent findingsRegarding the role of the angiotensin AT(2) receptor in kidney physiology, a major recent finding was that the AT(2) receptor-mediated inhibition of Na+-H+ exchanger-3 and Na+/K+-ATPase in the renal proximal tubules is caused by internalisation of these transporters, thus reducing reabsorption and increasing natriuresis/diuresis. Regarding renal pathology, several studies demonstrated an attenuation of renal injury caused by diabetes or by obesity with or without high-salt diet through anti-inflammatory, antifibrotic, and antioxidative mechanisms. Generally, AT(2) receptor expression seems increased and AT(2) receptor-mediated effects stronger in female and obese animals.SummaryThe recent findings about the role of the angiotensin AT(2) receptor in renal health and disease strongly suggest that pharmacological targeting of this receptor with selective agonists is a promising therapeutic strategy for inducing diuresis/natriuresis (also additive to established diuretics) and for the treatment of diabetic nephropathy or kidney disease of other pathogenesis.

The aim of this review was to summarize collected data on the role of orexin and orexin neurons in the control of sleep and blood pressure. Although orexins (hypocretins) have been known for only 20 years, an impressive amount of data is now available regarding their physiological role. Hypothalamic orexin neurons are responsible for the control of food intake and energy expenditure, motivation, circadian rhythm of sleep and wake, memory, cognitive functions, and the cardiovascular system. Multiple studies show that orexinergic stimulation results in increased blood pressure and heart rate and that this effect may be efficiently attenuated by orexinergic antagonism. Increased activity of orexinergic neurons is also observed in animal models of hypertension. Pharmacological intervention in the orexinergic system is now one of the therapeutic possibilities in insomnia. Although the role of orexin in the control of blood pressure is well described, we are still lacking clinical evidence that this is a possibility for a new approach in the treatment of cardiovascular diseases.

Focal brain ischemia markedly affects cerebrovascular reactivity. So far, these changes have mainly been related to alterations in the level of smooth muscle cell function while alterations of the endothelial lining have not yet been studied in detail. We have, therefore, investigated the effects of ischemia/reperfusion injury on bradykinin (BK)-induced relaxation since BK is an important mediator of tissue inflammation and affects vascular function in an endothelium-dependent manner. Focal brain ischemia was induced in rats by endovascular filament occlusion (2h) of the middle cerebral artery (MCA). After 22h reperfusion, both MCAs were harvested and the response to BK studied in organ bath experiments. Expression of the BK receptor subtypes 1 and 2 (B-1, B-2) was determined by real-time semi-quantitative RT-qPCR methodology, and whole mount immunofluorescence staining was performed to show the B-2 receptor protein expression. In control animals, BK did not induce significant vasomotor effects despite a functionally intact endothelium and robust expression of B-2 mRNA. After ischemia/reperfusion injury, BK induced a concentration-related sustained relaxation in all arteries studied, more pronounced in the ipsilateral than in the contralateral MCA. The B-2 mRNA was significantly upregulated and the B-1 mRNA displayed de novo expression, again more pronounced ipsi- than contralaterally. Endothelial cells displaying B-2 receptor immunofluorescence were observed scattered or clustered in previously occluded MCAs. Relaxation to BK was mediated by B-2 receptor activation, abolished after endothelium denudation, and largely diminished by blocking nitric oxide (NO) release or soluble guanylyl cyclase activity. Relaxation to BK was partially inhibited by charybdotoxin (ChTx), but not apamin or iberiotoxin suggesting activation of an endothelium-dependent hyperpolarization pathway. When the NO-cGMP pathway was blocked, BK induced a transient relaxation which was suppressed by ChTx. After ischemia/reperfusion injury BK elicits endothelium-dependent relaxation which was not detectable in control MCAs. This gain of function is mediated by B-2 receptor activation and involves the release of NO and activation of an endothelium-dependent hyperpolarization. It goes along with increased B-2 mRNA and protein expression, leaving the functional role of the de novo B-1 receptor expression still open.

Background Chronic kidney disease increases stroke incidence and severity but the mechanisms behind this cerebro-renal interaction are mostly unexplored. Since both vascular beds share similar features, microvascular dysfunction could be the possible missing link. Therefore, we examined the relationship between renal function and cerebral autoregulation in the early hours post ischemia and its impact on outcome. Methods We enrolled 46 ischemic strokes (middle cerebral artery). Dynamic cerebral autoregulation was assessed by transfer function (coherence, phase and gain) of spontaneous blood pressure oscillations to blood flow velocity within 6 h from symptom-onset. Estimated glomerular filtration rate (eGFR) was calculated. Hemorrhagic transformation (HT) and white matter lesions (WML) were collected from computed tomography performed at presentation and 24 h. Outcome was evaluated with modified Rankin Scale at 3 months. Results High gain (less effective autoregulation) was correlated with lower eGFR irrespective of infarct side (p

Standard therapies for heart failure with preserved ejection fraction (HFpEF) have been unsuccessful, demonstrating that the contribution of the underlying diastolic dysfunction pathophysiology differs from that of systolic dysfunction in heart failure and currently is far from being understood. Complicating the investigation of HFpEF is the contribution of several comorbidities. Here, we selected three established rat models of diastolic dysfunction defined by three major risk factors associated with HFpEF and researched their commonalities and differences. The top differentially expressed genes in the left ventricle of Dahl salt sensitive (Dahl/SS), spontaneous hypertensive heart failure (SHHF), and diabetes 1 induced HFpEF models were derived from published data in Gene Expression Omnibus and used for a comprehensive interpretation of the underlying pathophysiological context of each model. The diversity of the underlying transcriptomic of the heart of each model is clearly observed by the different panel of top regulated genes: the diabetic model has 20 genes in common with the Dahl/SS and 15 with the SHHF models. Advanced analytics performed in Ingenuity Pathway Analysis (IPA (R)) revealed that Dahl/SS heart tissue transcripts triggered by upstream regulators lead to dilated cardiomyopathy, hypertrophy of heart, arrhythmia, and failure of heart. In the heart of SHHF, a total of 26 genes were closely linked to cardiovascular disease including cardiotoxicity, pericarditis, ST-elevated myocardial infarction, and dilated cardiomyopathy. IPA Upstream Regulator analyses revealed that protection of cardiomyocytes is hampered by inhibition of the ERBB2 plasma membrane-bound receptor tyrosine kinases. Cardioprotective markers such as natriuretic peptide A (NPPA), heat shock 27 kDa protein 1 (HSPB1), and angiogenin (ANG) were upregulated in the diabetes 1 induced model; however, the model showed a different underlying mechanism with a majority of the regulated genes involved in metabolic disorders. In conclusion, our findings suggest that multiple mechanisms may contribute to diastolic dysfunction and HFpEF, and thus drug therapies may need to be guided more by phenotypic characteristics of the cardiac remodeling events than by the underlying molecular processes.

IntroductionAvailable evidence suggests that the renin-angiotensin-aldosterone (RAA) system is a good target for medical intervention on aortic root dilatation in Marfan syndrome (MFS). The effect of Compound 21 (C21), a non-peptide angiotensin II type 2 receptor (AT2R) agonist on aneurysm progression is was tested.MethodsMice with a mutation in fibrillin-1 (Fbn1C1039G/+) and wild-type (WT) mice were treated with vehicle, losartan, C21, enalapril or a combination. Blood pressure, aortic root diameter, and histological slides were evaluated.ResultsAll groups had a comparable blood pressure. Echographic evaluation of the aortic root diameter revealed a protective effect of angiotensin II type 1 receptor (AT1R) antagonist (losartan) and no effect of C21 treatment. None of the treatments had a beneficial effect on the histological changes in MFS.DiscussionThis study confirms that AT1R antagonism (losartan) decreases aortic aneurysm growth in a mouse model of Marfan syndrome. A non-peptide AT2R agonist (C21), at the doses studied, is was ineffective. Future studies are warranted to further elucidate the exact role of the RAA system in aneurysm formation in Marfan syndrome and identify alternative targets for intervention.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. ispartof: Journal of Cardiovascular Pharmacology vol:71 issue:4 pages:215-222 ispartof: location:United States status: published

In endothelial cells, the tight control of the redox environment is essential for the maintenance of vascular homeostasis. The imbalance between ROS production and antioxidant response can induce endothelial dysfunction, the initial event of many cardiovascular diseases. Recent studies have revealed that the endoplasmic reticulum could be a new player in the promotion of the pro- or antioxidative pathways and that in such a modulation, the unfolded protein response (UPR) pathways play an essential role. The UPR consists of a set of conserved signalling pathways evolved to restore the proteostasis during protein misfolding within the endoplasmic reticulum. Although the first outcome of the UPR pathways is the promotion of an adaptive response, the persistent activation of UPR leads to increased oxidative stress and cell death. This molecular switch has been correlated to the onset or to the exacerbation of the endothelial dysfunction in cardiovascular diseases. In this review, we highlight the multiple chances of the UPR to induce or ameliorate oxidative disturbances and propose the UPR pathways as a new therapeutic target for the clinical management of endothelial dysfunction.

We aimed to assess the potential effects of hesperidin and capsaicin, independently and in combination, to prevent the development of obesity and its related metabolic alterations in rats fed an obesogenic diet. Three-month-old male Wistar rats were divided into 5 groups: Control (animals fed a standard diet), WD (animals fed a high fat/sucrose (western) diet), HESP (animals fed a western diet + hesperidin (100 mg/kg/day)), CAP (animals fed a western diet + capsaicin (4 mg/kg/day)), and HESP + CAP (animals fed a western diet + hesperidin (100 mg/kg/day) + capsaicin (4 mg/kg/day)). Hesperidin and capsaicin were administered by gavage. Capsaicin decreased body fat gain and prevented insulin resistance, whereas hesperidin showed little effect on body fat gain and no apparent effects on insulin resistance. No additive effects were observed with the combination. Capsaicin and hesperidin, separately, improved blood lipid profile, diminished hepatic lipid accumulation, and prevented non-alcoholic steatohepatitis in western diet-fed rats, but the combination showed lower effects. Hesperidin alone, and to a lesser extent capsaicin or the combination, displayed hypotensive effects in western diet-fed rats. In conclusion, capsaicin and hesperidin, separately, exhibit health beneficial effects on metabolic syndrome-related alterations in western diet-fed rats, but the effects are mitigated with the combination., This work was supported by the Spanish Government (AGL2015-67019-P), and the Instituto de Salud Carlos III, Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y Nutricion, CIBERobn. Laboratory of Molecular Biology, Nutrition and Biotechnology is a member of the European Research Network of Excellence NuGO (The European Nutrigenomics Organization, EU Contract: no. FP6-506360). A. Mosqueda-Solis is a recipient of a doctoral fellowship from the CONACYT (Mexico).

The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin–angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 ± 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1–7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that—at least in astrocytes—both receptors functionally depend on each other.

Blood pressure, renal hemodynamics, electrolyte, and water excretion all display diurnal oscillation. Disturbance of these patterns is associated with hypertension and chronic kidney disease. Kidney oxygenation is dependent on oxygen delivery and consumption that in turn are determined by renal hemodynamics and metabolism. We hypothesized that kidney oxygenation also demonstrates 24-h periodicity. Telemetric oxygen-sensitive carbon paste electrodes were implanted in Sprague-Dawley rats (250-300 g), either in renal medulla (n = 9) or cortex (n = 7). Arterial pressure (MAP) and heart rate (HR) were monitored by telemetry in a separate group (n = 8). Data from 5 consecutive days were analyzed for rhythmicity by cosinor analysis. Diurnal electrolyte excretion was assessed by metabolic cages. During lights-off, oxygen levels increased to 105.3 +/- 2.1% in cortex and 105.2 +/- 3.8% inmedulla. MAP was 97.3 +/- 1.5mmHg and HR was 394.0 +/- 7.9 bpm during lights-off phase and 93.5 +/- 1.3 mmHg and 327.8 +/- 8.9 bpm during lights-on. During lights-on, oxygen levels decreased to 94.6 +/- 1.4% in cortex and 94.2 +/- 8.5% in medulla. There was significant 24-h periodicity in cortex and medulla oxygenation. Potassium excretion (1,737 +/- 779 vs. 895 +/- 132 ae mol/12 h, P = 0.005) and the distal Na+/K+ exchange (0.72 +/- 0.02 vs. 0.59 +/- 0.02 P

International audience; While ageing is frequently associated with l-arginine deficiency, clinical and experimental studies provided controversial data on the interest of a chronic l-arginine supplementation with beneficial, no or even deleterious effects. It was hypothesized that these discrepancies might relate to a deviation of l-arginine metabolism towards production of l-ornithine rather than nitric oxide as a result of age-induced increase in arginase activity. This study investigated the effect of ageing on arginase activity/expression in target tissues and determined whether l-arginine supplementation modulated the effect of ageing on arginase activity. Arginase activity and expression were measured in the heart, vessel, brain, lung, kidney and liver in young rats (3-months old) and aged Wistar rats (22–24-months-old) with or without l-arginine supplementation (2.25% in drinking water for 6 weeks). Plasma levels of l-arginine and l-ornithine were quantified in order to calculate the plasma l-arginine/l-ornithine ratio, considered as a reflection of arginase activity. Cardiovascular parameters (blood pressure, heart rate) and aortic vascular reactivity were also studied. Ageing dramatically reduced plasma l-arginine and l-arginine/l-ornithine ratio, decreased liver and kidney arginase activities but did not change activities in other tissues. l-Arginine supplementation normalized plasma l-arginine and l-arginine/l-ornithine ratio, improved endothelial function and decreased systolic blood pressure. These effects were associated with decreased arginase activity in aorta along with no change in the other tissues except in the lung in which activity was increased. A strong mismatch was therefore observed between arginase activity and expression in analyzed tissues. The present study reveals that ageing selectively changes arginase activity in clearance tissues, but does not support a role of the arginase pathway in the potential deleterious effect of the l-arginine supplementation in aged patients. Moreover, our data argue against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate arginase activity in aged patients.

International audience; We evaluated the vasorelaxant effect of camel and bovine casein tryptic hydrolysates (CTH and BTH, respectively) and their mechanism of action in aorta and mesenteric artery of Wistar Kyoto rats. CTH produced a more potent relaxation than that induced by BTH. This relaxation was endothelium-dependent and was mediated through the activation of the nitric oxide (NO)/cyclic guanosine 3,5-monophosphate (cGMP) pathway. The intracellular level of cGMP was increased by CTH. Moreover, CTH-induced relaxation was inhibited by HOE 140, a B2 bradykinin receptors antagonist, indicating that B2 bradykinin receptors play a role in the CTH effect. In endothelium-intact mesenteric artery, CTH and BTH produced a similar concentration-dependent relaxation with a lesser maximal effect than in aortic rings. Moreover, this relaxation was inhibited by Nu nitro-L-arginine methyl ester hydrochloride, a NO synthase inhibitor, but the addition of indomethacin, a cyclooxygenase inhibitor, and tetraethylammonium, a K+ channels blocker did not potentiate the inhibition.

International audience; We investigated the contribution of blood flow elevation in the cerebrovasculature to physical training-induced brain-derived neurotrophic factor (BDNF) levels elevation in the brain. Brain-derived neurotrophic factor protein levels were measured in the motor cortex 24 h after the last session of a forced treadmill walking (30 minutes a day, 18 m/minute for 7 consecutive days). Unilateral common carotid artery occlusion and modulation of exercise intensity (0 versus -10% inclination of the treadmill) were used as strategies to reduce the (normal) elevation of flow in the cerebrovasculature occurring during exercise. Administration of N-nitro-L-arginine methyl ester (L-NAME, 60 mg/kg before each exercise sessions) and genetic hypertension (spontaneously hypertensive rats) were used as approaches to reduce stimulation of nitric oxide production in response to shear stress elevation. Vascular occlusion totally and partially abolished the effect of physical training on BDNF levels in the hemisphere ipsilateral and contralateral to occlusion, respectively. BDNF levels were higher after high than low exercise intensity. In addition, both genetic hypertension and L-NAME treatment blunted the effects of physical training on BDNF. From these results, we propose that elevation of brain BDNF levels elicited by physical training involves changes in cerebral hemodynamics.

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases.

I Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in proteinuria is insufficient in many patients, and does not prevent further deterioration of renal function. Short-term studies have shown that a variety of treatment intensification strategies have a beneficial effect on blood pressure and proteinuria, including RAAS blockade using either dose escalation or multiple drugs, and restriction of dietary sodium. Large clinical trials have shown that RAAS blockade with multiple drugs does not improve patients' long-term renal or cardiovascular outcome. By contrast, two post-hoc analyses of landmark trials in nephrology show beneficial renal and cardiovascular effects from avoiding excessive dietary sodium intake during single-agent RAAS blockade therapy. The effects of dietary sodium restriction on renal or cardiovascular outcome still require prospective confirmation. However, current data support the implementation of lifestyle changes to reduce dietary sodium intake in combination with single-agent RAAS blockade, rather than dual-agent RAAS blockade, as a potent and feasible strategy to mitigate the burden of renal and cardiovascular disease in patients with CKD. Lambers Heerspink, H. J. et al. Nat. Rev. Nephrol. 9, 112-121 (2013); published online 18 December 2012; doi:10.1038/nrneph.2012.281

I Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in proteinuria is insufficient in many patients, and does not prevent further deterioration of renal function. Short-term studies have shown that a variety of treatment intensification strategies have a beneficial effect on blood pressure and proteinuria, including RAAS blockade using either dose escalation or multiple drugs, and restriction of dietary sodium. Large clinical trials have shown that RAAS blockade with multiple drugs does not improve patients' long-term renal or cardiovascular outcome. By contrast, two post-hoc analyses of landmark trials in nephrology show beneficial renal and cardiovascular effects from avoiding excessive dietary sodium intake during single-agent RAAS blockade therapy. The effects of dietary sodium restriction on renal or cardiovascular outcome still require prospective confirmation. However, current data support the implementation of lifestyle changes to reduce dietary sodium intake in combination with single-agent RAAS blockade, rather than dual-agent RAAS blockade, as a potent and feasible strategy to mitigate the burden of renal and cardiovascular disease in patients with CKD. Lambers Heerspink, H. J. et al. Nat. Rev. Nephrol. 9, 112-121 (2013); published online 18 December 2012; doi:10.1038/nrneph.2012.281

PURPOSE OF REVIEW: Angiotensin II is a main regulator of kidney function. Renal actions mediated by the angiotensin AT1 receptor have been well known for many years. In contrast, several details of angiotensin AT2 receptor actions in kidney physiology and pathophysiology were only described very recently. These findings are reviewed in this article.RECENT FINDINGS: Regarding the role of the angiotensin AT2 receptor in kidney physiology, a major recent finding was that the AT2 receptor-mediated inhibition of Na-H exchanger-3 and Na/K-ATPase in the renal proximal tubules is caused by internalisation of these transporters, thus reducing reabsorption and increasing natriuresis/diuresis. Regarding renal pathology, several studies demonstrated an attenuation of renal injury caused by diabetes or by obesity with or without high-salt diet through anti-inflammatory, antifibrotic, and antioxidative mechanisms. Generally, AT2 receptor expression seems increased and AT2 receptor-mediated effects stronger in female and obese animals.SUMMARY: The recent findings about the role of the angiotensin AT2 receptor in renal health and disease strongly suggest that pharmacological targeting of this receptor with selective agonists is a promising therapeutic strategy for inducing diuresis/natriuresis (also additive to established diuretics) and for the treatment of diabetic nephropathy or kidney disease of other pathogenesis.

Klotho is an anti-ageing protein that functions in many pathways that govern ageing, like regulation of phosphate homeostasis, insulin signaling, and Wnt signaling. Klotho expression levels and levels in blood decline during ageing. The vascular phenotype of Klotho deficiency features medial calcification, intima hyperplasia, endothelial dysfunction, arterial stiffening, hypertension, and impaired angiogenesis and vasculogenesis, with characteristics similar to aged human arteries. Klotho-deficient phenotypes can be prevented and rescued by Klotho gene expression or protein supplementation. High phosphate levels are likely to be directly pathogenic and are a prerequisite for medial calcification, but more important determinants are pathways that regulate cellular senescence, suggesting that deficiency of Klotho renders cells susceptible to phosphate toxicity. Overexpression of Klotho is shown to ameliorate medial calcification, endothelial dysfunction, and hypertension. Endogenous vascular Klotho expression is a controversial subject and, currently, no compelling evidence exists that supports the existence of vascular membrane-bound Klotho expression, as expressed in kidney. In vitro, Klotho has been shown to decrease oxidative stress and apoptosis in both SMCs and ECs, to reduce SMC calcification, to maintain the contractile SMC phenotype, and to prevent mu-calpain overactivation in ECs. Klotho has many protective effects with regard to the vasculature and constitutes a very promising therapeutic target. The purpose of this review is to explore the etiology of the vascular phenotype of Klotho deficiency and the therapeutic potential of Klotho in vascular disease. (C) 2016 Elsevier B.V. All rights reserved.

International audience; Background and purpose: Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its overactivity in obesity is thought to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesized that early MRA treatment may target obesity-related disorders and consequently delay the development of HF.Experimental approach: Twenty spontaneously hypertensive HF dyslipidaemic obese SHHF(cp/cp) rats and 18 non-dyslipidaemic lean SHHF(+/+) controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA treatment [eplerenone (eple), 100 mg∙kg(-1) ∙day(-1) ] from 1.5 to 12.5 months of age.Key results: Eleven months of eple treatment in obese rats (SHHF(cp/cp) eple) reduced the obesity-related metabolic disorders observed in untreated SHHF(cp/cp) rats by reducing weight gain, triglycerides and total cholesterol levels and by preserving adiponectinaemia. The MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating the eccentric cardiac hypertrophy observed in untreated SHHF(cp/cp) animals and preserving ejection fraction (70 ± 1 vs. 59 ± 1%). The MRA also improved survival independently of these pressure effects.Conclusion and implications: Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF(+/+) and SHHF(cp/cp) rats, whereas SHHF(cp/cp) rats further benefited from the MRA treatment through a reduction in their obesity and dyslipidaemia. These findings suggest that preventive MRA therapy may provide greater benefits in obese patients with additional risk factors of developing cardiovascular complications.

Bradykinin exerts its vascular actions via two types of receptors, the non-constitutively expressed bradykinin receptor type 1 (BR1) and the constitutive type 2 receptor (BR2). Bradykinin-induced vasorelaxation is age-dependent, a phenomenon related to the varying amounts of BR1 and BR2 in the vasculature. Isoleucine-proline-proline (Ile-Pro-Pro), a bioactive tripeptide, lowers elevated blood pressure and improves impaired endothelium-dependent vasorelaxation in hypertensive rats. It inhibits angiotensin converting enzyme 1 (ACE1). Other mechanisms of action have also been postulated. The aims of the study were to clarify the underlying mechanisms of the age-dependency of bradykinin-induced vasodilatation such as the roles of the two bradykinin receptors, themas-receptor and synergism with Ile-Pro-Pro. The vascular response studies were conducted using mesenteric artery and aorta rings from normotensive 6 wk. (young) and 22 wk. (old) Wistar rats. Cumulative dosing of acetylcholine, bradykinin and angiotensin(1-7) (Ang(1-7))were tested in phenylephrine-induced vasoconstriction with or without 10 min pre-incubation with antagonists against BR1-, BR2- or mas-receptors,Ang(1-7) or ACE1-inhibitors captopril and Ile-Pro-Pro. The bradykinin-induced vasorelaxation in vitro was age-dependent and it was improved by pre incubation with Ile-Pro-Pro, especially in old rats with endothelial dysfunction. The mas-receptor antagonist, D-Pro7-Ang(1-7) abolished bradykinin-induced relaxation totally. Interestingly, BR1 and BR2 antagonists only slightly reduced bradykinin-induced vasorelaxation, as an evidence for the involvement of other mechanisms in addition to receptor activation. In conclusion, bradykinin-induced vasorelaxation was age -dependent and He-Pro-Pro improved it. Mas receptor antagonist abolished relaxation while bradykinin receptor antagonist only slightly reduced it, suggesting that bradykinin-induced vasorelaxation is regulated also by other mechanisms than the classical BR1/BR2 pathway. (C) 2016 Elsevier Inc: All rights reserved.

Background: Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been evaluated together with an active control in an international clinical study. Objective: Assess tadalafil or tamsulosin versus placebo for LUTS/BPH. Design, setting, and participants: A randomised, double-blind, international, placebo-controlled, parallel-group study assessed men >= 45 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) >= 13, and maximum urinary flow rate (Q(max)) >= 4 to 0.1). The International Index of Erectile Function-Erectile Function domain improved versus placebo with tadalafil (4.0; p < 0.001) but not tamsulosin (-0.4; p = 0.699). Q(max) increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). Adverse event profiles were consistent with previous reports. This study was limited in not being powered to directly compare tadalafil versus tamsulosin. Conclusions: Monotherapy with tadalafil or tamsulosin resulted in significant and numerically similar improvements versus placebo in LUTS/BPH and Q(max). However, only tadalafil improved erectile dysfunction. Trial registration: Clinicaltrials. gov ID NCT00970632 (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Agents interfering with the renin-angiotensin system (RAS) system were consistently shown to lower the incidence of type 2 diabetes (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on glucose metabolism are not fully understood. In this paper, we will review the evidence from randomized-controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, since T2DM is characterized by beta-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in beta-cell function and insulin sensitivity.

Aldosterone, a steroid hormone with mineralocorticoid activity, is far more than merely a salt-and-water hormone. Aldosterone has a number of non-classical, mineralocorticoid receptor (MR)-mediated actions, including tissue remodeling, modulation of vascular tone and stimulating inflammation and fibrosis, which may fuel progression of end organ damage. Aldosterone breakthrough during blockade of the renin-angiotensin aldosterone system (RAAS) may explain why this treatment regimen only confers partial cardiovascular and renal protection. Of major interest, aldosterone is deleterious only if inappropriately high for its sodium status i.e. high aldosterone and high sodium. The mechanism of sodium dependence of aldosterone-induced renal and cardiovascular damage continues to fascinate. Aldosterone excess increases sodium and fluid retention and consequently increases blood pressure, which, in turn, mediates target organ damage. Moreover, blood pressure independent effects play a role with dissociation of low circulating and high tissue aldosterone levels during high sodium intake and possibly enhanced MR signaling. MR blockade is a valuable strategy, which has potency to halt the progressive end organ damage as observed during current treatments. In heart failure, MR blockade on top of RAAS blockade reduces hard clinical endpoints. Despite encouraging results on the intermediate endpoint proteinuria, long-term data on the efficacy and safety of MR blockade in preventing dialysis and/or cardiovascular endpoints in chronic kidney disease are still lacking. It is obligatory that future clinical studies on the effects of MR blockade on end-organ damage take into account the sodium status.

Background: Chronic renal failure (CRF) is associated with hypertension, proteinuria, loss of myogenic constriction (MC) of mesenteric arteries and increased production of reactive oxygen species (ROS) under experimental conditions. Previous results showed that ACE (angiotensin-converting enzyme activity) inhibitor therapy is effective in slowing down the progression of disease. Therefore, we wanted to study whether the inverse AT1(angiotensin II type 1) receptor agonist, losartan (LOS) was effective in preventing loss of MC in a rat model of CRF and whether acute ROS scavengers could improve MC.Methods: Rats underwent 5/6 nephrectomy (5/6 Nx) and were treated with vehicle or LOS (20 mg/kg/day; 5/6 Nx + LOS) for 12 weeks. Thereafter, the MC of the mesenteric arteries were measured in the presence and/or absence of tempol and catalase. Systolic blood pressure and proteinuria were measured weekly.Results: Systolic blood pressure and proteinuria in the 5/6 Nx + LOS group were significantly lower than in the 5/6 Nx group. Moreover, the MC of 5/6 Nx + LOS arteries was significantly increased compared with the untreated 5/6 Nx group (maximum MC, 32.3 ± 6.9 vs 8.9 ± 3.8% (p < 0.01)). Tempol + catalase significantly increased the MC in the 5/6 Nx group, but not in the 5/6 Nx + LOS group (increase in MC, 59.7 ± 13.0 (p < 0.05) vs. 17.0 ± 15.1%).Conclusion: These results support the roles of the RAAS (renin—angiotensin—aldosterone system) and ROS in the vascular dysfunction of systemic vessels in CRF.

Seaweed is more than the wrap that keeps rice together in sushi. Seaweed biomass is already used for a wide range of other products in food, including stabilising agents. Biorefineries with seaweed as feedstock are attracting worldwide interest and include low-volume, high value-added products and vice versa. Scientific research on bioactive compounds in seaweed usually takes place on just a few species and compounds. This paper reviews worldwide research on bioactive compounds, mainly of nine genera or species of seaweed, which are also available in European temperate Atlantic waters, i.e. Laminaria sp., Fucus sp., Ascophyllum nodosum, Chondrus crispus, Porphyra sp., Ulva sp., Sargassum sp., Gracilaria sp. and Palmaria palmata. In addition, Undaria pinnatifida is included in this review as this is globally one of the most commonly produced, investigated and available species. Fewer examples of other species abundant worldwide have also been included. This review will supply fundamental information for biorefineries in Atlantic Europe using seaweed as feedstock. Preliminary selection of one or several candidate seaweed species will be possible based on the summary tables and previous research described in this review. This applies either to the choice of high value-added bioactive products to be exploited in an available species or to the choice of seaweed species when a bioactive compound is desired. Data are presented in tables with species, effect and test organism (if present) with examples of uses to enhance comparisons. In addition, scientific experiments performed on seaweed used as animal feed are presented, and EU, US and Japanese legislation on functional foods is reviewed.

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.

Intervention in the RAAS (renin-angiotensin-aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type I receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1-7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factor signalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1-7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. Furthermore, aldosterone, bradykinin and AcSDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type I receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.

Therapeutic modulation of the renin-angiotensin system is not complete without taking into consideration the beneficial effects of angiotensin-(1-7) in cardiovascular pathology. Various pharmacological pathways are already exploited to involve this heptapeptide in therapy as both inhibitors of angiotensin-converting enzyme and angiotensin II type 1 receptor blockers increase its levels. These drugs and administered angiotensin-(1-7) elicit various common effects, and some effects of the drugs are partially mediated by angiotensin-(1-7). The pharmacodynamic profile of angiotensin-(1-7) is rather complex, and in vitro and in vivo studies demonstrated a wide palette of effects for angiotensin-(1-7), some of them potentially beneficial for cardiovascular disease. Using various animal models to study cardiovascular physiology and disease it was shown that angiotensin-(1-7) has antihypertensive, antihypertrophic, antifibrotic and antithrombotic properties, all properties that may prove beneficial in a clinical setting. We also observed a novel action of angiotensin-(1-7), namely its capacity to stimulate the proliferation of endothelial progenitor cells. Access of angiotensin-(1-7) to the clinic, however, is restricted due to its unfavorable pharmacokinetic properties. In order to benefit of the therapeutic potential of angiotensin-(1-7) it is crucial to increase its half-life, either by using more stable analogues, which are now under development, or specific delivery methods. We here review the pharmacological characteristics and therapeutic potential of angiotensin-(l-7), implementing the experimental strategies taken to exploit the pharmacological mechanism of this heptapeptide in a clinical setting, and present our contribution to this field of research. (C) 2008 Elsevier B.V. All rights reserved.

Therapeutic modulation of the renin-angiotensin system is not complete without taking into consideration the beneficial effects of angiotensin-(1-7) in cardiovascular pathology. Various pharmacological pathways are already exploited to involve this heptapeptide in therapy as both inhibitors of angiotensin-converting enzyme and angiotensin II type 1 receptor blockers increase its levels. These drugs and administered angiotensin-(1-7) elicit various common effects, and some effects of the drugs are partially mediated by angiotensin-(1-7). The pharmacodynamic profile of angiotensin-(1-7) is rather complex, and in vitro and in vivo studies demonstrated a wide palette of effects for angiotensin-(1-7), some of them potentially beneficial for cardiovascular disease. Using various animal models to study cardiovascular physiology and disease it was shown that angiotensin-(1-7) has antihypertensive, antihypertrophic, antifibrotic and antithrombotic properties, all properties that may prove beneficial in a clinical setting. We also observed a novel action of angiotensin-(1-7), namely its capacity to stimulate the proliferation of endothelial progenitor cells. Access of angiotensin-(1-7) to the clinic, however, is restricted due to its unfavorable pharmacokinetic properties. In order to benefit of the therapeutic potential of angiotensin-(1-7) it is crucial to increase its half-life, either by using more stable analogues, which are now under development, or specific delivery methods. We here review the pharmacological characteristics and therapeutic potential of angiotensin-(l-7), implementing the experimental strategies taken to exploit the pharmacological mechanism of this heptapeptide in a clinical setting, and present our contribution to this field of research. (C) 2008 Elsevier B.V. All rights reserved.

There is convincing evidence that angiotensin II, through activation of the angiotensin II type 1 (AT1) receptor, is involved in the atherosclerotic process. Similarly, angiotensin receptor blockers decrease vascular inflammation, hypertrophy and thrombosis, which are the key components of the progression of atherosclerosis. In addition, in several animal models, angiotensin receptor blockade was able to inhibit atherosclerosis. However, the effects of angiotensin receptor blockers on clinical outcome in cardiovascular patients remains to be established. Contradictory results have been found on the reduction of the risk on myocardial infarctions and in-stent restenosis, although there is solid evidence for cerebroprotective effects of these receptor blockers. These differences may be related to the role of the AT2 receptor. This review discusses the role of angiotensin II and angiotensin receptor blockers in the atherosclerotic process and its translation into clinical practice.

It has been suggested a role of fatty acid ethanolamides in control of feeding behavior. Among these, palmitoylethanolamide (PEA) has not been directly implicated in appetite regulation and weight gain. The aim of this study was to investigate the effect of PEA on food intake and body weight and the interaction between PEA and hypothalamic leptin signaling in ovariectomized rats. Ovariectomy produced hyperphagia and increased weight gain, making it an useful model of mild obesity. Ovariectomized rats were treated with PEA (30 mg/kg sc) for 5 weeks. Then, blood was collected, and hypothalamus and adipose tissue were removed for histological, cellular, and molecular measurements. We showed that PEA caused a reduction of food intake, body weight, and fat mass. The mechanisms underlying PEA effects involved an improvement in hypothalamic leptin signaling, through a raise in signal transducer and activator of transcription 3 phosphorylation. We also reported that PEA reduced AMP-activated protein kinase-α phosphorylation and modulated transcription of anorectic and orexigenic neuropeptides in the hypothalamus. Moreover, PEA increased AMP-activated protein kinase-α phosphorylation and carnitine palmitoyltransferase 1 transcription in adipose tissue, suggesting an increase in ATP-producing catabolic pathway. PEA also polarized adipose tissue macrophages to M2 lean phenotype, associated to a reduction of inflammatory cytokines/adipokines. To demonstrate the direct effect of PEA on leptin sensitivity without interference of adiposity loss, we obtained consistent data in PEA-treated sham-operated animals and in vitro in SH-SY5Y neuroblastoma cell line. Therefore, our data provide a rationale for the therapeutic use of PEA in obese postmenopausal woman.

Increased activation of the renin-angiotensin system (RAS) has been related to cardiovascular disease and type 2 diabetes mellitus. Most randomized clinical trials have demonstrated that RAS blockade reduces the incidence of type 2 diabetes, which has been explained by improved insulin secretion and insulin sensitivity. In this review, an overview of the mechanisms that may underlie the association between the RAS and type 2 diabetes will be provided, with focus on skeletal muscle and adipose tissue function. This will include discussion of several human studies performed in our laboratory to investigate the metabolic and hemodynamic effects of the RAS, combining in vivo measurements of whole-body and tissue metabolism with molecular and immunohistochemical approaches. Available data suggest that the detrimental effects of the RAS on insulin secretion are mediated by a reduction in pancreatic blood flow and induction of islet fibrosis, oxidative stress as well as inflammation, whereas both impaired skeletal muscle function and adipose tissue dysfunction may underlie RAS-induced insulin resistance. Thus, although future studies in humans are warranted, current evidence supports that targeting the RAS in intervention studies may improve metabolic and cardiovascular function in conditions of insulin resistance like obesity and type 2 diabetes. Copyright (c) 2012 S. Karger GmbH, Freiburg.

Context: Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent. Objective: Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with alpha 1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH). Evidence acquisition: A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, alpha-blockers, and alpha 1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology. Evidence synthesis: Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with alpha 1-adrenergic blockers versus alpha 1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p < 0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p < 0.0001) but not the maximum flow rate (Q(max)) (-0.00; p = not significant) at the end of the study as compared with placebo. The association of PDE5-Is and alpha 1-adrenergic blockers improved the IIEF score (+3.6; p < 0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p < 0.0001) at the end of the study as compared with alpha-blockers alone. Conclusions: The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Context: This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies. Objective: We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS. Evidence acquisition: We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction. Evidence synthesis: We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH. Conclusions: Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some alpha-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of alpha-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and alpha 1-adrenergic blockers seems superior to PDE5-I monotherapy. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Background. Several studies in patients with primary aldosteronism (PA) have suggested that aldosterone (ALD) is directly contributing to albuminuria. However, there are limited data pertaining to the direct role of ALD in in vivo models in regard to the induction of renal injury and the involved mechanisms. In the present study, we established a high-dose ALD-infused rat model to evaluate urinary albumin excretion rate (UAER) and podocyte damage. Moreover, we studied the effect of eplerenone (EPL), telmisartan (TEL) and amlodipine (AML) on ALD-induced renal structural and functional changes. Methods. Immunohistochemical and real-time PCR analyses, and TUNEL assays were performed to evaluate nephrin expression and podocyte injury. Results. ALD-receiving rats (ARR) showed a progressive increase in BP, UAER and proteinuria when compared with control rats (CR). Conversely, BP was significantly reduced in ALD + EPL (A/ERR)-, ALD + AML (A/ARR)- and ALD + TEL (A/TRR)-treated rats. However, UAER and proteinuria were decreased only in A/ERR and A/TRR, but not in A/ARR. Only EPL administration provided protection against ALD-induced podocyte apoptosis. Renal tissue of ARR revealed enhanced expression of nephrin protein and mRNA. This effect of ALD was inhibited by EPL, but not by TEL or AML. Conclusions. ALD induces direct glomerular injury independent of its haemodynamic effects; this effect of ALD is, at least in part, mediated through activation of the mineralocorticoid receptor.