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Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17ß oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies. [ABSTRACT FROM AUTHOR]

Ischaemic heart disease (IHD) is the most frequent cause of mortality among men and women. Many epidemiological studies have demonstrated that premenopausal women have a reduced risk for IHD compared with their male counterparts. The incidence of IHD in women increases after menopause, suggesting that IHD is related to declining oestrogen levels. Experimental observations have confirmed the results of epidemiological studies investigating sex-specific differences in cardiac tolerance to ischaemia. Female sex appears also to favourably influence cardiac remodelling after ischaemia/reperfusion injury. Furthermore, sex-related differences in ischaemic tolerance of the adult myocardium can be influenced by interventions during the early phases of ontogenetic development. Detailed mechanisms of these sex-related differences remain unknown; however, they involve the genomic and non-genomic effects of sex steroid hormones, particularly the oestrogens, which have been the most extensively studied. Although the protective effects of oestrogen have many potential therapeutic implications, clinical trials have shown that oestrogen replacement in postmenopausal women may actually increase the incidence of IHD. The results of these trials have illustrated the complexity underlying the mechanisms involved in sex-related differences in cardiac tolerance to ischaemia. Sex-related differences in cardiac sensitivity to ischaemia/reperfusion injury may also influence therapeutic strategies in women with acute coronary syndrome. Women undergo coronary intervention less frequently and a lower proportion of women receive evidence-based therapy compared with men. Although our understanding of this important topic has increased in recent years, there is an urgent need for intensive experimental and clinical research to develop female-specific therapeutic strategies. Only then we will be able to offer patients better evidence-based treatment, a better quality of life and lower mortality. [ABSTRACT FROM AUTHOR]

Background and Purpose Gender differences in inflammation are well described, with females often showing more robust, oestrogen-associated responses. Here, we investigated the influence of gender, oestrogen and the anti-inflammatory protein annexin A1 ( AnxA1) on lipopolysaccharide ( LPS)-induced leukocyte-endothelial cell interactions in murine cerebral and mesenteric microvascular beds. Experimental Approach Intravital microscopy was used to visualize and quantify the effects of LPS (10 μg·per mouse i.p.) on leukocyte-endothelial interactions in male and female wild-type ( WT) mice. The effects of ovariectomy ± oestrogen replacement were examined in WT and AnxA1-null ( AnxA1−/−) female mice. Key Results LPS increased leukocyte adherence in the cerebral and mesenteric beds of both male and female WT mice; females showed exacerbated responses in the brain versus males, but not the mesentery. Ovariectomy further enhanced LPS-induced adhesion in the brain but not the mesentery; its effects were reversed by oestrogen treatment. OVX AnxA1−/− mice also showed exaggerated adhesive responses to LPS in the brain. However, these were unresponsive to ovariectomy and, paradoxically, responded to oestrogen with a pronounced increase in basal and LPS-induced leukocyte adhesion in the cerebrovasculature. Conclusions and Implications Our data confirm the fundamental role of AnxA1 in limiting the inflammatory response in the central and peripheral microvasculature. They also (i) show that oestrogen acts via an AnxA1-dependent mechanism to protect the cerebral, but not the mesenteric, vasculature from the damaging effects of LPS and (ii) reveal a paradoxical and potentially toxic effect of the steroid in potentiating the central response to LPS in the absence of AnxA1. [ABSTRACT FROM AUTHOR]

Background and Purpose Oestrogen receptor alpha ( ERα) binds to different ligand which can function as complete/partial oestrogen-agonist or antagonist. This depends on the chemical structure of the ligands which modulates the transcriptional activity of the oestrogen-responsive genes by altering the conformation of the liganded- ERα complex. This study determined the molecular mechanism of oestrogen-agonistic/antagonistic action of structurally similar ligands, bisphenol ( BP) and bisphenol A ( BPA) on cell proliferation and apoptosis of ERα + ve breast cancer cells. Experimental Approach DNA was measured to assess the proliferation and apoptosis of breast cancer cells. RT- PCR and ChIP assays were performed to quantify the transcripts of TFF1 gene and recruitment of ERα and SRC3 at the promoter of TFF1 gene respectively. Molecular docking was used to delineate the binding modes of BP and BPA with the ERα. PCR-based arrays were used to study the regulation of the apoptotic genes. Key Results BP and BPA induced the proliferation of breast cancer cells; however, unlike BPA, BP failed to induce apoptosis. BPA consistently acted as an agonist in our studies but BP exhibited mixed agonistic/antagonistic properties. Molecular docking revealed agonistic and antagonistic mode of binding for BPA and BP respectively. BPA treatment resembled E2 treatment in terms of PCR-based regulation of apoptotic genes whereas BP was similar to 4OHT treatment. Conclusions and Implications The chemical structure of ERα ligand determines the agonistic or antagonistic biological responses by the virtue of their binding mode, conformation of the liganded- ERα complex and the context of the cellular function. [ABSTRACT FROM AUTHOR]

Approximately one third of all deaths are attributed to cardiovascular disease (CVD), making it the biggest killer worldwide. Despite a number of therapeutic options available, the burden of CVD morbidity continues to grow indicating the need for continued research to address this unmet need. In this respect, investigation of the mechanisms underlying the protection that premenopausal females enjoy from cardiovascular-related disease and mortality is of interest. In this review, we discuss the essential role that rodent animal models play in enabling this field of research. In particular, we focus our discussion on models of hypertension and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: Oestrogen confers cardioprotection by down-regulating the beta(1)-adrenoceptor and suppressing the expression and activity of protein kinase A. We hypothesized that oestrogen may also protect the heart by suppressing Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), another signalling messenger activated by the beta(1)-adrenoceptor, that enhances apoptosis.Experimental Approach: We first determined the expression of CaMKII in the heart from sham and ovariectomized rats with and without oestrogen replacement. We then determined the effects of CaMKII inhibition (KN93, 2.5 micromolxL(-1)) in the presence or absence of 10(-7) molxL(-1) isoprenaline, a non-selective beta-adrenoceptor agonist. We also determined the percentage apoptosis in myocytes from rats in each group with or without beta-adrenoceptor stimulation.Key Results: Both CaMKIIdelta and phosphorylated CaMKII were up-regulated in the hearts from ovariectomized rats, and they were restored to normal by oestrogen replacement. The infarct size and lactate dehydrogenase release were significantly greater after ovariectomy. Similarly, cardiac contractility, the amplitude of the electrically induced intracellular Ca(2+) transient and the number of apoptotic cells were also greater in ovariectomized rats upon ischaemia/reperfusion in the presence or absence of isoprenaline. Most importantly, the responses to ischaemic insult in ovariectomized rats were reversed not only by oestrogen replacement, but by blockade of CaMKII with KN93.Conclusions and Implications: Oestrogen confers cardioprotection at least partly by suppressing CaMKIIdelta. This effect of oestrogen on CaMKII is independent of the beta-adrenoceptor and occurs in addition to down-regulation of the receptor. [ABSTRACT FROM AUTHOR]

Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drugs that act as oestrogen receptor antagonists (antioestrogen) or aromatase inhibitors. The physiological and pharmacological basis for the effects of oestrogen blockade in men, but not women, are reviewed. [ABSTRACT FROM AUTHOR]

Background and purpose:Selective oestrogen receptor (ER) modulators (SERMs) are of great value in the treatment of breast cancer and osteoporosis. The aim of this study was to characterize pharmacologically a new class of SERMs synthesized based on the core structure of raloxifene.Experimental approach:Competitive receptor binding and luciferase-based reporter methods were used to study the bioactivities of raloxifene analogues, followed by efficacy determination in breast cancer cell proliferation assay. ER antagonist effects were investigated in female rats by measuring uterine and mammary gland growth, using wet weight, BrdU incorporation and terminal end bud (TEB) as indicators.Key results:Five analogues, belonging to two different structural series and display higher binding affinities for ERα than ERβ were functionally evaluated. One such analogue, Y134, exhibited potent antagonist activity at ERs in CV-1 cells cotransfected with plasmids containing ERα or ERβ and oestrogen-response element-driven luciferase. The estimated IC50 value was 0.52 nM for ERα and 2.94 nM for ERβ, comparable to that of raloxifene. Little cytotoxicity was observed at Y134 concentrations below 10 μM. Y134 suppressed oestrogen-stimulated proliferation of ER-positive human breast cancer MCF-7 and T47D cells. At an identical dose, administered to ovariectomized rats, Y134 was more effective than raloxifene at arresting oestrogen-induced outgrowth of TEB and mammary gland DNA synthesis, but their inhibitory effects on the uterus were comparable.Conclusions and Implications:Y134 is a potent ER antagonist with better mammary gland selectivity than raloxifene and shows potential for development as a new SERM for therapeutic use.British Journal of Pharmacology (2007) 150, 19–28. doi:10.1038/sj.bjp.0706960; published online 20 November 2006 [ABSTRACT FROM AUTHOR]

We previously showed that oestrogen confers cardioprotection by downregulating the cardiacß1-adrenoceptor (ß1-AR). The present study examined the effect of oestrogen on the postß1-AR signalling cascade, with particular emphasis on the activity of protein kinase A (PKA) and its influence on the L-type Ca2+ channel.Three groups of adult female Sprague-Dawley rats were used: sham-operated controls, bilaterally ovariectomized (Ovx) rats, and Ovx rats with oestrogen replacement (Ovx+E2), which restored the oestrogen concentration to normal.The electrically induced intracellular Ca2+ transient (E[Ca2+]i),45Ca2+-uptake through cardiac L-type Ca2+ channels (Ca2+ channels), heart rate and force of contraction in response toß-AR stimulation with 10?nM isoprenaline (Iso) in hearts from Ovx rats were significantly greater than those of control and Ovx+E2 rats. The basal and Iso-induced PKA activities were also higher in hearts from Ovx rats. KT5720, a selective PKA inhibitor, completely inhibited its potentiating effect on basal Ca2+ channel activity in the Ovx rat heart. On the other hand, expression of G proteins (Gas and Gai1-3), basal and forskolin-stimulated cAMP accumulation, and responsiveness of PKA to cAMP, were not altered by Ovx.Interestingly, the PKA inhibitor at the same concentration significantly reduced the increases in PKA activity and Ca2+ channel activity uponß-AR stimulation in all three groups of rats and the inhibitions were significantly greater in the Ovx rat than in the other two groups of rats.This study provides the first evidence that, in addition to downregulation ofß1-AR shown previously, suppression of PKA activity, which is partly responsible for the suppressed Ca2+ channel activity, also determines the E[Ca2+]i and cardiac contractility followingß-AR stimulation in the female rat.British Journal of Pharmacology (2005) 144, 972-981. doi:10.1038/sj.bjp.0706123 [ABSTRACT FROM AUTHOR]

1: We investigated the effect of chronic (7 days) treatment of male rats with the isoflavone daidzein (0.2?mg?kg-1 sc per day) or 17ß-oestradiol (0.1?mg?kg-1 sc per day) on the contribution of nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarising factor (EDHF) to endothelium-dependent relaxation of isolated aortic rings. 2: The sensitivity and maximum relaxation to acetylcholine (ACh) were significantly greater in aortic rings from rats treated with daidzein or 17ß-oestradiol, in comparison to vehicle-treated rats. Inhibition of nitric oxide synthase with N-nitro-L-arginine (L-NOARG) abolished ACh-induced relaxation in the aortae from vehicle-treated rats, but only attenuated relaxation in aortae from daidzein or 17ß-oestradiol-treated rats. The presence of haemoglobin in addition to L-NOARG did not cause any further inhibition of relaxation. 3: The cyclooxygenase inhibitor indomethacin had no effect on endothelium-dependent relaxation in aortae from any treatment group. Charybdotoxin (ChTX), which blocks large-conductance calcium-activated potassium channels (BKCa) and intermediate-conductance calcium-activated potassium channels (IKCa), plus apamin, which blocks small-conductance calcium-activated potassium channels (SKCa), but not iberiotoxin, which only blocks BKCa, attenuated endothelium-dependent relaxation of aortae from daidzein or 17ß-oestradiol-treated rats. Blockade of KCa channels had no effect on the responses to ACh in aortae from vehicle-treated rats. In aortae from daidzein- or 17ß-oestradiol-treated rats, endothelium-dependent relaxation was also attenuated by inhibition of cytochrome P450 (CYP450) epoxygenase with 6-(2-propargylloxyphenyl)hexanoic acid (PPOH) or inhibition of KIR channels and Na+/K+-ATPase with barium and oubain, respectively. 4: This study demonstrates that endothelium-dependent relaxation of male rat aorta is normally entirely mediated by NO, whereas treatment with daidzein or 17ß-oestradiol stimulates a contribution from a non-NO, nonprostaglandin factor acting through the opening of SKCa and IKCa channels, and involving activation of Na/K-ATPase, KIR and CYP450 epoxygenase. This pattern of sensitivity to the tested inhibitors is consistent with the contribution of EDHF to relaxation. Thus, EDHF contributes to the enhanced endothelium-dependent relaxation that is observed after chronic treatment with the phytoestrogen daidzein or with 17ß-oestradiol.British Journal of Pharmacology (2004) 141, 322-328. doi:10.1038/sj.bjp.0705603 [ABSTRACT FROM AUTHOR]

In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and self-administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic (strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague-Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic, developmental and endocrine factors in driving cannabis use and dependence. [ABSTRACT FROM AUTHOR]