WAGNER László1, LACZY Boglárka1, CSEH Judit1, TAMASKÓ Mónika1, MAZÁK István1, MARKÓ Lajos1, MOLNÁR Gergő Attila1, WAGNER Zoltán1, MOHÁS Márton1, FEKETE Andrea2, WITTMANN István1
JUNE 20, 2010
Hypertension and nephrology - 2010;14(03)
[Endothelial nitric oxide synthase enzyme is regulated through the phosphorylation of the Ser(1177) and the Thr(495) sites, which influence the biological availabilaty of nitric oxide. We examined the acute effect of cigarette smoke, which decreases nitric oxide production. Endothelial cells were treated with different concentrations and for different times with cigarette smoke buffer, then with reduced glutathione or different protein kinase inhibitors. We determined the total and the phosphorylated nitric oxide synthase levels with Western blot. Cigarette smoke increased phosphorylation in a concentration- and time dependent manner at the Ser(1177) site and more pronounced at the Thr(495) site. Besides, it also led to the dissociation of the active dimer form of the enzyme. Reduced glutathione inhibited these phosphorylations and prevented the dissociation of endothelial nitric oxide synthase enzyme. The inhibition of protein kinase A or B did not influence the effect of cigarette smoke. However, protein kinase C inhibitors increased the phosphorylation caused by cigarette smoke at Ser(1177), but decreased it at Thr(495) sites. Summarized, cigarette smoke shifts the phosphorylation of the enzyme towards an inhibitory state, further on, it leads to the dissociation of the enzymatically active form. This results in the decreased biological availabilaty of nitric oxide, in which protein kinase C may play an important role.]
Hypertension and nephrology
[The incidence of chronic kidney disease continuously increases worldwide. Studies suggest that kidney disease is an as powerful cardiovascular risk factor as diabetes mellitus. Because of the high prevalence of lipid disorders, it is likely that dyslipidaemia plays a major role in the high cardiovascular risk of these patients. Evidence supports treating dyslipidaemia in patients with mild or moderate kidney disease, but the results of statin trials in dialysed patients are inconclusive. A practical treatment algorithm is proposed considering the special aspects, the effectiveness and safety of the drugs in the whole spectrum of kidney disease.]
Hypertension and nephrology
[Sevelamer HCl is a non-metal and non-calcium based phosphate binder, ion exchange resin, which not selectively binds the phosphate ions in the gastrointestinal tract. In Hungary since 2005, on the basis of strict professional guidelines, sevelamer is available therapy for chronic kidney disease patients with severe hyperphosphatemia on dialysis. On the basis of 17 prospective and retrospective studies, sevelamer HCl is an at least as effective phosphate binder as other calcium based binders, in reducing the serum phosphate level. The advantage of sevelamer compared to the other widely used calcium based phosphate binders is the significantly lower serum calcium level and less hypercalcemic episodes. Sevelamer therapy in chronic kidney disease patients reduces the progression of cardiovascular calcification and it has also a positive effect on cholesterol and LDL-cholesterol levels. The side effects of sevelamer therapy may be acidosis, and gastrointestinal complaints. This year the improved form, sevelamer carbonate, becomes available in Hungary. Sevelamer carbonate has similar phosphate and cholesterol binding capacity as that of sevelamer HCl, but it has several advantages: it has a positive effect on acid-base parameters, and may be administered in powder form, which is beneficial for children and for patients with swallowing disorders. The primary analysis of the DCOR study has not revealed any significant difference in the survival and cardiovascular mortality between patient groups treated with calcium based binder or sevelamer. The RIND trial data showed improved survival of new dialysis patients, who were initially treated with sevelamer. Further clinical studies are needed to kaverify the benefits of sevelamer therapy (mortality, cardiovascular calcification) in chronic kidney disease patients. The management of hyperphosphatemia in chronic renal failure is a major challenge even in the first decade of the 21th century. This is the fact, despite that recently three different groups of phosphate binders are available in the clinical practice: the calcium based binders (calcium carbonate, calcium acetate), sevelamer and lanthanum. Which is the best binder? A calcium based or a non-calcium based one? Over the past decade, these issues are in the mainstream of clinical research of nephrology.]
Hypertension and nephrology
[The primary aim of cardiovascular prevention is to reach adequate blood pressure control. To prevent the development of target organ lesion it is essential to use long-acting, well tolerable drugs without significant side effects. Angiotensin-converting enzyme (ACE) inhibitors are popular and excellent preparations but their side effects reduce life long patient compliance. Angiotensin II receptor blockers (ARBs) are effective drugs having unique tolerability and a capability to reduce cardiovascular morbidity and mortality to the same extent as the ACE inhibitors. Especially high risk patients benefit from their combination with thiazide diuretics or with calcium channel blockers. Clinical trials proved that telmisartan can be safely given and well tolerable alone or in combination to high risk cardiovascular patients, in heart and renal, peripheral vascular and cerebrovascular diseases combined or not with diabetes.]
Hypertension and nephrology
[In this article a practice-oriented narrative review of the depressive disorders in chronic kidney disease is provided. Depressive disorders affect approximately one fourth of the chronic kidney disease population. These mental disorders interfere with physical, cognitive and social functioning and are associated with poor prognosis of patients with chronic kidney disease. Bio-psycho-social factors, including immuno-inflammatory processes, disturbance in glucose- insulin homeostasis, sleep disorders, chronic pain, sexual difficulties, changes in social roles, losses in multiple areas of life and low social support increase the risk for the development of depression. Routine, regular screening of depression in the chronic kidney disease population seems to be warranted. Only limited published evidence is available on the therapeutic possibilities of depression in chronic kidney disease. Preliminary evidence indicates that short, structured psychotherapy may be effective for acute treatment and prevention of psychological distress. Some antidepressants can be applied without the need for dose adjustments. On the other hand, some of the psychotropic medications require dose reduction or should be avoided.]
Hypertension and nephrology
[In the ÉRV Programme of the Hungarian Society of Hypertension hypertensive patients were screened for the presence of peripheral arterial disease (PAD). Ankle/brachial index (ABI) and major cardiovascular risk factors were recorded before the five years long prospective phase of the program. A total of 21 892 hypertensive men and women (9162 males; mean age: 61.45 years) who were attended at 55 hypertension outpatient clinics in Hungary during a 17 month period, were included in the study. The prevalence of PAD defined by low ABI (≤0.9) was 14.0%. In the two blood pressure target groups (140/90 mmHg and 130/80 mmHg) the ratio of patients with controlled blood pressure was 45% and 33%, respectively. The prevalence of PAD (ABI≤0.9) was 10.9% in the controlled and 16.1% in the uncontrolled group (p<0.0001). During the control visits a significant decrease of blood pressure was observed. ÉRV Registry was initiated for ABI screening in subjects at risk for PAD in the general practice. The prevalence of PAD was 18.3%. The prevalence of PAD (low ABI value) is high in hypertensive patients. Uncontrolled hypertension increases the risk of PAD. The results indicate, that ABI screening is a simple and cost-effective method for the diagnosis of preclinical atherosclerosis, which may improve cardiovascular risk prediction.]
Lege Artis Medicinae
[Nitric oxide is a key molecule of the human body. Since its discovery, a library of books and papers have been published on its physiological and pathophysiological role. It is involved in almost all pathological processes. In healthy individuals nitric oxide plays a crucial role in the vascular regulation by protecting against atherosclerosis, myocardial infarction and stroke. In the central nervous system, nitric oxide in its function as a neurotransmitter is responsible for synaptic plasticity, long-term potentiation, memory and a number of neuroendocrine control mechanisms. Furthermore, during inflammation and host defense, macrophages and neutrophils produce nitric oxide that has antibacterial, antiviral, and tumour cell killing activity. In pathologic conditions, however, nitric oxide reacts with superoxide anion to form peroxynitrite that damages the enzymes of the mitochondrial respiratory chain, superoxide-dismutase, reduced glutathion and activates or inactivates signalling molecules. During ischaemia- reperfusion, nitric oxide and peroxynitrite contribute to nitrative/nitrosative stress, DNAfragmentation and consequent polyADP-ribosepolymerase- 1 enzyme activation both in coronary thrombosis and ischaemic stroke.]
Hypertension and nephrology
[Author presents the formation of nitric oxide as a largest vasodilator of human endothelium as well as the endothelial dysfunction a result of formation at adrenergic stimulus. He demonstrates in detail the benefits of selective β-1 blocker and β-3 adrenergic agonist nebivolol in the vascular system. This drug has also receptor independent effects. Complex effects of nebivolol causes vasodilation, inhibits oxidative stress and it is capable to neutralize the effects of free oxygen radicals and as a result the endothelial function will be better. Its clinical effects and the less wellknown beneficial properties are listed. The use of drug is discussed especially in hypertensives with smoking, COPD or PAD. The β-3 agonist effect provides positive reactions not only in the adipocytes and the myocardial tissue. but in the skeletal muscle as well: Increase in energy expenditure - as a compensatory mechanism - is increased in obesity and the glucose uptake + storage on skeletal muscle cells are increased in hyperglycemia. The insulin sensitivity will be better, leptin level is decreased, adiponectin level is increased by nebivolol. It is assumed this drug has antidiabetic and anti-obesity effects.]
Lege Artis Medicinae
[Dyslipidaemia is one of the known main risk factors of atherosclerosis by causing endothelial dysfunction that initiates and promotes vascular remodelling. Recent data from experimental and clinical studies suggest the existence of lipoprotein- neurohormonal interactions that may adversely affect vascular structure and function. Elevated lipid levels enhance the activation of the renin-angiotensin system, and, on the other hand, activation of the renin-angiotensin system leads to increased LDL cholesterol biosynthesis and oxidized-LDL uptake. These findings may explain the synergistic effect on cardiovascular risk observed in patients with coexisting hypertension and dyslipidaemia. The combined use of cholesterol-lowering drugs and inhibition of the tissue renin-angiotensin system may be more efficient in reducing cardiovascular risk.]
Lege Artis Medicinae
[The microvascular bed is an anatomical entity, which constitutes of blood vessels smaller than 50 μm (i.e. arterioles, capillaries and venules), and its major function is the nutritive perfusion of organs and tissues. In search of cardiovascular diseases, there are growing evidences that impaired microcirculation plays an important role in the patophysiology of arterial diseases. Beside the well known consequence of diabetic microangiopathy in the development of diabetic complications, new data support the role of microcirculation in the pathogenesis of hypertension and atherosclerosis, as well. There are different non-invasive methods for the investigation of the microcirculation. Capillarmicroscopy, laser doppler flowmetry and transcutaneous oxygen pressure measurement are used not only in the scientific research, but also in the clinical practice. Laser doppler flowmetry gives us the possibility to assess microvascular endothelial function and other early microcirculatory disturbances. Capillarmicroscopy is particularly useful in the diagnosis of different autoimmune diseases. Transcutaneous oxygen pressure measurement is mostly used in the diagnosis of critical limb ischemia, because it has proven prognostic relevance. Vascular specialist should prescribe all investigations. General practitioners play key role in the early diagnosis of vascular diseases that can be achieved through the screening of patients at risk for vascular disease. In case of suspected vascular disease, the patient should refer to angiology outpatient clinic, to decide further investigations and prescribe therapy. The conservative treatment includes the complex cardiovascular risk management supplemented with medication, acting on the microcirculation.]
Lege Artis Medicinae
[The author presents a review about the fundamental principles of normal endothelial function and the main causes for the development of endothelial dysfunction. First of all, endothelial dysfunction results in structural alterations in the wall of the vessel - the „vascular remodelling” in hypertension - and that is the base of hypertensive microangiopathy and target organ damage. In patients with high blood pressure the reactivity of vessels is impaired by the endothelial dysfunction. The members of the main drug groups can influence the vasoactive factors produced in endothelium differently. This different effects of drugs create different clinical benefits. Especially, the ACE inhibitors, the calcium antagonists (mostly the new generation of dihydropyridines) have endothelial protective effects, but some β-blockers, α-1 adrenergic blockers and - in a totally different way of action - the statins are capable of influencing the endothelial dysfunction.]
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