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- Volume 12, Issue 6, 2014
Current Vascular Pharmacology - Volume 12, Issue 6, 2014
Volume 12, Issue 6, 2014
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Mechanisms of Renal Microvascular Dysfunction in Type 1 Diabetes: Potential Contribution to End Organ Damage
More LessThe mechanisms underlying initiation and progression of diabetic nephropathy are not well understood, despite the fact that diabetes represents the chief underlying cause of end-stage renal disease. The onset of diabetic hyperglycemia is now known to evoke functional alterations in the renal microvasculature, glomeruli and tubular epithelium. Although the scope of these effects is not yet fully recognized, the renal vascular dysfunction evident early after onset of T1D likely encompasses impaired electromechanical coupling in preglomerular vascular smooth muscle and altered interactions between tubular transport and vascular function. These changes, which arise in environment conducive to oxidative stress and inflammation, are thought to either initiate or facilitate the eventual development of diabetic nephropathy in susceptible individuals.
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Myogenic Tone as a Therapeutic Target for Ischemic Stroke
Authors: Sara M. Palomares and Marilyn J. CipollaIschemic stroke causes vascular paralysis and impaired autoregulation in the brain, the degree of which is dependent on the depth and duration of ischemia and reperfusion (I/R). Ischemic stroke also impairs the myogenic response of middle cerebral arteries (MCA) that may be an underlying mechanism by which autoregulation is impaired. Myogenic responses are affected by I/R through several mechanisms, including production of peroxynitrite, depolymerization of F-actin in vascular smooth muscle, and circulating vasoactive factors. The vascular endothelium is also significantly affected during focal ischemia that has a particularly large influence on vascular tone in the cerebral circulation. Endothelial nitric oxide (NO) and endothelin-1 (ET-1) are important endothelium-dependent vasoactive substances that can influence the level of myogenic tone in cerebral arteries and arterioles that are significantly affected during ischemic stroke. Unlike MCA, brain penetrating arterioles have considerable myogenic tone that appears less affected by focal ischemia. The persistent tone of brain parenchymal arterioles during focal ischemia could contribute to perfusion deficit and infarct expansion. These arterioles within the cerebral cortex are also unique from MCA in that they constrict to small– and intermediate- conductance calcium-activated potassium channel (SKCa and IKCa, respectively) inhibition, suggesting basal endothelium-derived hyperpolarizing factor (EDHF) is preserved during focal ischemia. This review will highlight our current understanding of the effects of I/R on myogenic response in both MCA and parenchymal arterioles and discuss underlying mechanisms by which focal ischemia affects myogenic tone in these different vascular segments.
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Renal Blood Flow Dynamics in Inbred Rat Strains Provides Insight into Autoregulation
Authors: Nicholas G.A. Mitrou and William A. CupplesRenal autoregulation maintains stable renal blood flow in the face of constantly fluctuating blood pressure. Autoregulation is also the only mechanism that protects the delicate glomerular capillaries when blood pressure increases. In order to understand autoregulation, the renal blood flow response to changing blood pressure is studied. The steadystate response of blood flow is informative, but limits investigation of the individual mechanisms of autoregulation. The dynamics of autoregulation can be probed with transfer function analysis. The frequency-domain analysis of autoregulation allows investigators to probe the relative activity of each mechanism of autoregulation. We discuss the methodology and interpretation of transfer function analysis. Autoregulation is routinely studied in the rat, of which there are many inbred strains. There are multiple strains of rat that are either selected or inbred as models of human pathology. We discuss relevant characteristics of Brown Norway, Spontaneously hypertensive, Dahl, and Fawn-Hooded hypertensive rats and explore differences among these strains in blood pressure, dynamic autoregulation, and susceptibility to hypertensive renal injury. Finally we show that the use of transfer function analysis in these rat strains has contributed to our understanding of the physiology and pathophysiology of autoregulation and hypertensive renal disease.Interestingly all these strains demonstrate effective tubuloglomerular feedback suggesting that this mechanism is not sufficient for effective autoregulation. In contrast, obligatory or conditional failure of the myogenic mechanism suggests that this component is both necessary and sufficient for autoregulation.
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Endogenous Events Modulating Myogenic Regulation of Cerebrovascular Function
Authors: Debebe Gebremedhin, Sandeep Gopalakrishnan and David R. HarderThe existence of arterial myogenic tone was first described by Bayliss in 1902, however, its association with pressure-dependent membrane depolarization was not observed until 1984. The factors that mediate myogenic arterial constriction remain unknown. One possible clue was a finding by our laboratory that cerebral arterial muscle cells express CYP 4A ω-hydroxylase enzyme that catalyzes the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid (AA), the production of which increased by elevations of intravascular pressure. 20-HETE activates protein kinase C (PKC), inhibits Ca2+-activated K+ (KCa) channels, depolarizes arterial muscle cell membrane, activates L-type Ca2+ channels, increases intracellular Ca2+ ([Ca2+]i) and mediates autoregulation of cerebral blood flow. Emerging evidence indicates that 20-HETE level increases in ischemia/reperfusion injury and stimulates production of reactive oxygen species (ROS) resulting in oxidative stress induced ischemic stroke injury, which can be prevented by inhibition of 20-HETE synthesis or action. The brain also expresses CYP epoxygenases that convert AA to the vasodilator epoxyeicosatrienoic acids (EETs), the production of which increases in ischemia and provide protection against ischemia-induced tissue damage. Basal or stimulus released ROS act to modify cerebral myogenic tone. Similar to other enzymes CYP epoxygenase and ω-hydroxylase also generate ROS that modify myogenic cerebral reactivity. Hypoxia per se or adenosine released during hypoxia induces increased production of ROS that alter cerebrovascular function. The capacity of the brain to express CYP enzymes that produce bioactive EETs and 20-HETE and generate ROS has a significant bearing in regulating the dynamics of cerebral blood flow and serve as potential therapeutic targets for the management of pathologic disorders of the cerebral circulation.
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P2 Receptors in Renal Autoregulation
Authors: Zhengrong Guan, Robert C. Fellner, Justin Van Beusecum and Edward W. InschoAutoregulation of renal blood flow and glomerular filtration rate is an essential function of the renal microcirculation. While the existence of this phenomenon has been known for many years, the exact mechanisms that underlie this regulatory system remain poorly understood. The work of many investigators has provided insights into many aspects of the autoregulatory mechanism, but many critical components remain elusive. This review is intended to update the reader on the role of P2 purinoceptors as a postulated mechanism responsible for renal autoregulatory resistance adjustments. It will summarize recent advances in normal function and it will touch on more recent ideas regarding autoregulatory insufficiency in hypertension and inflammation. Current thoughts on the nature of the mechanosensor responsible for myogenic behavior will be also be discussed as well as current thoughts on the mechanisms involved in ATP release to the extracellular fluid space.
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Myogenic Properties of Brain and Cardiac Vessels and their Relation to Disease
Authors: Ashley S. Izzard and Anthony M. HeagertyIntrinsic arterial myogenic function comprises the degree of constriction (myogenic tone), the arterial constriction to an increase in intraluminal pressure and vice versa (myogenic response), and forced dilation at high intraluminal pressure. Although the development of myogenic tone at 40-60 mmHg involves the influx of calcium (Ca2+) through voltage- dependent Ca2+ channels and an elevation in arterial intracellular Ca2+ (Ca2+ i), myogenic responses between 60-140 mmHg involves predominantly Rho kinase (ROK)-mediated changes in Ca2+ sensitivity. In the cerebral circulation an impaired myogenic response results in impaired cerebral autoregulation and susceptibility hypertension-induced cerebral haemorrhage. An impaired cerebral artery myogenic response, due to blunted ROK mediated changes in Ca2+ sensitivity, may be a consequence of defective mechanotransduction of the intraluminal pressure stimulus; this may be a result of abnormalities in the extracellular matrix. In the coronary circulation distinctions between the mechanisms involved in the development of myogenic tone and the myogenic response have not been clearly defined. However, coronary artery myogenic tone is dependent on both Ca2+ entry through voltage –dependent Ca2+ channels and protein kinase C (PKC) activity. Impaired coronary myogenic tone has been observed in animal models of disease but the implications of these findings are currently uncertain.
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Vildagliptin Restores Renal Myogenic Function and Attenuates Renal Sclerosis Independently of Effects on Blood Glucose or Proteinuria in Zucker Diabetic Fatty Rat
Type 2 diabetes mellitus (T2DM) is associated with risk for chronic kidney disease (CKD), which is associated with a decrease in renal myogenic tone - part of renal autoregulatory mechanisms. Novel class of drugs used for the treatment of T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitors, have protective effects on the cardiovascular system. A Zucker Diabetic Fatty (ZDF) rat is an animal model of T2DM that displays progressive nephropathy in which inflammation leads to initiation of renal fibrosis and CKD. We hypothesized that CKD in the ZDF rat is related to decrease in myogenic constriction (MC) of intrarenal arteries and that treatment with the DPP-4 inhibitor, vildagliptin, prevents such changes. Renal arteries isolated from 25 weeks old lean, ZDF and ZDF treated with vildagliptin (n=7 in each group) were transferred to an arteriograph to assess agonist and pressure induced contractile responses. Furthermore, blood glucose, proteinuria, focal glomerulosclerosis (FGS) and p22phox mRNA expression of renal tissue were measured. Compared to lean controls, ZDF had significantly increased plasma glucose and cholesterol levels, focal glomerulosclerosis and interstitial α-SMA expression, and urinary protein excretion. ZDF rats also had impaired MC of renal arteries and increased renal p22phox expression. Vildagliptin did not affect plasma glucose levels or proteinuria, but effectively decreased glomerulosclerosis and restored MC and p22phox expression to the levels found in lean rats. Based on these data, it can be suggested that vildagliptin treatment protects diabetic rats from the loss of renal vascular reactivity and the development of glomerulosclerosis perhaps secondary to a reduction in oxidative stress.
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Molecular Mechanisms of Renal Blood Flow Autoregulation
Authors: Marilyn Burke, Mallikarjuna R. Pabbidi, Jerry Farley and Richard J. RomanDiabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater transmission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the myogenic response of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteriole in response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the factors initiating the myogenic response and the signaling pathways involved in the myogenic response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myogenic control of renal vascular tone, the interrelationships between the myogenic response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients.
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Impaired Renal Autoregulation in Susceptible Models of Renal Disease
Authors: Sydney Murphy and Jan M. WilliamsOne of the major functions of the kidney is to maintain constant renal blood flow and glomerular filtration rate in response to increases in renal perfusion pressure. This phenomenon is referred to autoregulation and involves two independent mechanisms: tubular glomerular feedback and myogenic response. The latter, the renal myogenic response, involves constriction of the preglomerular vasculature to increases in transmural pressure. Over the last three decades, there has been substantial evidence that demonstrates that the myogenic response plays an important role in protecting the kidney from hypertension-induced renal injury. Furthermore, impairment of the renal myogenic response allows the transmission of systemic pressures to the glomerular capillaries leading to the development of glomerular injury and progressive proteinuria during hypertension. This review article discusses the role of the myogenic response in the pathogenesis of renal disease in various genetic and experimental rodent models that develop hypertension-induced renal injury.
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Pleiotropic Effects of Statin in Therapy in Heart Failure: A Review
Clinical trials demonstrated that statin therapy is associated with a significant reduction in cardiovascular morbidity and mortality when used for either primary or secondary prevention of cardiovascular events. Several studies have shown that statins, having an important effect in the prevention of acute coronary syndromes, are also able to prevent heart failure (HF) in patients with coronary artery disease. This review summarizes the experimental and clinical evidence regarding the role of statins in the management of HF.
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Different Patterns of Statin Use in Patients with Acute Myocardial Infarction
Authors: Stella S. Daskalopoulou, Robert J. Doonan, Joseph A. Delaney and Louise PiloteBackground/Objective: Statins have well-established cardiovascular benefits, and recent evidence suggests that discontinuing statin therapy after acute myocardial infarction (AMI) is harmful. Our objective was to assess the association between statin discontinuation post-AMI and 1-year all-cause mortality in a real world setting. Methods: Data on survivors of AMI between 2000 and 2007 were extracted from the hospital discharge summary database of Quebec and the provincial physician and drug claims database. Statin prescription filling was used to establish cohort groups. Previous statin use was defined as having filled a statin prescription in the 90 days pre-AMI, while post-AMI statin use was filling a prescription between discharge from hospital post-AMI and 90 days post-discharge. AMI patients who survived 90 days (n=48,229) were divided into 4 groups: i) non-users (n=11,657), did not receive statins pre- or post- AMI (reference group), ii) starters (n=22,452), received statins only post-AMI, iii) stoppers (n=488), received statins prebut not post-AMI, and, iv) users (n=13,632), received statins pre- and post-AMI. Cox proportional hazards models were used to calculate hazard ratios (HR). Results: Compared with non-users, stoppers had increased 1-year all-cause mortality (adjusted HR 1.36; 95% CI 1.08- 1.70, P=0.008). Starters (HR 0.65; 95% CI 0.59-0.71, P<0.0001) and users (HR 0.81; 95% CI 0.74-0.88, P<0.0001) had lower mortality than non-users. Conclusion: Discontinuation of statins in survivors of AMI was associated with an increase in 1-year all-cause mortality. Physicians should use caution when discontinuing statins post-AMI.
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Effect of Low Molecular Weight Heparins and Fondaparinux Upon Thrombin Generation Triggered by Human Pancreatic Cancer Cells BXPC3
Low molecular weight heparins (LMWHs) and fondaparinux are widely used for prophylaxis and treatment of venous thromboembolic disease in cancer patients. However, the optimization of the antithrombotic treatment especially in patients with adenocarcinoma of the pancreas is a challenging issue. The understanding of the mechanism of action of the LMWHs and fondaparinux in cancer-induced hypercoagulability might help to optimize antithrombotic treatment. To this aim, we investigated the influence of BXPC3 pancreas adenocarcinoma cells on the antithrombotic activity of LMWHs and fondaparinux. Thrombin generation (TG) in normal platelet poor (PPP) and platelet rich plasma (PRP) spiked with clinically relevant concentrations of dalteparin, enoxaparin, nadroparin tinzaparin and fondaparinux was assessed with the Calibrated Automated Thrombogram assay. BXPC3 (5 cells/μl) were added to plasma. The mean rate index (MRI) of the propagation phase of TG and the endogenous thrombin potential (ETP) were analyzed. The IC50 of the studied compounds were determined and compared on the basis of anti-Xa and anti-IIa equivalent units. We demonstrate that the specific antithrombin (AT)-dependent anti-Xa activity of LMWHs and fondaparinux almost selectively inhibits the propagation phase of TG. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the selective inhibition of FXa warrants abrogation of TG. The mean molecular weight and anti-Xa/anti-IIa ratio of the AT-dependent agents cannot predict the alteration of their capacity to inhibit TG. Tinzaparin was the most potent inhibitor of TG than the other LMWHs. Enoxaparin was more potent than nadroparin and dalteparin.
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Exploring In-hospital Death from Myocardial Infarction in Eastern Europe: From the International Registry of Acute Coronary Syndromes in Transitional Countries (ISACS-TC); on the Behalf of the Working Group on Coronary Pathophysiology & Microcirculation of the European Society of Cardiology
Introduction: The aim of the current study was to investigate the outcomes of coronary reperfusion therapies and ST-segment elevation myocardial infarction (STEMI) in patients of Eastern countries with economies in transition. Federation, and Serbia. The overall population consisted of 23,486 consecutive patients admitted to hospitals from January 1st to December 31st 2009. Registry data and statistics from the Organization for Economic Cooperation and Development (OECD) countries for the same period were used for comparison (2009-2010). In-hospital mortality was between 4% and 5% in the Western countries. In comparison mortality data were significantly larger in Serbia (10.8%) and Bosnia and Herzegovina (11.2%), intermediate in Russian Federation (7.2%) and similar in Hungary (5.0%). The rates of primary percutaneous coronary intervention (primary PCI) were very low in Bosnia and Herzegovina (18.3%), low in Russian Federation (20.6%) and Serbia (22%), and high in Hungary (70%). Major risk factors for death appear to be lack of reperfusion therapy, longer time delay from symptoms onset to hospital presentation as well as the higher percentage of patients with clinical presentation in Killip class III/IV. Conclusion: In-hospital STEMI case-fatality rates ranges widely in the former Eastern Bloc countries. Beyond the quality of care provided in hospitals, differences in time delay from symptoms onset to hospital admission may strongly influence STEMI patients’ outcome.
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Volumes & issues
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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)