195 research outputs found
Pharmacology of non-psychoactive phytocannabinoids and their potential for treatment of cardiometabolic disease.
No full textThe use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646–1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances
New insights into the yin and yang of the endocannabinoid system in health and disease
No full textThis article is part of a themed section on Endocannabionoids, of which the author is guest editor. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc
Return to work with chronic pain: employers' and employees' views
No full textThis conference papers given to the Society of Occupational Medicine's Annual Scientific Meeting discusses tensions and some possible ameliorating activities from our 2013 paper of the same name., published in their journal: Wainwright, E., Wainwright, D., Keogh, E. and Eccleston, C. Return to work with chronic pain: employers’ and employees’ views. Occupational Medicine 2013: doi:0.1093/occmed/kqt109. The conference homepage is here;http://www.som-asm.org.uk/Programme_SOM_ASM.aspAbstractBackgroundThe sickness certification and return to work (RTW) of people with chronic pain are important health and economic issues for employees, employers, taxpayers and the UK government. The ‘fit note’ and a national educational programme promoting RTW were introduced in 2010 to curb rising rates of sickness absence. AimsTo investigate employers’ and employees’ experiences of managing RTW when someone has taken sick leave for chronic pain, and to explore the perceived efficacy of the fit note.MethodsA qualitative study, comprising semi-structured interviews with employers who had managed sick leave cases and employees who had experienced sick leave for chronic pain. Interviews were recorded, transcribed and the data analysed using constructivist grounded theory principles.ResultsFive themes were elicited. Firstly, frequent enquiry after health status was seen as intrusive by some employees but part of good practice by employers and acknowledging this difference was useful. Secondly, being able to trust employees due to their performance track record was helpful for employers when dealing with complex chronic pain conditions. Thirdly, feeling valued increased employees’ motivation to return to work. Fourthly, guidelines about maintaining contact with absent employees were useful if used flexibly. Finally, both parties valued the fit note for its positive language, interrogative format and biomedical authority. ConclusionsThe fit note was perceived to be helpful if used in combination with other strategies for managing sick leave and RTW for people with chronic pain. These strategies may be applicable to other fluctuating, long-term conditions with medically unexplained elements. <br/
Natural products as sources of novel drugs.
No full textThis book reflects the state of the art in the field of natural product drug discovery. The work explores what advances have been made in discovering novel compounds from terrestrial, marine and microbial sources for use in the treatment and management of both non-communicable (e.g. cardiovascular, neurodegenerative) and communicable (e.g. malaria) diseases. Each chapter is authored by international experts who present detailed analysis of the pipeline of natural product-derived drugs in their field. This book makes a valuable contribution to the field and appeals to researchers in all branches of natural product research
Studies on the role of GPR55 in cardiovascular physiology and pathophysiology.
No full textAtherosclerosis is a multifactorial, chronic inflammatory condition characterised by endothelial dysfunction, hyperlipidaemia and the accumulation of fatty deposits within the tunica intima of medium-to-large sized muscular arteries. This disease can prove fatal with patients suffering lethal myocardial infarction or stroke. Recently, two studies investigating the role of G-protein-coupled receptor 55 (GPR55) in atherosclerosis reported conflicting results; one reported a pro-atherogenic role for GPR55 and the other, an anti-atherogenic role for this receptor. Interestingly, another study demonstrated that the activation of GPR55 by lysophosphatidylinositol (LPI) in cultured rat neonatal ventricular cardiomyocytes provokes distinct cellular functions that are dependent on the location of GPR55, leading to suggestions that GPR55 may regulate cardiomyocyte function at two cellular sites and be a potential therapeutic target for cardiac disorders. While it has been demonstrated that GPR55 is important in the maintenance of cardiac function of healthy mice, what is currently unknown is if GPR55 has a role in the cardiovascular remodelling and cardiac function of atherosclerosis prone mice. To address this, the present studies were conducted to investigate 1) the role of GPR55 in atherogenesis, 2) if GPR55 has a role in the cardiac function of mice suffering from atherosclerosis, 3) the signalling pathway by which LPI activates cardiomyocytes, 4) the impact of GPR55 activation on the outcome of myocardial ischaemia/reperfusion (I/R) injury and, 5) the signalling mechanisms by which GPR55 elicits any observed effects on the myocardium in response to such injury. Using C57BL/6 (wildtype; WT), apolipoprotein E knockout (ApoE-/-; mouse model of atherosclerosis), GPR55 knockout (GPR55-/-) and novel ApoE-/-/GPR55-/- mice, this study has established that in the presence of high fat feeding (to accelerate atherosclerosis), GPR55 has a complex role whereby it both regulates risk factors associated with atherosclerosis (i.e. body weight and fat mass) yet promotes the development of fatty streaks within the vasculature, via a lipid independent mechanism. In terms of cardiac function, GPR55 exerted a protective role by maintaining the systolic function of high fat fed ApoE-/- mice, yet negatively affected the contractile reserve of these mice. With regard to infarct size, the present study established that LPI-induced activation of GPR55 (pre-global ischaemia) exacerbates myocardial tissue injury via a Rho-associated protein kinase (ROCK) dependent mechanism. Finally, this study established that LPI signals through the same signalling pathway as it did in the isolated heart, in both mouse and human-induced pluripotent stem cell-derived cardiomyocytes thus suggesting a translational role for GPR55 in the human heart. In conclusion, despite further research being required, the data presented within this thesis provides evidence that GPR55 may have the potential to be targeted for therapeutic gains in atherosclerosis and myocardial I/R injury
Determining the role of the LPI/GPR55 system in the development of obesity and associated cardiovascular consequences.
No full textObesity has reached worldwide epidemic proportions and with this increased incidence of obesity, comes an increase in incidence of the comorbidities associated with obesity such as diabetes and cardiovascular disease (CVD). The underlying mechanisms which connect these diseases are still poorly understood. One system which has been shown to be up-regulated in the setting of obesity and diabetes is that of the G-protein coupled receptor-55/Lysophosphatidylinositol (GPR55/LPI). Despite being upregulated in the setting of obesity, the function of GPR55 in obesity and other disease states remains elusive. Therefore, the present study aimed to 1) investigate the role of GPR55 in obesity by characterising the phenotype of the GPR55 knockout (GPR55-/-) mouse when challenged with a high fat diet (HFD) intervention, 2) elucidate any effect of the GPR55 knockout and HFD intervention on the myocardial infarct size sustained following a period of ischaemia/reperfusion (I/R) and 3) make use of an in vitro model to elucidate the mechanisms by which changes occur in the adipose tissue of mice fed a HFD. GPR55-/- mice fed a HFD for 12-weeks gained significantly more weight in the form of fat mass, compared to wild-type (WT) controls and consequently become obese. Obese GPR55-/- mice displayed hypertrophic adipose tissue concurrent with the significant dysregulation of plasma lipids, increases in specific circulating LPI species, increased lipid deposition within the liver and a change in adipose tissue gene expression profile. These changes were not observed in GPR55-/- mice fed a standard diet or WT mice fed a HFD. Following a period of I/R, the myocardial infarct size in hearts from WT HFD fed mice was significantly smaller than in hearts from WT standard diet fed mice. This reduction in infarct size due to HFD intervention was not dependent on RISK-pathway activation and was not observed in hearts from GPR55-/- mice, therefore demonstrating that the cardio-protective effect of a HFD on infarct size is dependent on GPR55. In vitro studies using 3T3-L1 cells determined that the changes in adipose tissue gene expression of HFD fed mice was not due to enhanced stimulation with LPI or via hypoxic mechanisms. The results of these studies demonstrate that GPR55 has an anti-obesity function in vivo and also mediates the cardio-protective effect of a HFD on myocardial infarct size, through currently unknown mechanisms
Cellular mechanisms of acute hypoxic pulmonary vasoconstriction in intrapulmonary veins.
No full textIn the pulmonary circulation, alveolar hypoxia contributes to blood flow regulation. Hypoxic pulmonary vasoconstriction (HPV) involves both pulmonary arteries and veins, but little is known of the contractile mechanisms specific to the veins. The aim of these studies was to examine the hypoxic response in small porcine intrapulmonary veins in relation to the arterial response, and investigate the effects of hypoxia on ion conductances in single myocytes from intrapulmonary veins. In wire myography experiments, intrapulmonary veins contracted more than sizematched arteries in response to hypoxia and agonists KCl and PGF2α. Venous contractions were inhibited by removal of extracellular Ca2+ or in the presence of Clchannel blocker NFA, effects not seen in the arteries. To examine the mechanisms of venous contraction at cellular level, single pulmonary vein smooth muscle cells (PVSMC) were freshly isolated and characterised morphologically and electrophysiologically for the first time. In patch-clamp studies, hypoxia reversibly inhibited a whole-cell outward current in the presence of BKCa channel antagonist Penitrem A. By subtracting currents recorded in normoxia and hypoxia, a novel hypoxia-sensitive K+ current (IK(H)) was revealed in PVSMC. IK(H) was a rapidly activating, partially inactivating current and was sensitive to KV channel blocker 4-AP. The biophysical properties of IK(H) revealed the voltage window of current availability with a peak near the resting membrane potential of PVSMC. In conclusion, these findings highlight differences between the contractile properties of veins and arteries and reveal a significant contribution of Ca2+ influx and an NFA-sensitive conductance during venous contraction to agonists and hypoxia. Furthermore, the results suggest that a novel hypoxia-sensitive KV current contributes to membrane potential under resting conditions in PVSMC and its inhibition by hypoxia may contribute to the initiation of HPV in porcine intrapulmonary veins
The design, synthesis and evaluation of selective, non invasive imaging agents for atherosclerotic plaque.
No full textThe aim of this research study was the synthesis of an imaging agent, which could be used to non-invasively image atherosclerotic plaques via MRI. In order to achieve this, a library of peptide substrates designed to be substrate specific for either legumain or MMP-2/9 were synthesized. This was achieved via a combination of both solid and solution phase peptide synthesis. The first phase of the research study focused on the synthesis of a targeted MRI contrast agent designed to image legumain expressing atherosclerotic plaques. This was achieved by using a Fluorescent Resonance Energy Transfer (FRET) active system to evaluate the substrate specificity of synthesized peptide sequences for legumain. The self quenched FRET substrates were engineered to carry a legumain sensitive bond in between the donor (5(6)-carboxyfluorescein) and quencher (aminoanthraquinone) moiety. Legumain mediated activation of the FRET substrates was measured via fluorescence spectroscopic analysis which showed the release in fluorescence that was initially quenched by the anthraquinone moiety. Optimized peptide sequences were then covalently coupled to the gadolinium chelate (Gd-DOTA) so that, upon enzymatic cleavage, the contrast agent could be released at the site of activation. Mass spectrometric analysis on the post enzyme digested samples (incubated with recombinant human legumain) showed that the substrates were fragmented by the activated enzyme in vitro. The targeted MRI contrast agent and FRET substrates were successfully synthesized and then characterized by low/high resolution mass spectrometry. Additionally cytotoxic studies on selected compounds and a model of the enzyme-digested product [Lys(DOTA-Gd)-Sp-AQ] via MTT assay demonstrated that the compounds did not affect the cell viability of MDA-MB-231 cell line. The second phase of this project was the synthesis of an aminoanthraquinone peptide substrate coupled to a contrast agent (CA). This substrate was designed to be specific to MMP-2/9. Although the synthetic strategy was successful, subsequent reaction optimization will be required (increasing yield) before in vitro CA release could be evaluated. Thus, the targeted MRI CAs synthesized during this research study provide a starting point for novel imaging agents. These agents, which upon successful in vitro and in vivo trials could potentially be used to image legumain expression or MMP (2/9) expression or atherosclerotic plaques
Studies investigating the mechanisms of the cardioprotective effects of Cannabidiol.
No full textThe phytocannabinoid cannabidiol (CBD) has a complex pharmacology which is thought to include, but is not limited to, an ability to act as an inverse agonist at the CB1 and CB2 receptors and an antagonist of GPR55. Moreover, is has been shown to reduce infarct size and ameliorate reductions in left ventricular function in vivo. These improvements in the pathogenesis of experimental MI are accompanied by a reduction in inflammatory cell migration to the area at risk. More recently it has been shown that CBD is anti-arrhythmic in acute experimental MI. Thus, it was suggested that the cardioprotective effects of CBD might be due to an anti-inflammatory action. In addition, GPR55 receptor activation is acknowledged to mediate mobilisation of intracellular Ca2+ (Ca2+i) which could potentially be pro-arrhythmic and so CBD, as an antagonist may confer cardioprotection via GPR55. However, the receptors and/or mechanisms responsible for mediating the cardioprotective effects of CBD are get to be determined. The present studies were therefore performed to; (1) better understand the pharmacology of CBD by assessing haemodynamic responses to CBD and other cannabinoids ligands in anaesthetised rats, (2) investigate the receptors involved in the anti-arrhythmic effect of CBD in a rat model of coronary artery occlusion (CAO), and (3) investigate if CBD can alter [Ca2+]i in isolated rat cardiomyocytes. The characterisation of the pharmacology of CBD in vivo showed that; firstly, CB1 receptor activation causes a hypotensive response which can be dose-dependently inhibited by AM251; secondly, both CBD and AM251 alone (a CB1 receptor antagonist and GPR55 agonist) can induce vasodepressor responses and finally, CBD can potentiate the AM251-mediated hypotension when co-administered, suggesting possible cross-talk between the CB1 and GPR55. Results from CAO studies showed that CBD and AM251 each have the capacity to reduce arrhythmias. Moreover, when CBD and AM251 were co-administered the anti-arrhythmic capacity of either alone was potentiated. However, the degree of potentiation was dependent on the order of administration, suggesting that more than one receptor is involved in the summative anti-arrhythmic effects. The investigation of cardiomyocyte [Ca2+]i suggested that AM251 can modulate [Ca2+]i at the level of the cardiomyocyte, while CBD cannot. These data give novel insight into the anti-arrhythmic effects of CBD and, moreover, for the first time demonstrate that AM251 is anti-arrhythmic. In addition, these data suggest a role for GPR55 in increasing [Ca2+]i via AM251
Studies to determine the mechanisms of the anti-atherosclerotic effects of eicosapentaenoic acid: possible role for endocannabinoids?
No full textThe ω-3 polyunsaturated fatty acids (ω-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to have cardioprotective and antiatherosclerotic actions. While it has been proposed that ω-3 PUFAs may structurally stabilise atherosclerotic lesions, the underlying mechanisms have yet to be fully elucidated. There is evidence that increased dietary intake of ω-3 PUFAs alters the concentration of endocannabinoids (ECs) in central and peripheral tissues and, since synthetic cannabinoid agonists have been shown to exert anti-atherosclerotic effects, this thesis explored whether a link exists between the endocannabinoid system and the beneficial effects of ω-3 PUFAs in the setting of experimental atherosclerosis. Therefore, the present studies were performed to (1) determine the impact of long-term intervention with ω-3 PUFAs on several physiological parameters, including the function of the endocannabinoid system, in an in vivo model of hypercholesterolaemia and (2) to examine the role, if any, of the activated endocannabinoid system in the activity of an in vitro model of macrophage lipid accumulation. At the cellular level, the present study demonstrated the interference of cannabinoid receptor signalling with intracellular uptake and accumulation of DHA, an effect which was demonstrated to be mediated, at least in part, via CB2 receptor signalling. Moreover, the study provided the novel observation that DHA treatment of activated macrophages significantly inhibited 2- arachidonoylglycerol (2-AG) synthesis. This finding is strongly suggestive of an association between the effects of ω-3 PUFAs and regulation of the endocannabinoid system and its function. In the ApoE-/- mouse model of experimental atherosclerosis, maintenance on an atherogenic diet induced significant hyperlipidaemia, an effect which was associated with endothelial dysfunction, cardiac remodelling, and significantly elevated anandamide (AEA) and 2-AG levels in brain, heart and aortic tissues. Supplementation of the atherogenic diet with the EPA, while having a negligible impact on endothelial dysfunction or cardiac remodelling, improved the hypercholesterolaemic profile and normalised the overproduction of ECs in both central (brain) and peripheral (heart and vascular) tissues. Fenofibrate, a lipid lowering control administered as a supplement to the atherogenic diet, was observed to significantly attenuate hypercholesterolaemia, endothelial dysfunction and elevated EC levels although no effect on cardiac remodelling was observed. In light of the observation that hypercholesterolaemia was associated with elevated tissue EC levels, together with the demonstration that EPA improved hypercholeseterolaemia and attenuated EC levels suggests (1) a detrimental role of the endocannabinoid system in hypercholesterolaemia in the ApoE-/- model and (2) regulation of this interaction by ω-3 PUFAs. Given the mounting evidence implicating the endocannabinoid system in various disease pathologies, the capacity of ω-3 PUFAs to influence the activation and function of this system may prove key to their beneficial effects
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