Current Vascular Pharmacology - Volume 7, Issue 1, 2009
Volume 7, Issue 1, 2009
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Purines as Neurotransmitters and Neuromodulators in Blood Vessels
By Vera RalevicATP is an important neurotransmitter being released with noradrenaline (NA) and neuropeptide Y (NPY) from perivascular sympathetic nerves; it acts at postjunctional P2X receptors to evoke vascular smooth muscle contraction, often synergising with the effects of NA acting at α-adrenoceptors. There is growing evidence for ATP as a neurotransmitter in perivascular non-adrenergic non-cholinergic nerves. In addition, ATP can act as a facilitatory and inhibitory neuromodulator via prejunctional P2 receptors. ATP is rapidly broken down, by ectonucleotidases, to adenosine which can also regulate the release of neurotransmitters via inhibitory prejunctional A1 adenosine receptors. The relative contributions of ATP and NA as functional cotransmitters varies with species, age, type and size of blood vessel, frequency and duration of stimulation, the tone/pressure of the blood vessel, and in disease. Blood vessel tone/pressure itself can be influenced by the vasocontractile and vasorelaxant actions of purines at different subtypes of P1 and P2 receptors, following release from the endothelium, smooth muscle, erythrocytes and platelets, as well as from perivascular nerves. This review focuses on the role of ATP as a cotransmitter in perivascular nerves in physiological and pathophysiological conditions; neuromodulator roles of purines are also discussed.
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Cannabinoid Modulation of Perivascular Sympathetic and Sensory Neurotransmission
Authors: Vera Ralevic and David A. KendallCannabinoids are signalling molecules which elicit their vascular effects mainly via G protein-coupled CB1 receptors and transient receptor potential (TRP) channels (chiefly vanilloid TRPV1 receptors). Cannabinoids can act at prejunctional CB1 receptors to inhibit perivascular sympathetic neurotransmission. The effects of cannabinoids on perivascular capsaicin-sensitive sensory nerves are more complex. Certain cannabinoids can activate sensory nerves through actions on TRPV1 receptors and other TRP channels, which leads to sensory neurotransmitter release (mainly calcitonin generelated peptide) and vasorelaxation. However, activation of TRP/TRPV1 channels can also lead to desensitization and loss of sensory nerve activity. Concentration and time of exposure may be critical in determining which of these opposite effects of cannabinoids prevails. In addition, there is evidence for the expression of CB1 receptors on perivascular capsaicinsensitive sensory nerves, coupled to inhibition of neurotransmitter release. There is evidence that the archetypal cannabinoid anandamide is released as a neurotransmitter in the central nervous system, and from sensory ganglia, but a release of cannabinoids from perivascular nerves has yet to be clearly demonstrated. Hence, with regard to perivascular nerves, cannabinoids appear to act principally as prejunctional modulators of neurotransmission. The diverse prejunctional effects of cannabinoids may be novel targets for therapies designed to treat vascular disease.
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Cerebrovascular Endothelin Receptor Upregulation in Cerebral Ischemia
More LessStroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery either by an embolus or by local thrombosis. Several studies have shown an involvement of the endothelin system in ischemic stroke. This review aims to examine the alterations of vascular endothelin receptor expression in ischemic stroke. Furthermore, studies of the intracellular signalling pathways leading to the enhanced expression of vascular endothelin receptors show that both protein kinase C (PKC) and mitogen activating protein kinase (MAPK) play important roles. The results from this work provide new perspectives on the pathophysiology of ischemic stroke, and give a possible explanation to the beneficial effects of treatment with PKC and MAPK inhibitors to limit the infarct volume.
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Neuronal Regulators and Vascular Dysfunction in Raynaud's Phenomenon and Systemic Sclerosis
Authors: Carmen Fonseca, David Abraham and Markella PonticosRaynaud's phenomenon (RP) results from an exaggerated cutaneous vasospastic response to cold or emotional stress. The mechanisms that lead to impaired cutaneous vascular tone are complex. The regulation of cutaneous vasoconstriction and vasodilation, involves altered sympathetic nerve activity and a host of neuronal regulators, including adrenergic and non-adrenergic, as well as REDOX signalling and other signalling such as the RhoA/ROCK pathway. This review summarises the literature concerning the regulation of vascular tone by neurohumoral factors that may be involved in RP and systemic sclerosis (SSc).
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Neuronal Regulation of Aortic Valve Cusps
Authors: Ismail El-Hamamsy, Magdi H. Yacoub and Adrian H. ChesterHeart valves have long been considered exclusively passive structures that open and close in response to changes in transvalvular pressure during the cardiac cycle. Although this is partly true, recent evidence suggests that valves are far more sophisticated structures. Microscopic examination of heart valves reveals a complex network of endothelial cells, interstitial cells, an extracellular matrix and a rich network of intrinsic nerves. The distribution of these nerve networks varies between the four valves, but is remarkably conserved between species. The present review will focus mainly on aortic valve innervation for several reasons: it is most commonly involved in disease processes, it lies in a unique hemodynamic environment and is exposed to extreme mechanical forces. These nerves are likely to play a significant role in the modulation of aortic valve structure and function and its adaptation to different hemodynamic and humoral conditions. The objectives of this review are first to describe the anatomy of aortic valve innervation, then detail the functional significance of innervation to the valve and finally make the case for the clinical relevance of understanding the neural control of aortic valves and its potential pharmacologic implications.
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The Saphenous Vein as a Bypass Conduit: The Potential Role of Vascular Nerves in Graft Performance
Authors: Michael R. Dashwood and Andrzej LoeschThe saphenous vein is the most commonly used conduit in patients undergoing coronary artery bypass surgery. However, a high proportion of vein grafts occlude within the first year and over 50% patients require further grafting within 10 years. Using conventional harvesting techniques the saphenous vein is damaged due to considerable surgical and mechanical trauma, a situation that affects graft patency. As a superficial vessel located in the leg, the saphenous vein in man is subjected to variations in orthostatic pressure associated with exercise and alterations in posture. These conditions require the vein's calibre to be regulated predominantly by the autonomic nervous system. While posture-induced changes occur in man, and other bipeds, such alterations in pressure may not occur or be more subtle in other species, conditions that may limit the usefulness of various experimental models. The neural control of the saphenous vein is under the influence of a plethora of neurotransmitters and neuropeptides which, apart from affecting vascular tone, possess mitogenic properties that may contribute to morphological changes caused by vascular injury. In addition to their neurotransmitter role a number of factors have a direct action on vascular smooth muscle cells that affects neural blood flow with subsequent influence on peripheral nerve conduction. Such neurovascular actions may potentially play a role in the altered vein reactivity and structure involved in graft failure. In this review we discuss the pressure changes experienced by the saphenous vein, its innervation and use as a bypass graft for revascularization of ischaemic tissue, in particular the myocardium. Also, we consider the value of various common experimental techniques for studying vasoactive and mitogenic factors and their potential role in vein graft performance.
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On the Sympathetic Innervation of the Human Greater Saphenous Vein: Relevance to Clinical Practice
Authors: Andrzej Loesch and Michael R. DashwoodThis review focuses on sympathetic perivascular innervation of human saphenous vein. It shows the distribution of the nerves in the vein wall, including an association of the nerves with the vasa vasorum system. An account of a possible contribution of sympathetic nerves to the physiology of the saphenous vein, as well as their relevance to the outcome of coronary artery bypass surgery that uses the vein as a graft, is discussed.
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Postprandial Glucose - A Potential Therapeutic Target to Reduce Cardiovascular Mortality
Authors: Raj Peter, Onyebuchi E. Okoseime, Alan Rees and David R. OwensCardiovascular disease (CVD) accounts for almost 75% of mortality in subjects with type 2 diabetes (T2DM). The relationship between hypertension, dyslipidaemia and CVD is now well established. However, the precise link between glycaemia and macrovascular complications has remained unclear. There is now emerging evidence that postprandial glucose (PPG) contributes significantly to CVD risk, although to date there are no large scale interventional studies underway which test the hypothesis that targeting PPG will reduce CVD risk. Until recently, there was no consensus about the definition of postprandial hyperglycaemia. The International Diabetes Federation (IDF) has now developed new clinical guidelines for postprandial glucose and recommend that 2-hour post meal glucose levels are kept <7.8 mmol/L. In the last few years more has become known about the cellular mechanisms triggered in response to glucose excursions which may explain this increased susceptibility to CVD. Recently, investigation into the contribution of PPG to HbA1c in subjects with T2DM, has shown that this is maximal in relatively well controlled diabetic subjects. Hence PPG is emerging as a legitimate therapeutic target to minimise CVD risk. This review addresses the evidence linking postprandial hyperglycaemia to cardiovascular disease, the cellular mechanisms explaining this enhanced risk and a therapeutic strategy to address postprandial glucose excursions.
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Models to Study Atherosclerosis: A Mechanistic Insight
Authors: Vishal Singh, Rajiv L. Tiwari, Madhu Dikshit and Manoj K. BarthwalThe recent failure of candidate drugs like cholesterol ester transfer protein (CETP) and acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors calls for a revised approach for screening anti-atherosclerotic drugs and development of new models of atherosclerosis. For this it is important to understand the mechanism of the disease in a particular model. Models simultaneously showing hyperlipidemia, inflammation and associated complications of diabetes and hypertension will serve the purpose better as they mimic the actual clinical condition. Besides this, analyzing candidate molecules in vivo, in vitro and at various levels of atherosclerosis progression is important. Models based on various cells and process involved in atherosclerosis should be used for screening candidate molecules. The challenge lies in bridging the gap between genetically friendly small animal and human-like bigger animal models. Sequencing of the mouse and human genome, development of a single nucleotide polymorphism (SNP) database and in silico quantitative trait loci (QTL) linkage analysis may enhance the understanding of atherosclerosis and help develop new therapeutic targets.
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Volumes & issues
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Volume 23 (2025)
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Volume 22 (2024)
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Volume 21 (2023)
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Volume 20 (2022)
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Volume 19 (2021)
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Volume 18 (2020)
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Volume 17 (2019)
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Volume 16 (2018)
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Volume 15 (2017)
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Volume 14 (2016)
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Volume 13 (2015)
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Volume 12 (2014)
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Volume 11 (2013)
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Volume 10 (2012)
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Volume 9 (2011)
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Volume 8 (2010)
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Volume 7 (2009)
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Volume 6 (2008)
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Volume 5 (2007)
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Volume 4 (2006)
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Volume 3 (2005)
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Volume 2 (2004)
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Volume 1 (2003)
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