Pressor Substance Research Articles

Is there a role for endothelial dysfunction in the pathogenesis of lumbar disc degeneration? A hypothesis that needs to be tested

Low back pain is a painful condition affecting most people at least once in their life. It can be the expression of lumbar disc degeneration, a condition whose progression is influenced by environmental, individual and genetic factors. The pathogenesis of this condition implies the reduction of sustenance for the tissues within the intervertebral disc (ID) due to a decreased blood flow in the local microcirculation. In fact, it is known that the ID is an avascular structure that receives nutritive molecules and exchanges waste products through a process of osmotic diffusion from the capillaries located at the ID–vertebral body interface. The maintenance of a correct oxygen supply is essential for the health of disc cells also because ID is subjected to continuous compression stress due to its bearing function between vertebral bodies. This vital condition is guaranteed by proper dilation of blood vessels in response to mechanical stress, thanks to a finely balanced homeostasis between vasodilatory factors, such as nitric oxide, and vasoconstrictive substances produced by the endothelium. Endothelial dysfunction may disrupt this delicate equilibrium, causing a reduced oxygen supply eventually resulting in ID degeneration.Our hypothesis is that endothelial dysfunction, a systemic condition of reduced vessel dilation in response to mechanical stress, should be considered as an important pathological factor implicated intervertebral disc degeneration. This relationship may pave the way for a change in therapeutic approach to low back pain, especially in the early stages.

English

With progressive vascular dysfunction, the endothelial cells mediate increased vessel tone by the synthesis and release of the vasoconstrictor substances primarily endothelin and endothelium-derived constricting factor(s), and by reduced elaboration of vasodilator products primarily nitric oxide. With this background, our study sought correlation of altered lipid profile; a cause of progressive vascular dysfunction, to the relative derangement of the two contrasting vascular biomarkers with respect to anthropometry in apparently healthy individuals. This was a case-control pilot study comprising of 30 overweight/obese healthy subjects (BMI >= 25 kg/m2 and/or WHR (female>0.85; male>1) and 30 non-obese healthy subjects (BMI< 25 kg/m2 and/or WHR (female<0.85; male<1) excluding all subjects with secondary cause of abnormal blood flow. Reactive hyperemia (RH) for indirect evaluation of nitric oxide levels was measured by impedance plethysmography (NICOMON, Larsen & Toubro) in the subject's forearm along with fasting plasma glucose, serum lipids and serum endothelin-1. A significant difference in blood flow index (BFI) at 1 min post-occlusion time (mean ± % SD) {control 1.81 ± 0.42 vs. study 1.60 ± 0.38} (P=0.041) was detected but RH, plasma glucose, lipid profile and serum endothelin were comparable in both the groups with lipid profile derangement present in either group, though not significant. So the two groups were clubbed to seek further association. Out of the two contrasting biomarkers, endothelin-1 and nitric oxide, only latter was significantly altered (raised) in subjects with deranged serum VLDL (P=0.026) and serum triglyceride (P=0.044). Therefore we concluded that altered lipid profile irrespective of measured anthropometric variables, affects the release of nitric oxide and it's like, before any detectable change in serum endothelin-1 levels. This in turn suggested the use of the former to predict the 'subclinical prelude' to 'manifest' metabolic disorder in such apparently healthy subjects and thus ensuring timely premorbid level care.

Current state of endothelin receptor antagonism in hypertension and pulmonary hypertension.

Endothelin 1 (ET-1), a potent vasoconstrictive substance, was discovered in 1988 by Yanagisawa and colleagues, and since then, a quarter of a century has passed. Understanding the biology of ET-1 has rapidly developed by characterizing the components of its receptors and processing enzymes. Numerous studies have revealed not only physiological but also various pathophysiological roles of the ET system. At first, ET-1 was the attractive and promising target for the treatment of hypertension owing to its potent vasoconstrictive nature and a variety of ET receptor antagonists (ERAs) were studied. However, the clinical application to treat hypertension was disappointing because of the side effects, including liver toxicity and fluid retention. On the other hand, ERAs have been established as orphan drugs for the treatment of pulmonary arterial hypertension and improved the prognosis of patients. Furthermore, multipotency of the ET system in the pathogenesis of multiple diseases has led to the development of translational research not only in the field of hypertension but in a variety of fields. Furthermore, a range of studies are ongoing to apply ERAs to clinical situations. In this article, we review the pathophysiological roles of the ET system in hypertension and pulmonary hypertension and the potential of ET receptor antagonism for the treatment of these diseases.

The evolution of insulin glargine and its continuing contribution to diabetes care.

The epoch-making discovery of insulin heralded a new dawn in the management of diabetes. However, the earliest, unmodified soluble insulin preparations were limited by their short duration of action, necessitating multiple daily injections. Initial attempts to protract the duration of action of insulin involved the use of various additives, including vasoconstrictor substances, which met with limited success. The subsequent elucidation of the chemical and three-dimensional structure of insulin and its chemical synthesis and biosynthesis allowed modification of the insulin molecule itself, resulting in insulin analogs that are designed to mimic normal endogenous insulin secretion during both fasting and prandial conditions. Insulin glargine was the first once-daily, long-acting insulin analog to be introduced into clinical practice more than 10 years ago and is specifically designed to provide basal insulin requirements. It has a prolonged duration of action and no distinct insulin peak, making it suitable for once-daily administration and reducing the risk of nocturnal hypoglycemia that is seen with intermediate-acting insulins. Insulin glargine can be used in combination with prandial insulin preparations and non-insulin anti-diabetic agents according to individual requirements.Electronic supplementary materialThe online version of this article (doi:10.1007/s40265-014-0226-4) contains supplementary material, which is available to authorized users.

Reduced skin reactivity to vasoconstrictor and vasodilator substances in atopic eczema

Atopic eczema is a common chronic inflammatory disease with itchy skin and altered skin reactions to acetylcholine and nicotinic acid compared to healthy non-atopic individuals. The aim of this study was to evaluate skin reactivity to 11 vasoactive substances and peptides by skin prick and intradermal tests in 20 patients with atopic eczema and 20 healthy controls. Skin reactions, blanching, wheal and flare areas were measured by planimetry, 15 minutes after provocation. Patients with atopic eczema had significantly smaller reactions at certain concentrations of the vasodilators acetylcholine, bradykinin, calcitonin gene-related peptide, substance P and vasoactive intestinal peptide for flare, and of substance P and vasoactive intestinal peptide for wheals, in intradermal testing and/or in skin prick testing. Testing of the vasoconstrictors angiotensin-II, arginine-vasopressin, endothelin-1 and noradrenaline in atopic eczema resulted in significantly smaller reactions at certain concentrations for blanching in intradermal testing and/or skin prick testing. Significantly smaller reactions were seen with arginine-vasopressin for wheals and with arginine-vasopressin and noradrenaline for flares in intradermal testing and/or skin prick testing at certain concentrations. Significantly larger wheals were seen with angiotensin-II and endothelin-1 in intradermal testing and/or skin prick testing at certain concentrations. No significant differences were found for prostaglandin E2. These results demonstrate not only a reduced responsiveness to vasodilators but also to vasoconstrictor substances and peptides in patients with atopic eczema, which may be considered a general feature of atopic eczema skin.

Combined Antiplatelet Therapy: Still a Sweeping Combination in Cardiology

Platelets play a key role in the pathogenesis of atherothrombosis, involved in both the development and progression of atherosclerotic heart disease, and the attendant acute thrombotic complications. Antiplatelet therapy constitutes a mainstay therapy for patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, dual antiplatelet therapy (DAPT) for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin plus clopidogrel. However, a most important pertaining issue emerged, that of the occurrence of drug-resistance or tolerance observed in some patients for both these antithrombotic agents, which limited the efficacy and applicability of this combined therapy.The availability of the newer thienopyridine, prasugrel, and the cyclopentyl-triazolopyrimidine, ticagrelor, represents an important addition to the physician's armamentarium. Dual antiplatelet therapy with aspirin and clopidogrel or one of the newer agents interferes with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A2, which is a prothrombotic and vasoconstrictive substance. Thienopyridines (clopidogrel/prasugrel) irreversibly and ticagrelor reversibly prevent and inhibit platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y12 receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Each of these antiplatelet agents has a protective effect against adverse vascular events; classical DAPT with aspirin and clopidogrel has an even stronger antiplatelet effect compared with either agent alone, however DAPT combining aspirin with one of the newer more potent agents translates into superior antithrombotic protection in atherothrobotic vascular disease, albeit at an increased, though not inordinately, risk for bleeding complications. A number of randomized clinical trials have demonstrated and confirmed the incremental benefit and efficacy of DAPT with use of either classical or newer agents, above and beyond that of each antiplatelet agent alone. Data have also been obtained from studies where indications for the use of DAPT continue to expand into other patient groups, rendering and maintaining DAPT a sweeping combination in Cardiology. This article is a comprehensive review of all these data and the landmark trials on the two classical and also the newer antiplatelet agents, the issues involved and the current recommendations for their use in patients with atherosclerotic heart disease and other cardiovascular disorders and procedures.

Effect of Anger on Endothelial-derived Vasoactive Factors in Spontaneously Hypertensive Rats

We tested whether anger affects the balance between endothelium-derived vasodilators and vasoconstrictors in spontaneously hypertensive rats (SHRs). Five endothelium-produced vasoactive factors (nitric oxide, prostacyclin, urotensin, endothelin and thromboxane B2) were measured in an established SHR behavioural model of anger, in "non-angry" SHR rats, and in control Wistar-Kyoto rats. All angry SHR rats showed the typical angry behaviour and angry SHR rats had significantly higher blood pressure and heart rate than control rats. Angry rats had significantly lower levels of two vasodilators, nitric oxide and prostacyclin, and significantly higher levels of two vasoconstrictors, endothelin and thromboxane B2 than either non-angry SHR or control rats. Levels of a third vasoconstrictor, urotensin, were significantly lower in angry SHR than in non-angry SHR or control rats. Our results suggest that anger causes an imbalance of endothelium-produced vasodilating and vasoconstricting substances. This may have implications for the development and/or progression of hypertension.

ATP as a mediator of erythrocyte‐dependent regulation of skeletal muscle blood flow and oxygen delivery in humans

In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation. This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g(-1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise. Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle.

Twenty-Four-Hour Patterns in Occurrence and Pathophysiology of Acute Cardiovascular Events and Ischemic Heart Disease

The scientific literature clearly establishes the occurrence of cardiovascular (CV) accidents and myocardial ischemic episodes is unevenly distributed during the 24 h. Such temporal patterns result from corresponding temporal variation in pathophysiologic mechanisms and cyclic environmental triggers that elicit the onset of clinical events. Moreover, both the pharmacokinetics and pharmacodynamics of many, though not all, CV medications have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. Twenty-four-hour rhythmic organization of CV functions is such that defense mechanisms against acute events are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent evening (in diurnally active persons), to aggressive mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables, such as blood pressure (BP), heart rate (HR), rate pressure product (systolic BP × HR, surrogate measure of myocardial oxygen demand), sympathetic activation, and plasma levels of endogenous vasoconstricting substances, are aligned together at the same circadian time, the risk of acute events becomes significantly elevated such that even relatively minor and usually harmless physical and mental stress and environmental phenomena can precipitate dramatic life-threatening clinical manifestations. Hence, the delivery of CV medications needs to be synchronized in time, i.e., circadian time, in proportion to need as determined by established temporal patterns in risk of CV events, and in a manner that averts or minimizes undesired side effects. (Author correspondence: prf@unife.it)

Forthcoming Issues

We sought to identify soluble vasoconstrictor substances that are released during stent implantation into saphenous vein aortocoronary bypass grafts.Atherosclerotic saphenous vein aortocoronary bypass grafts are particularly vulnerable to plaque rupture. Protection devices prevent particulate debris from being embolized. Additional soluble vasoconstrictor substances possibly also contribute to impaired microvascular perfusion.Peripheral venous blood (VB) and aspirate (AS) were obtained from 14 patients with a significant stenosis in a saphenous vein graft during stent implantation under protection with a distal balloon occlusion device. In five additional patients, arterial blood (AB) was also taken distal to the stented lesion before intervention. Vasomotor substances in VB, AB, and AS plasma were identified in a bioassay of rat mesenteric arteries with intact (+E) and denuded endothelium (−E). Vasoconstriction was normalized to that induced by potassium chloride depolarization (100%).Venous blood, AB, and AS plasma induced maximum vasoconstriction within six minutes. The AS plasma induced a vasoconstriction of 138 ± 13% (−E) and 87 ± 14% (+E); VB, of 70 ± 14% (−E) and 23 ± 4% (+E); and AB plasma obtained before intervention, of 49 ± 9% (−E) and 36 ± 8% (+E). The vasoconstrictor potency of AS plasma in endothelium-denuded vessels was related to the severity of anginal symptoms, angiographic stenosis severity, plaque volume, and plaque burden as determined by intravascular ultrasound. The AS plasma-induced vasoconstriction was largely attenuated by combined serotonin/5-hydroxytryptamine (5-HT)2A/2C- and 5-HT1A/1B-receptor blockade and eliminated by additional thromboxane A2 thromboxane-prostanoid (TP)-receptor blockade.Stent implantation releases, apart from and in addition to particulate debris, soluble vasoconstrictor substances that possibly contribute to impaired microvascular perfusion.

Soluble CD163, a marker of Kupffer cell activation, is related to portal hypertension in patients with liver cirrhosis

Activation of Kupffer cells may be involved in the pathogenesis of portal hypertension by release of vasoconstrictive substances and fibrosis due to co-activation of hepatic stellate cells. To study soluble plasma (s) CD163, a specific marker of activated macrophages, as a biomarker for portal hypertension in patients with liver cirrhosis. We measured sCD163 concentration and the hepatic venous pressure gradient (HVPG) by liver vein catheterisation in 81 cirrhosis patients (Child-Pugh CP-A: n = 26, CP-B: n = 29, CP-C: n = 26) and 22 healthy subjects. We also measured their cardiac output (CO), cardiac index and systemic vascular resistance (SVR). Liver status was examined by Child-Pugh and MELD-score. In cirrhosis, sCD163 concentration was nearly three times higher than in controls (4.7 ± 2.5 vs. 1.6 ± 0.5 mg/L, P < 0.001). sCD163 was also higher, as measured in steps by CP-score (P < 0.001). The HVPG rose steeply to an asymptote of 22 mmHg with sCD163 up to about 5 mg/L and not to higher values with higher sCD163. In a multivariate analysis, sCD163 was the only independent predictor of the HVPG but did not predict any of the systemic circulatory findings. sCD163 > 3.95 mg/L (upper normal limit) predicted HVPG ≥ 10 mmHg with a positive predictive value of 0.99. Circulating sCD163 originating from activated Kupffer cells is increased in cirrhosis with increasing Child-Pugh score and with increasing HVPG, and it is an independent predictor for HVPG. These findings support a primary role of macrophage activation in portal hypertension, and may indicate a target for biological intervention.

Increased urotensin-II activity in patients with Raynaud’s phenomenon and systemic lupus erythematosus

Raynaud's phenomenon (RP) commonly co-exists with systemic lupus erythematosus (SLE). The obvious pathophysiological mechanism in RP is vasoconstriction. Although the roles of certain vasoconstrictor substances, like endothelin-1, have been identified in RP, underlying mechanisms remain unclear. In this pilot study, we researched a relatively recently identified, very potent vasoconstrictor peptide, urotensin-II (U-II), in SLE patients versus those without RP. In addition to its vasoconstrictor effect, U-II has been implicated in cardiovascular events and atherosclerosis. Increased frequencies of atherosclerosis and cardiovascular events comprise another issue in SLE patients. To address these effects, we included 15 Raynaud's (+) and 15 Raynaud's (-) SLE patients and compared both cohorts against age and sex-matched controls. We found significantly elevated U-II activity in both RP (+) and RP (-) SLE patients, relative to controls (P < 0.0001); however, the difference among RP (+) SLE patients was more prominent. U-II was significantly elevated in RP (+) SLE patients when compared to RP (-) SLE patients (P < 0.001). The results of our study suggest that, either as a cause or by-product, U-II may have some role in Raynaud's-related vasoconstriction. It also might contribute to atherosclerosis and cardiovascular diseases in SLE patients. Further studies clearly are warranted.

Single Ventricle By-Pass: the Fontan-Kreutzer Procedure. Novel Human Circulation

* National Honorary Member and Ex President of Sociedad Argentina de Cardiologia. Ex Chief of Cardiology Unit Hospital de Nnos Ricardo Gutierrez In the evolutionary scale there are many species whose hearts have one (fishes) or two (amphibians and some reptiles) auricles, but only one ventricular chamber. In mammals and humans are the four known chambers. There is, however, a group of congenital heart diseases in humans in which the blood circulation is sustained by a single ventricle, either by hypoplasia of the other as seen in tricuspid atresia or by the visible absence of the other in the different shapes of univentricular heart. They have similar cameras to the left ventricle or right ventricle or to more undifferentiated, primitive and difficult ones to classify. Many of these hearts are frequently associated with asplenia and other types of visceral heterotaxies. The chances of surviving to reach adulthood are scarce and if this occurs should be essentially to the fact of having a pulmonar stenosis, usually infundibular, allowing the absence of pulmonary hyper flow and hypertension. And besides, having an acceptable arterial saturation that, whimsically, we could establish between 85% and 90%. This implies to have an acceptable pulmonary hyper flow with a Qp-Qs about 2:1. What has been mentioned, of course, it implies a simplification of the topic, and there are many additional factors that may complicate the picture, mainly strokes, infections and multiple alterations that chronic hypoxia carries on all tissues. The other possibility of prolonging survival is given by two types of palliative surgery, including pulmonary artery banding (PAD) when there is hyper flow, for lack of pulmonary obstruction and hypertension, or systemic-pulmonary anastomosis or type Glenn venous anastomosis when there is stenosis or severe hypoxia. The history of medicine has many discoveries performed by different groups of researchers who were unaware of the findings of others. The most notable case and related to Sociedad Argentina de Cardiologia is the discovery of, perhaps the brightest of its founders, Dr. Eduardo Braun Menendez, a renal pressor substance which he called hipertensin. At the same time, Dr. Irving Page in Cleveland discovered the same substance and gave it the name of angiotonine. Meeting both researchers, published the famous paper in Science [1942, 958:127 (3292)] which received its current name: angiotensin. Something similar happened in 1971 when Dr. William Kreutzer at Hospital de Ninos de Buenos Aires operated on a patient with tricuspid atresia with a technique quite new, with which is established a new human circulation. At the same time, Dr. Fontan in France carried out another operation even though it had similarities with that of Kreutzer, he carried out it with different anatomic and hemodynamic concepts. This is clearly explained in the review article by William O. Kreutzer (1) that encourages this editorial commentary which shows that the proposed of Hopital de Ninos was correct. In the early nineteenth century, an unknown young German researcher, Grotefend, for the first time deciphered the Babylonian cuneiform writing, commitment in which other well-known professors had failed. On this extraordinary discovery, C. W. Ceram (2) stated: “The main characteristic of genius is to see in a simple way which is complicated and recognize the ordering principle that basically every complex problem has. Grotefend’ idea was of an amazing simplicity. “ I think, and speak in first person as someone who lived through that exciting time, that this is perfectly applicable to the Fontan-Kreutzer procedure.

More about plasma renin and cardiovascular mortality

This editorial refers to ‘Association of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure’, by A. Tomaschitz et al. doi:10.1093/eurheartj/ehr150. Renin, the renal pressor substance, was discovered and described by Tigerstedt and Bergman in classic experiments published in 1898. It was not, however, until 1934 that Goldblatt identified the relevance of renin by showing that renal secretion of renin caused sustained renovascular hypertension in dogs. Others subsequently demonstrated that renin itself is not the pressor element, but rather is the rate-limiting component of the newly defined renin–angiotensin–aldosterone control system (RAAS).1 This RAAS has since become recognized as a key regulator of blood pressure control and a participating factor in its pathological consequences. In the past half century, the role of the RAAS in the pathophysiology of hypertension and as a basis for antihypertensive drug development was established.2,3 Plasma renin has also been associated with cardiovascular morbidity and mortality in hypertensive patients ( Figure 1 ).4,5 Tomaschitz et al. have now extended that finding to patients in whom plasma renin was measured while taking antihypertensive drugs.6 Figure 1 Adapted by permission from Macmillan Publishers Ltd: American Journal of Hypertension , Michael H. Alderman, Wee Lock Ooi, Hillel Cohen, Shantha Madhavan, Jean E. Sealey, John H. Laragh, Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients, copyright (1997). Tomaschitz et al. measured the plasma renin concentration (PRC) using a sensitive automated immunoreactive chemiluminscence method that is comparable with the more traditional enzyme kinetic radioimmunoassay renin activity (PRA) assay. An exception is …

Dual Angiotensin II and Endothelin Receptor Antagonists

Endothelin and angiotensin II are potent vasoconstrictor substances that also can exert proliferative and proinflammatory effects. Dysregulation of these systems can induce or mediate endothelial dysfunction and organ damage in systemic hypertension. Dual-acting angiotensin II and endothelin receptor blockers have been shown to reduce systemic blood pressure in animal models and in hypertensive patients. Preliminary data in smaller human studies have shown that these agents are safe and well tolerated. Larger randomized trials evaluating the efficacy and safety of these agents are underway and show potential as a new class of antihypertensives.

Livedo Reticularis and Related Disorders

Livedo reticularis is a violaceous mottling of the skin with a "fishnet" reticular appearance. Primary and secondary etiologies exist, including a pathologic variant termed livedo racemosa. No evidence-based medicine exists to guide therapy for this disorder, but most patients with primary and secondary livedo reticularis are asymptomatic and do not require treatment. In the rare instance that a patient with primary livedo reticularis experiences mild symptoms such as episodic numbness and tingling, avoidance of cold and vasoconstricting substances should be encouraged. Lastly, judicious dosing of a vasodilator such as a calcium channel blocker can be prescribed. Patients with secondary livedo reticularis or livedo racemosa may benefit from these same therapeutic suggestions; however, treating the proximate cause of livedo with a systemic association is encouraged and is most likely to yield cutaneous improvement. Although antiplatelet and/or anticoagulant therapy is often required when treating a patient with the antiphospholipid antibody syndrome or Sneddon's syndrome, the attendant livedo racemosa typically remains unchanged or progresses despite this treatment.

Endothelium-Derived Hyperpolarizing Factor and Vascular Function

Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO), an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF). Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.

Nitric oxide – the endothelium-derived relaxing factor and its role in endothelial functions

Vascular endothelium plays a key role in the local regulation of vascular tone and vascular architecture by release of vasodilator and vasoconstrictor substances, as well as factors with pro-coagulant, anticoagulant, fibrinolytic, antibacterial properties, growth factors, chemokines, free radicals, etc. Release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarizing factor, as well as vasoconstricting factors such as endothelin, superoxide and thromboxanes play an influential role in the maintenance and regulation of vascular tone and the corresponding peripheral vascular resistance. Under physiological conditions, the release of anticoagulant and smooth muscle relaxing factors exceeds the release of other substances. The first part of this review presents the functions of the endothelium itself, the nature of the endothelium-derived relaxing factor, its production by NO synthases, mechanisms of its action via activation of soluble guanylyl cyclase and production of cyclic 3'-5'-guanosine monophosphate. The resulting biological effects include vasodilatation, regulation of vessel wall structure, increased regional blood perfusion, lowering of systemic blood pressure, antithrombosis and antiatherosclerosis effects, which counteract the vascular actions of endogenous vasoconstrictor substances. Impaired endothelial function, either as a consequence of reduced production/release or increased inactivation of endothelium-derived vasodilators, as well as interactions of NO with angiotensin, reactive oxygen species and oxidized lipoproteins, has detrimental functional consequences and is one of the most important cardiovascular risk factors. Therefore the second part of this review assesses the pathophysiologic impact of the endothelium in examples of cardiovascular pathologies, e.g. endotheliopathies caused by increased angiotensin production, lipid peroxidation, ischemia/reperfusion or diabetes.

Three decades of endothelium research: From the detection of NO to the everyday implementation of endothelial function measurements in cardiovascular diseases

The endothelium is more than just a passive interface between the blood and the vessel wall. Since the pioneering discovery of nitric oxide as an important endothelium-derived vasorelaxing molecule three decades ago, vascular research has developed exponentially and remains fascinating for the entire research community. Endothelial dysfunction is a pathological condition characterized by an imbalance between vasodilatating and vasoconstricting substances. Most, if not all, cardiovascular risk factors have been attributed with endothelial dysfunction and their therapeutic modification with an improvement in vascular function. This overview aims to provide a glimpse into this fascinating research field with the emphasis on vasoactive substances and the assessment of endothelial function.

Evaluation of nasal patency in patients with vasomotor rhinitis

To measure the nasal patency in patients with vasomotor rhinitis (VMR) and healthy controls and to assess its correlation with visual analogue scale (VAS). A total of 105 patients with VMR and 71 healthy controls were included in this study. By using nasal rhinomanometry, the pressure-flow curve and got total nasal resistances of 75 Pa and 150 Pa were measured. By means of acoustic rhinometry, the area-distance curve before and after using nasal vasoconstrictor substance was obtained, got the nasal minimum cross-sectional area (MCA), then calculated nasal congestion index (NCI). The outcomes of nasal resistance and acoustic rhinometry in two groups were compared. The correlation between VAS and nasal patency of VMR was evaluated. The correlation between the outcomes with nasal resistance and acoustic rhinometry and VAS of nasal symptom showed no statistical significance in VMR patients (all P > 0.05). MCA before and after decongestion showed no difference (Z value were -1.541 and -0.626, each P > 0.05), NCI had statistic differences in two groups (Z = -2.707, P < 0.05). Nasal resistance of 75 Pa had statistic differences in two groups (Z = -4.334, P < 0.05), 150 Pa showed no difference (Z = -1.314, P > 0.05). Vasomotor rhinitis is one of the most common non-allergic rhinitis. Subjective symptoms has no correlation with objective nasal patency tests. In clinical practice, comprehensive evaluation of subjective symptoms and objective test results of the patient is required.