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Anorektika a plicní hypertenze [Anorectics and pulmonary hypertension]

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Abstract

Anorectics (appetite-suppressant drugs) are frequently requested by patients. Their usage, however, can have serious, life-threatening side effects, such as pulmonary hypertension and valve defects. The association of anorexigen use with pulmonary hypertension was first detected at the end of the sixties. Back than, the incidence of pulmonary hypertension, diagnosed as primary, increased soon after an anorexigen, aminorex was introduced. After aminorex was recalled several years latter, the incidence of the disease returned to the usual low levels. A recent epidemiological study proved that a newer anorexigen, fenfluramine (or its stereoisomer, dexfenfluramine) considerably increases the risk of pulmonary hypertension. Currently, it is unclear how the anorectics contribute to the development of pulmonary hypertension. One possibility may be the increase in plasma serotonin concentration. Serotonin is a pulmonary vasoconstrictor in many species. However, even if this mechanism plays any role in humans, it cannot completely explain the influence of anorectics on the pulmonary circulation. The anorectics cause membrane depolarization of the pulmonary vascular smooth muscle cells by inhibiting potassium channel activity. The depolarization activates voltage-operated calcium channels, thus increasing intracellular calcium ion concentration, which is the well-known stimulus for vasoconstriction. The increase in vascular tension can be especially significant when there is a deficiency in mechanisms acting against vasoconstriction, such as endothelial production of nitric oxide (NO). Such pre-existing defects may be the reason why only a fraction of patients using anorectics actually develop pulmonary hypertension.
... Vznik PAH souvisí u anorektik s délkou uÏívání, vût‰inou ji lze nalézt po ‰esti mûsících uÏívání anorektik. (13,14) Ke zv˘‰ení tlaku v plicnici mÛÏe v‰ak dojít nûkdy i jen po 3-4 t˘dnech uÏívání tûchto látek. ...
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The term pulmonary arterial hypertension (PAH) refers to idiopathic and familiar pulmonary hypertension, furthermore to PAH in collagen vascular disease, PAH in congenital left-to-right shunt defects, PAH in portal hypertension, PAH in HIV infection and after anorectic drugs or toxic agent abuse. The body of our knowledge regarding the pathogenesis of PAH has expanded dramatically, as reflected in novel therapeutic modalities. PAH is a condition associated with proliferation (of smooth muscle and endothelial cells) and vascular occlusion due both to thrombosis and proliferative changes. Remodeling may be triggered by mechanical (vascular wall stress) or humoral (inflammation mediators) stimuli. The pulmonary arterial endothelium responds to these stimuli, resulting in endothelial dysfunction followed by excess production of vasoconstrictors and growth factors. e. g., endothelin-1, thromboxane, also contributing to thrombosis formation in tiny pulmonary arterioles, and platelet growth factor. The above agents result not only in vasoconstriction, they presumably stimulate vascular remodeling. PAH is associated with an imbalance between prostacyclin and thromboxane in favor of thromboxane. As regards vasoconstrictors, mention should be of endothelin-1, a potent vasoconstrictor also stimulating pulmonary arterial smooth muscle proliferation. The plasma levels of endothelin-1 are increased in PAH. Endothelin levels correlate with PAH severity and even with PAH prognosis. A reduction in prostacyclin levels and excess endothelin production in PAH are actually the reasons why prostanoids and endothelin receptor inhibitors have become the mainstay of PAH therapy.
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The large K⁺ channel functional diversity in the pulmonary vasculature results from the multitude of genes expressed encoding K⁺ channels, alternative RNA splicing, the post-transcriptional modifications, the presence of homomeric or heteromeric assemblies of the pore-forming α-subunits and the existence of accessory β-subunits modulating the functional properties of the channel. K⁺ channels can also be regulated at multiple levels by different factors controlling channel activity, trafficking, recycling and degradation. The activity of these channels is the primary determinant of membrane potential (Em) in pulmonary artery smooth muscle cells (PASMC), providing an essential regulatory mechanism to dilate or contract pulmonary arteries (PA). K⁺ channels are also expressed in pulmonary artery endothelial cells (PAEC) where they control resting Em, Ca²⁺ entry and the production of different vasoactive factors. The activity of K⁺ channels is also important in regulating the population and phenotype of PASMC in the pulmonary vasculature, since they are involved in cell apoptosis, survival and proliferation. Notably, K⁺ channels play a major role in the development of pulmonary hypertension (PH). Impaired K⁺ channel activity in PH results from: 1) loss of function mutations, 2) downregulation of its expression, which involves transcription factors and microRNAs, or 3) decreased channel current as a result of increased vasoactive factors (e.g., hypoxia, 5-HT, endothelin-1 or thromboxane), exposure to drugs with channel-blocking properties, or by a reduction in factors that positively regulate K⁺ channel activity (e.g., NO and prostacyclin). Restoring K⁺ channel expression, its intracellular trafficking and the channel activity is an attractive therapeutic strategy in PH.
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