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Potencial terapĂȘutico dos antagonistas da endotelina
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Abstract(s)
A Endotelina é um péptido produzido essencialmente pelas células endoteliais em resposta
a vĂĄrios estĂmulos, sendo considerado o pĂ©ptido vasoconstritor mais potente. A
endotelina liga-se a dois recetores acoplados Ă proteĂna G, o recetor ETA e o recetor
ETB. O recetor ETA predomina a nĂvel do mĂșsculo liso vascular e a sua ativação provoca
essencialmente vasoconstrição, por sua vez o recetor ETB tem maior expressĂŁo a nĂvel
do endotélio e a sua ativação provoca vasodilatação, podendo também em menor grau
relativamente ao ETA, causar vasoconstrição. Em condiçÔes patológicas ocorre a desregulação
dos nĂveis de endotelina sendo que os recetores da endotelina contribuem para
os efeitos prejudiciais deste pĂ©ptido. A desregulação dos nĂveis plasmĂĄticos de endotelina
contribui para o desenvolvimento de diversas patologias como a hipertensĂŁo arterial
pulmonar, a insuficiĂȘncia cardĂaca ou a doença renal crĂłnica. O estudo dos recetores da
endotelina levou Ă descoberta de compostos capazes de antagonizar estes recetores com
potencial terapĂȘutico. Alguns fĂĄrmacos jĂĄ se encontram disponĂveis para uso clĂnico, em
particular destacam-se o bosentano o ambrisentano e o macitentano, no entanto muitos
outros ainda se encontram em fase de ensaios clĂnicos. Neste trabalho pretende-se fazer
uma revisĂŁo bibliogrĂĄfica de todos os mecanismos fisiopatolĂłgicos do sistema da endotelina,
o seu envolvimento nas vĂĄrias patologias bem como as vĂĄrias opçÔes terapĂȘuticas
disponĂveis. Pretende-se, ainda, fazer uma pesquisa relativamente aos vĂĄrios compostos
destinados a modular o sistema da endotelina em fase de ensaios clĂnicos, avaliando o
seu potencial clĂnico.
Endothelin is a peptide produced essentially by endothelial cells in response to various stimuli, being considered the most potent vasoconstrictor peptide. Endothelin binds to two G protein coupled receptors, the ETA receptor and the ETB receptor. The ETA receptor predominates at vascular smooth muscle level and its activation essentially causes vasoconstriction. In turn, the ETB receptor has a greater expression at the endothelium level and its activation causes vasodilation, and may also cause vasoconstriction to a lesser degree with respect to ETA. Under pathological conditions deregulation of endothelin levels occurs and endothelin receptors contribute to the detrimental effects of this peptide. Deregulation of plasma levels of endothelin contributes to the development of several pathologies such as pulmonary arterial hypertension, heart failure or chronic kidney disease. The study of endothelin receptors led to the discovery of compounds capable of antagonizing these receptors with therapeutic potencial. Some drugs are already available for clinical use, in particular bosentan, ambrisentan and macitentan, but many others are still in clinical trials. In this work we intend to make a bibliographical review of all pathophysiological mechanisms of the endothelin system, its involvement in the various pathologies as well as the various therapeutic options available. It is also intended to perform a research on the various compounds intended to modulate the endothelin system in the clinical trials phase, assessing its clinical potencial.
Endothelin is a peptide produced essentially by endothelial cells in response to various stimuli, being considered the most potent vasoconstrictor peptide. Endothelin binds to two G protein coupled receptors, the ETA receptor and the ETB receptor. The ETA receptor predominates at vascular smooth muscle level and its activation essentially causes vasoconstriction. In turn, the ETB receptor has a greater expression at the endothelium level and its activation causes vasodilation, and may also cause vasoconstriction to a lesser degree with respect to ETA. Under pathological conditions deregulation of endothelin levels occurs and endothelin receptors contribute to the detrimental effects of this peptide. Deregulation of plasma levels of endothelin contributes to the development of several pathologies such as pulmonary arterial hypertension, heart failure or chronic kidney disease. The study of endothelin receptors led to the discovery of compounds capable of antagonizing these receptors with therapeutic potencial. Some drugs are already available for clinical use, in particular bosentan, ambrisentan and macitentan, but many others are still in clinical trials. In this work we intend to make a bibliographical review of all pathophysiological mechanisms of the endothelin system, its involvement in the various pathologies as well as the various therapeutic options available. It is also intended to perform a research on the various compounds intended to modulate the endothelin system in the clinical trials phase, assessing its clinical potencial.
Description
Keywords
Endotelina HipertensĂŁo arterial pulmonar Antagonistas ETA ETB Bosentano Ambrisentano Macitentano Endothelin Pulmonary arterial hypertension Antagonists ETA ETB Bosentan Ambrisentan Macitentan