Current Vascular Pharmacology - Volume 4, Issue 1, 2006
Volume 4, Issue 1, 2006
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The Effects of Olprinone, a Phosphodiesterase 3 Inhibitor, on Systemic and Cerebral Circulation
Authors: Takashi Ueda and Katsufumi MizushigeOlprinone, a phosphodiesterase (PDE) 3 inhibitor, is used to treat heart failure due to its positive inotropic and vasodilative effects. Selective inhibition of the PDE 3 isozyme increases intracellular adenosine 3'5'-cyclic monophosphate and enhances Ca2+ influx into cardiac muscle cells. The most significant advantage of PDE 3 inhibitors is their ability not only to enhance myocardial contraction, but to reduce, through vasodilatory action, the stress to which the heart is subjected. In peripheral vessels, the decrease of cytosolic free Ca2+ induces the vasorelaxation of vascular smooth muscle cells. In this way, olprinone reduces mean aortic and pulmonary artery pressures. Additionally, olprinone exerts differential vasodilatory effects on peripheral vessels in each organ, based on the differences in the distribution of PDE 3 among the organs. With respect to the cerebral circulation, olprinone augments blood flow in the cerebral cortex through direct vasodilatory effects on small cerebral arteries or arterioles. Olprinone increases hepatosplanchnic blood flow and improves oxygen supply. While long-term therapy with PDE 3 inhibitors in patients with chronic heart failure may accelerate the progress of the underlying disease and provoke serious ventricular arrhythmia, olprinone shows good potential for short-term treatment in patients who have experienced severe heart failure or patients who have undergone cardiac surgery.
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The Influence of Sex Hormones on Pulmonary Vascular Reactivity: Possible Vasodilator Therapies for the Treatment of Pulmonary Hypertension
Authors: A. M. Smith, R. D. Jones and K. S. ChannerPulmonary hypertension is a rare disease of the pulmonary vasculature defined as a mean pulmonary artery pressure >25 mmHg at rest or 30 mmHg with exercise. Recent therapies such as epoprostenol, bosentan and sildenafil are directed at the arterial vascular bed, causing vasodilatation and reducing pulmonary vascular resistance. However idiopathic pulmonary artery hypertension (IPAH) occurs predominantly in women, with three times the incidence compared to men and this suggests that sex hormones may be involved in the pathogenesis. 17b -oestradiol is a pulmonary vasodilator, proposed to act via an endothelium-dependant pathway, involving nitric oxide (NO) and has also been shown to alter responses to hypoxia. Progesterone is also a pulmonary vasodilator but differs from 17β-oestradiol in having endothelial-dependant and independent processes implicated. Interestingly testosterone has been shown to be a vasodilator in both the coronary and pulmonary circulation with a mechanism of action involving calcium channel blockade of the vascular smooth muscle and without endothelial involvement. In clinical trials testosterone confers symptomatic benefits in patients with coronary heart disease and heart failure, acting as a vasodilator. These observations lend support to the notion that testosterone could be a potential treatment for patients with PAH as vasodilator therapy remains the mainstay of treatment. Other potential beneficial effects of testosterone in the pulmonary circulation include immuno-modulation, altering expression of cytokines and an anti-thrombotic action. In this review the influence of sex hormones on the pulmonary vasculature will be discussed, with specific focus on pulmonary hypertension and the potential treatment of this condition.
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Hydrogen Sulfide as a New Endogenous Gaseous Transmitter in the Cardiovascular System
Authors: Chaoshu Tang, Xiaohui Li and Junbao DuHydrogen sulfide (H2S) is a well-known toxic gas with the smell of rotten eggs. Recent studies have shown that H2S is generated in vivo in human and animal organisms and that it participates in many pathophysiological processes. H2S is produced endogenously in mammalian tissues from L-cysteine metabolism mainly by 3 enzymes: cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptosulfurtransferase (MST). H2S may not only function as a neuromodulator in the central nervous system but it also relaxes gastrointestinal smooth muscles. More importantly, present evidence shows that H2S exerts regulatory effects on the pathogenesis of various cardiovascular diseases such as hypertension, pulmonary hypertension, shock and myocardial injury. The genomic basis of cystathioninuria in humans is 2 nonsense and 2 sense mutations in CSE. This review reveals that H2S is a new endogenous gaseous transmitter in the cardiovascular system.
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Chronic Inhibition of Na+/H+-Exchanger in the Heart
More LessThe incidence and prevalence of heart failure (HF) has increased over the last decades. The main reasons for this increase are the ageing population and an increase in survival rate after myocardial infarction and other cardiovascular diseases. Although, pharmacotherapy has significantly improved survival, the prognosis of HF is still rather poor. Total mortality is high and approximately half of the deaths are sudden and unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors generally given with diuretic and digoxin are the standard treatment for patients with HF. Despite the established benefits of ACE-inhibitors there is a need for new pharmacological tools for the treatment of HF. Recent experimental evidence has shown that activity of the Na+/H+-exchanger in the heart (NHE-1) is increased in HF. Because NHE-1 exchanges intracellular H+ for extracellular Na+ in a one by one stoichiometry, the intracellular ionic changes resulting from increased activity, will be a increased pHi and intracellular sodium ([Na+]i). Activation of NHE-1 results only in a small increase in pHi, under physiological conditions where bicarbonate-dependent mechanisms are active. However, a considerable increase in [Na+]i was always present. The elevation of [Na+]i might be responsible for the increase of intracellular calcium ([Ca2+]i) levels mediated by the Na+/Ca2+-exchanger (NCX). Increases in [Na+]i, pHi and [Ca2+]i, features of cardiac myocytes isolated from failing hearts, are recognized as a cell growth signal And thus may play a role in the hypertrophic response, cellular remodeling and finally the development of HF. Acute application of cariporide, an inhibitor of NHE-1, on failing myocytes not only normalized [Na+]i but also cytoplasmic and sarcoplasmic reticulum calcium handling and the propensity to develop delayed after depolarizations (DAD's). In several animal models of HF it has been shown the chronic inhibition of NHE-1 attenuates the development of hypertrophy and whole heart remodeling. Recently, in a volume and pressure overload model of HF in rabbits it has been demonstrated that chronic treatment also prevents the development of HF and cellular ionic and electrophysiological remodeling. Therefore, chronic treatment with an inhibitor of NHE-1 might prove beneficial in patients at risk of developing HF, especially when given at an early stage.
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Thrombolytic Therapy in Acute Ischemic Stroke - Basic Concepts
Authors: Atte Meretoja and Turgut TatlisumakThrombolytic therapy with alteplase in acute ischemic stroke is currently established within 3 h from symptom onset in carefully selected patients. Expansion of the time window is being assessed in trials with alteplase and desmoteplase. Also, tenecteplase, reteplase and staphylokinase are being evaluated in stroke patients. A better understanding of the coagulation and fibrinolytic systems may provide insight into drug development, interactions, complications, and may ultimately improve patient triage and treatment regimens. Future adjuvant and additional therapies could prove useful for patients who do not benefit from standard thrombolytic treatment or may augment the overall gain.
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Towards Newer Molecular Targets for Chronic Diabetic Complications
Authors: Zia A. Khan, Hana Farhangkhoee and Subrata ChakrabartiPrior to the discovery of insulin, the major cause of death in the diabetic population was ketoacidosis. Although insulin and improved glycemic control have improved the longevity of diabetic patients, they still suffer from significant morbidity and mortality due to chronic secondary complications. Long standing diabetes leads to structural and functional alterations in both the micro- and macrovasculature. These complications, involving the retina, kidney, and peripheral nerves, as well as cardiovascular system, severely compromise the quality and expectancy of life. Large scale clinical trials have identified hyperglycemia as the key determinant for the development of such complications. Therapeutic modalities have been developed to target glucose-induced alterations, such as protein kinase C activation, augmented polyol pathway activity, non-enzymatic glycation and oxidative stress to ameliorate chronic complications. However, clinical trials targeting these biochemical alterations have failed to show significant beneficial effects. The plethora of biochemical anomalies that govern the development of chronic diabetic complications may therefore be subject to cross-interaction and complex interplays. Studies in both animal and human diabetes have, however, showed alteration of several vasoactive effector molecules such as endothelins. These molecules may be instrumental in mediating diabetes-induced structural and functional deficits at both the early and late stages of the disease. This review will discuss the current mechanistic understanding of chronic diabetic complications and will explore the potential novel therapeutic interventions.
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Therapeutic Potential of Endothelial Progenitor Cells for Cardiovascular Diseases
Authors: Lijing Jia, Masafumi Takahashi, Toru Yoshioka, Hajime Morimoto, Hirohiko Ise and Uichi IkedaIn the past decade, researchers have defined committed stem or progenitor cells from various tissues, including bone marrow, peripheral blood, brain, liver and reproductive organs, in both adult animals and humans. Recently, endothelial progenitor cells (EPCs) were isolated from peripheral blood mononuclear cells and were shown to be incorporated into foci of neovascularization. This finding that circulating EPCs may home into sites of neovascularization and differentiate into mature endothelial cells in situ is consistent with the concept of 'vasculogenesis' and suggests that vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization. Furthermore, experimental and clinical studies on ischemic cardiovascular diseases suggest a therapeutic potential for EPC transplantation. In this review, we summarize the biological features of EPCs and discuss their therapeutic potential for the treatment of cardiovascular diseases.
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Angiotensin II Regulates Vascular and Endothelial Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor Signaling in the Vasculature
Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT1), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT1 receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.
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The Effects of Obesity-Related Peptides on the Vasculature
Authors: Michael R. Skilton and David S. CelermajerObesity and its related metabolic diseases, including type 2 diabetes, are associated with alterations in the circulating levels of various peptides. These include the adipocytokines (peptides released by adipocytes which circulate, such as leptin, adiponectin and resistin), and other peptides whose levels are altered in association with obesity (such as ghrelin, neuropeptide Y, interleukin-1β and tumour necrosis factor-α). While the primary action of these peptides is linked with the regulation and maintenance of energy balance and metabolism, many of them have also been shown to possess vasoactive, inflammatory and other properties that influence vascular biology, vascular physiology and atherogenesis. As such, they may form an important mechanistic link between obesity and cardiovascular disease. In this review, we will outline the vasoactive properties of adipocytokines and other obesity-related peptides. In particular, as pharmacotherapies suggested to achieve weight loss will alter the pathways associated with these peptides, such treatments might have either beneficial or deleterious effects on the incidence and progression of cardiovascular disease.
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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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