[The physiological and pathophysiological significance of endothelins]

Endothelin-1 (ET-1) is a vasoconstrictor peptide of endothelial origin belonging to a family of four isopeptides consisting of ET-1, ET-2, ET-3, and vasoactive intestinal constrictor also called ET-4. These peptides show considerable homology with the sarafotoxins which are cardiotoxic molecules present in the venom of the snake Israeli burrowing asp. ET-1 is the most potent vasoconstrictor known, ten times more potent than angiotensin II. It is synthesized in response to stress, hypoxia, and other vasoactive substances. The physiological role of the endothelins and site of synthesis for ET-2 and ET-3 are still unknown. Two endothelin receptors have been cloned. Elevated plasma levels of ET-1 have been measured in patients suffering from various diseases such as myocardial infarction, cardiogenic shock, septic shock, renal failure, subarachnoid haemorrhage and pre-eclampsia. ET-receptor antagonists and ET-1 synthesis inhibitors are now available. It has been shown that these inhibitors, and also ET-1 antibodies, ameliorate the consequences of severely impaired blood flow in the kidney and in the brain. In animals, infusion of endothelin antibody has been shown to limit the size of myocardial infarction. ET-1 inhibitors can be expected to play a therapeutic role in the future.