Endothelin as a Clinical Target in the Treatment of Systemic Hypertension

Abstract

Endothelin is a potent vasoconstrictor substance that also can exert proliferative, inflammatory, and fibrotic changes in blood vessels and other organs. It acts on tissues in a paracrine and autocrine fashion, with local production and regulation occurring in both endothelial and nonendothelial cells. Endothelin stimulation of ETA and ETB receptors results in different and often opposing effects, which under physiologic conditions, establishes a balance that contributes to the regulation of vascular tone and blood pressure. Dysregulation of the endothelin system can induce or mediate endothelial dysfunction and organ damage in systemic hypertension (HTN), effects which may be ameliorated by endothelin antagonists. Endothelin receptor antagonists are currently being used in the treatment of pulmonary HTN. Both selective and dual-acting endothelin receptor blockers can also reduce systemic blood pressure in animal models and in hypertensive patients. Clinical trials evaluating the efficacy and safety of these agents are underway, and show potential as a new class of antihypertensives. Studies are also in progress with a single moiety dual angiotensin-endothelin A receptor antagonist, which is being evaluated in HTN. Issues that need to be addressed include the net contribution of endothelin in the pathophysiology of HTN, its interaction with other neurohormonal systems such as the renin-angiotensin-aldosterone system, and the clinical demonstration of the effect of endothelin receptor antagonism on end-organ damage in hypertensive patients.

ETA Activation Mediates Angiotensin II-Induced Infiltration of Renal Cortical T Cells

“…ET receptor antagonists are utilized for pulmonary hypertension, and a selective ET A receptor antagonist is currently in clinical trials with promising results, in patients with resistant hypertension. 29 Our data would suggest that ET A receptor antagonists may be more efficacious in this subset of patients by diminishing the involvement of T lymphocytes in chronic renal injury. We also found that increased BP induces increased numbers of T cells in the outer medulla and monocytes/macrophages in both the renal cortex and outer medulla.…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…[60,61] ET-1 is a 21-amino acid peptide produced by multiple cell types including macrophages, [62] neurons, and endothelial cells. [63,64] It is released in response to endothelial cell activation, an event that occurs during vaso-occlusive episodes. Other factors that induce ET-1 production include proinflammatory cytokines, growth factors, angiotensin II, mechanical stress, peripheral tissue injury, and hypoxia.…”

Type 1 Diabetes Mellitus: Redefining the Future of Cardiovascular Complications with Novel Treatments

“…Later on, Yanagisawa et al isolated the same substance from cultured porcine aortic and endothelial cells and renamed it endothelin. Endothelin (ET) is a naturally occurring polypeptide (Prasad et al, 2009) produced by the endothelium (Shah et al,2009;Wikes et al, 2003;Ying wu, 2003) and consists of 21 amino acids. It is present in three isoforms ET-1, ET-2 and ET-3 (Agapitov et al, 2002;Prasad et al, 2009).…”

“…Endothelin (ET) is a naturally occurring polypeptide (Prasad et al, 2009) produced by the endothelium (Shah et al,2009;Wikes et al, 2003;Ying wu, 2003) and consists of 21 amino acids. It is present in three isoforms ET-1, ET-2 and ET-3 (Agapitov et al, 2002;Prasad et al, 2009). These three isoforms are encoded by different genes but have similar structure and function (Wilkes et al, 2003).…”

“…These three isoforms are encoded by different genes but have similar structure and function (Wilkes et al, 2003). They have conserved sequences of amino acids mainly at the 6 C terminus and 4 cysteine residues that form 2 disulfide bridges between residues 1 to 15 and 3 to 11 and the main difference is at the Nterminus (Prasad et al, 2009). They are vasoconstrictors synthesized by vascular, right atrial and left ventricular endothelial cells, vascular smooth muscle cells and fibromyocytes.…”