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There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ETA receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.British Journal of Pharmacology (2008) 153, 1105–1119; doi:10.1038/sj.bjp.0707516; published online 29 October 2007 [ABSTRACT FROM AUTHOR]

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized. [ABSTRACT FROM AUTHOR]

The ability of glucocorticoids to directly alter arterial function, structure and the inflammatory response to vascular injury may contribute to their well-established link with the development of cardiovascular disease. Recent studies have emphasised the importance of tissue-specific regulation of glucocorticoid availability by the 11 β-hydroxysteroid dehydrogenase (11HSD) isozymes, which inter-convert active glucocorticoids and their inactive metabolites. The expression of both type 1 and type 2 11HSDs in the arterial wall suggests that prereceptor metabolism of glucocorticoids may have a direct impact on vascular physiology. Indeed there is evidence that 11HSDs influence glucocorticoid-mediated changes in vascular contractility, vascular structure, the inflammatory response to injury and the growth of new blood vessels. Hence, inhibition of 11HSD isozymes may provide a novel therapeutic target in vascular disease. [ABSTRACT FROM AUTHOR]

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids, amplifying intracellular actions. 11β-HSD1 deficiency or inhibition improves metabolic syndrome and attenuates atherosclerosis in vulnerable rodent strains and is a target for drug development. However, 11β-HSD1 also catalyses conversion of 7-ketocholesterol,5 which accumulates in fatty tissues,6 to potentially more atherogenic 7β-hydroxycholesterol. Whether atheroprotection with 11β-HSD1 deficiency is dependent on glucocorticoid or oxysterol effects is unknown. Male atherosclerosis-prone ApoE-/- and ApoE-/-.11β-HSD1-/- double knockout (DKO) mice underwent adrenalectomy or sham surgery (n=8/group), then received a high (0.2%) cholesterol Western diet for 12-weeks. The aorta and branches were perfusion-fixed. Lesion volume and extracellular lipids were determined by 3D optical projection tomography. Data are mean±SE of the means. Adrenalectomy had no effect on body/organ weights in either genotype. Removal of endogenous glucocorticoids by adrenalectomy in ApoE-/- mice did not reduce lesion volume (232±24 vs 235±34-α/4m³ sham control). DKO mice had reduced lesion volumes (139±17-α/4m³) compared with ApoE-/- (p<0.05). Adrenalectomy reversed this effect (263±52-α/4m³). Adrenalectomised DKO mice had increased extracellular lipids (73.6±2.6-α/4m³) within the lesion compared with either ApoE-/- adrenalectomised (37.4±5.2-α/4m³), ApoE-/- sham (42.9±5.5-α/4m³) or DKO sham (44.2±12-α/4m³) group. Thus circulating glucocorticoids are necessary for 11β-HSD1 deficiency to attenuate atherosclerosis. However, 11β-HSD1 deficiency increases the lipid content of plaques in the absence of glucocorticoids, perhaps owing to accumulation of 7-ketocholesterol? Consequently, both reactions of 11β-HSD1 may be involved in the effects of the enzyme on atherogenesis. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) in utero influence embryonic development with consequent programmed effects on adult physiology and pathophysiology and altered susceptibility to cardiovascular disease. However, in viviparous species, studies of these processes are compromised by secondary maternal influences. The zebrafish, being fertilised externally, avoids this problem and has been used here to investigate the effects of transient alterations in GC activity during early development. Embryonic fish were treated either with dexamethasone (a synthetic GC), an antisense GC receptor (GR) morpholino (GR Mo), or hypoxia for the first 120 h post fertilisation (hpf); responses were measured during embryonic treatment or later, post treatment, in adults. All treatments reduced cortisol levels in embryonic fish to similar levels. However, morpholino- and hypoxia-treated embryos showed delayed physical development (slower hatching and straightening of head-trunk angle, shorter body length), less locomotor activity, reduced tactile responses and anxiogenic activity. In contrast, dexamethasone-treated embryos showed advanced development and thigmotaxis but no change in locomotor activity or tactile responses. Gene expression changes were consistent with increased (dexamethasone) and decreased (hypoxia, GR Mo) GC activity. In adults, stressed cortisol values were increased with dexamethasone and decreased by GR Mo and hypoxia pre-treatments. Other responses were similarly differentially affected. In three separate tests of behaviour, dexamethasone-programmed fish appeared 'bolder' than matched controls, whereas Mo and hypoxia pre-treated fish were unaffected or more reserved. Similarly, the dexamethasone group but not the Mo or hypoxia groups were heavier, longer and had a greater girth than controls. Hyperglycaemia and expression of GC responsive gene (pepck) were also increased in the dexamethasone group. We conclude that GC activity controls many aspects of early-life growth and development in the zebrafish and that, like other species, manipulating GC status pharmacologically, physiologically or genetically in early life leads to programmable metabolic and behavioural traits in adulthood. [ABSTRACT FROM AUTHOR]

Background: Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males.Methods: Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks.Results: DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females.Conclusions: Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females. [ABSTRACT FROM AUTHOR]

Key points Glucocorticoids are known to be present in the developing zebrafish embryo but little is known about their physiological role at this early stage., The zebrafish embryo demonstrates a functional glucocorticoid system from around 48 h post fertilisation., This system and the stress response is amenable to pharmacological and genetic manipulation in a manner predicted by mammalian physiology., Glucocorticoids play a key developmental role in hatching, swimming and stress response., The zebrafish embryo is a relevant model for the study of glucocorticoid physiology., Abstract While glucocorticoids (GCs) are known to be present in the zebrafish embryo, little is known about their physiological roles at this stage. We hypothesised that GCs play key roles in stress response, hatching and swim activity during early development. To test this, whole embryo cortisol (WEC) and corticosteroid-related genes were measured in embryos from 6 to 120 h post fertilisation (hpf) by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). Stress response was assessed by change in WEC following stirring, hypoxia or brief electrical impulses applied to the bathing water. The impact of pharmacological and molecular GC manipulation on the stress response, spontaneous hatching and swim activity at different stages of development was also assessed. WEC levels demonstrated a biphasic pattern during development with a decrease from 0 to 36 hpf followed by a progressive increase towards 120 hpf. This was accompanied by a significant and sustained increase in the expression of genes encoding cyp11b1 (GC biosynthesis), hsd11b2 (GC metabolism) and gr (GC receptor) from 48 to 120 hpf. Metyrapone (Met), an inhibitor of 11β-hydroxylase (encoded by cyp11b1), and cyp11b1 morpholino (Mo) knockdown significantly reduced basal and stress-induced WEC levels at 72 and 120 hpf but not at 24 hpf. Spontaneous hatching and swim activity were significantly affected by manipulation of GC action from approximately 48 hpf onwards. We have identified a number of key roles of GCs in zebrafish embryos contributing to adaptive physiological responses under adverse conditions. The ability to alter GC action in the zebrafish embryo also highlights its potential value for GC research. [ABSTRACT FROM AUTHOR]

Background/aims: Endothelial cell dysfunction in the ocular circulation may contribute to normal pressure glaucoma (NPG). This study aimed to investigate the contributions made by endothelium derived relaxing factors to relaxation of (1) subcutaneous resistance arteries from patients with NPG, and (2) porcine ciliary arteries. Methods: Human gluteal resistance arteries were isolated from seven patients with NPG and matched controls. Human and porcine arteries produced endothelium dependent relaxation when exposed to acelylcholine (ACh) (10-9 -3 × 10-5 M) or bradykinin (10-10 -3 × 10-6 M). Pharmacological agents were used to inhibit the nitric oxide pathway (L-arginine analogues, soluble guanylate cyclase inhibitor), endothelium derived hyperpolarising factor (EDHF) activity (potassium channel antagonists), and prostaglandin synthesis (cyclo-oxygenase inhibitors). Results: In all arteries, endothelium dependent relaxation was attenuated by nitric oxide (NO) inhibition or potassium channel blockade, but not by cyclo-oxygenase inhibition. Inhibition of ACh mediated relaxation by potassium channel antagonists was greater (p<0.05) in patients with NPG (Emax, 55.4% (SD 8.16%) relaxation, n =4) than controls (Emax, 81.8% (6.0%), n = 5). In contrast, combined inhibition of NO synthase (NOS) and cyclo-oxygenase produced similar inhibition of ACh mediated relaxation in both groups. Conclusions: The enhanced contribution of EDHF to ACh mediated relaxation in systemic resistance arteries from NPG patients may contribute to the maintained endothelium mediated relaxation in these vessels. EDHF also contributes significantly to bradykinin mediated relaxation in porcine ocular ciliary arteries. Therefore, similar changes in the balance of relaxing factors in the ocular circulation could influence the response of the eye to vascular endothelial dysfunction in NPG. [ABSTRACT FROM AUTHOR]

An abstract of the article "Myeloid Cell 11β-HSD1 Regulates the Inflammatory Response During Myocardial Infarct Healing and Protects the Heart From Detrimental Remodeling After Irradiation and Bone Marrow Transfer," by K. J. Mylonas and colleagues is presented.

Air pollution has been linked to the development of atherosclerosis and cardiovascular disease. Diesel exhaust particulate (DEP) accounts for a substantial proportion of urban air pollution but its effects on atherogenesis are unknown. We hypothesised that DEP will exacerbate plaque formation in a murine model of atherosclerosis. Apolipoprotein E knockout (ApoE) mice (10-12 weeks; n=16) were fed a 'Western diet-tm) (21% cholesterol) for 8 weeks to induce the development of 'complex-tm) atherosclerotic plaques. During the last 4 weeks of feeding, mice underwent twice-weekly intratracheal instillation of 35 α/4l DEP (1 mg/ml; National Institute of Standards and Technology) or vehicle (saline). Histological sections of the brachiocephalic artery from ApoE knockout mice showed large, foam cell-filled fibrous plaques. Plaque burden was increased (p=0.025; n=5-6) in DEP-treated mice (69±9%) compared with vehicle-treated controls (42±7%). Furthermore, plaques from DEP-treated mice exhibited a greater number of adjoining (2.3±0.2%) and buried (1.2±0.3%) fibrous caps than control mice (1.7±0.2% and 0.2±0.1%, respectively; p<0.05 n=5). There was no evidence of systemic inflammation, increased circulating blood lipids or endothelial dysfunction in DEP-treated animals. This is the first study to show that pulmonary exposure to the particulate matter within diesel exhaust enhances atherogenesis. This action may, therefore, contribute to the increased cardiovascular morbidity and mortality associated with air pollution. This model will allow identification of the constituents of DEP that mediate this atherogenic effect and provide an important insight into potential interventions to reduce the impact of vehicular emissions. [ABSTRACT FROM AUTHOR]

We have previously shown that high-dose glucocorticoid treatment reduces neointimal proliferation following arterial injury in mice, but is associated with increased local thrombosis. Clinically, glucocorticoid excess, either in Cushing's syndrome or with chronic treatment, is associated with increased coagulation and decreased fibrinolysis. The few animal (rat) studies which have investigated these effects support the conclusion that glucocorticoid treatment reduces fibrinolysis. This study aimed to determine the influence of glucocorticoid administration on the thrombotic potential in mice. Male C57Bl/6J mice (aged 10-12 weeks) received either vehicle or dexamethasone (dex; 0.1 or 0.8 mg/kg/day) orally for 5 weeks (n=8/group). Tail tip bleeding time was reduced by high-dose dex (52.9±5.6 s) compared with vehicle (87.1±13.6 s; p<0.05). High-dose dex increased plasminogen activator inhibitor-1 (PAI-1; 139.5±15.1% vs vehicle 100.0±10.7%; p<0.05 and decreased tissue plasminogen activator (tPA; 55.9±4.9% vs vehicle 100.0±10.3%; p<0.05) mRNA levels in the heart. In addition, high-dose dex increased total PAI-1 (3.53±0.59 ng/ml vs vehicle 0.96±0.17 ng/ml; p<0.001) and active PAI-1 (0.92±0.09 ng/ml vs vehicle 0.31±0.07 ng/ml; p<0.001) plasma antigen levels. High-dose dex did not alter platelet activation as measured by p-selectin expression using flow cytometry. Low-dose dex had no effect on any parameters described. Dexamethasone-induced thrombosis at the site of intraluminal wire injury may be attributable to alterations in the endogenous fibrinolytic system rather than changes in platelet activity. These results suggest that beneficial inhibition of neointimal proliferation mediated by systemic glucocorticoid administration is negated in part by changes in fibrinolysis leading to large, semi-occlusive thrombi formation at the site of injury. [ABSTRACT FROM AUTHOR]