ENDOTHELIN - PATHOPHYSIOLOGIC FUNCTIONS A ND THERAPEUTIC ASPECTS

The Endothelins (ETs) are a family of three known types of 21 amino-ac id peptides, which were first described in 1988 as a vasoactive peptid e produced in the endothelial cells of the porcine aorta, ETs have a w ide range of actions including vasoconstriction, vasodilation, broncho constriction and mitogenesis, They also contribute to the development of neuro-ectodermal structures. The biological effects of ETs are medi ated via specific receptors, The gene nucleotide and amino acid sequen ce of two receptors with different pharmacological actions have been i dentified (ET(A)- and ET(B)-receptors). In experimental settings ET(A) and ET(B) receptors are detected indirectly by stimulation with selec tive agonists and antagonists, In the lung, endothelin produces bronch oconstriction and vasoconstriction followed by edema formation. In the bronchopulmonal tissue, the endothelin-induced effects seem to be med iated predominantly via ET(B)-receptors, whereas vasoconstriction is m ediated via ET(A)-receptors. The activation of the cyclooxygenase path way followed by an increase of thromboxane and prostacyclin levels and in the enhancement of NO-synthesis, seem to be dependent on ET(A)-rec eptor activation, ETs act as vasoconstrictors in coronary circulation and in the cerebral vasculature. Furthermore, ETs are able to activate macrophages, These results point towards the role of endothelins as m ediators in various diseases including the systemic inflammatory respo nse syndrome, ARDS and sepsis as well as cardio- and pulmonary vascula r diseases. This was evidenced by elevated plasma levels of endothelin s in these diseases, The establishment of specific endotheline recepto r antagonists as therapeutic tools is under current investigation.