The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Abstract

The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

DNA microarray analysis of the antihypertensive effect of milk fermented by Lactobacillus helveticus H9 on spontaneously hypertensive rats

“…ETa is a kind of endothelin receptor. Binding endothelins to ETa will result in vasoconstriction and an increase in blood pressure (Hynynen and Khalil 2006). Previous studies also reported that ETa antagonists could block the endothelin-induced effects and prevent cardiovascular diseases .…”

“…Endothelins can induce vasoconstriction and play a key role in the regulation of vascular tone (Kedzierski and Yanagisawa 2001). Previous studies suggested that endothelins were involved significantly in the regulation of hypertension (Hynynen and Khalil 2006). Upregulation of the endothelin system occurred in human hypertension and experimental animal models of severe hypertension (Schiffrin 2001).…”

Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

“…16 An upregulation of the ET1 system has been linked to numerous pathologies, including salt-sensitive hypertension. 20,21,32,33 Because of these functions the endothelin system might in large part contribute to the hypertrophy and the endothelial dysfunction observed in DOCA-salt hypertension. In an attempt to test this we (i) treated DOCA-salt hypertensive rats for 3weeks with the NEP/ECE inhibitor SOL1 and (ii) studied the endothelium-dependent structural effects of imposed changes in blood flow in DOCA salt hypertensive rats.…”

The role of endothelin-1 and new therapeutic approaches in sepsis and septic shock

“…Travma veya enflamasyon sırasında salıverilen vazokonstriktör mediyatörler ET salıverilmesini uyarmaktadır. Endotelin salıverilmesini indükleyen ve önleyen mediyatörler Tablo 1'de belirtilmiş-tir (52)(53)(54)(55)(56)(57)(58)(59)(60)(61).…”