Plasma endothelin

P12. Pittet, J.-F., Morel, D. R., Hemsen, A., Gunning, K., Lacroix, J.-S., Suter, P. M., and Lundberg, J. M., Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann. Surg. 213,261-264 (1991). 

V3. Vermes, I., Spooren, P. F. M. J., Kalsbeek-Batenburg, E. M., and Haanen, C., In addition to von Willebrand factor and urinary albumin excretion, plasma endothelin is an indicator of endothelial dysfunction in diabetes mellitus. Diabetes 36,472-473 (1993). 

Barden, A. E., Herbison, C. E., Beilin, L. J., Michael, C. A., Walters, B. N., and Van Bockxmeer, E. M. (2001) Association between the endotheUn-l gene Lysl98Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J. Hypertens. 19, 1775-1782. 

Y. Saito, K. Nakao, M. Mukoyama, H. Imura, Increased plasma endothelin level in patients with essential hypertension, N. Engl. J. Med. 322 (1990) 205. 

Bruno CM, Meli S, Marcinno M, Ierna D, Sciacca C, Neri S. Plasma endothelin-1 levels and albumin excretion rate in normotensive, microalbuminuric type 2 diabetic patients. J Biol Regul Homeost Agents 2002 16 114-117. 

Zhou XJ, Pandian D, Wang QX, Vaziri ND (1997) Erythropoietin-induced hypertension is not mediated by alterations of plasma endothelin, vasopressin, or atrial natriuretic peptide levels. J Am Soc Nephrol 8 901-905... 

Endothelin has been implicated in myocardial infarction, coronary vasospasm and re-stenosis subsequent to percutaneous transluminal coronary angioplasty. The potent, prolonged coronary vasoconstrictor and mitogenic actions of endothelin are well-documented (see earlier section) and thus endothelin is certainly able to produce the biological effects seen in these disease states. Although a reduction in infarct size has been demonstrated in a rat model of myocardial infarction with an endothelin antibody [185], and with phosphoramidon [186], the argument for a role for endothelin in ischaemic heart disease has been based mainly on the finding of increased plasma endothelin levels in patients with myocardial infarction [187-190], coronary vasospasm [191, 192] and re-stenosis post-PTCA [193-195]. 

The potential nephrotoxic effects of RCM have also been recognised. Again, endothelin may be a mediator. In a pacing-induced heart failure dog model, intravenous infusion of RCM produced significant elevation of plasma and urinary endothelin [203]. Similarly, RCM-induced elevation of plasma endothelin has been observed in the rat [204] and in man [205]. Furthermore, the ET receptor antagonist, CP170687, attenuated the fall in renal blood flow induced by RCM in the rat [206]. 

Moore, K., Wendon, X, Frazer, M., Karani, X, Williams, R., Badr, K. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. New Engl. J. Med. 1992 327 1774-1778... 

Chang, H. Wu, G.-J. Wang, S.-M. Hung, C. Plasma endothelin level changes during hemorrhagic shock. 

Buchler M, Leibenguth P, Le Guellec C, Carayon A,Watier H, Odoul F, Autret-Lec, E, Lebranchu Y, and Paintaud G. 2004. Relationship between calcineurin inhibition and plasma endothelin concentrations in cyclosporine-A-treated kidney transplant patients. EurJClin Pharmacol 60 703-708. 

Kinugawa T, Kato M, Ogino K, Osaki S, Igawa O, Hisatome I, et al. Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure. J Card Fail 2003 9 318-24. 

Grekas D, Bamichas G, Karamouzis M, Bacharaki D, Savidis N, Tourkantonis A. Plasma endothelin in cyclosporine A-treated renal transplant patients. Transplant Proc 1999 31 1703-1705. 

Yoshibayashi, M., Nishioka, K., Nakao, K., et al. (1991). Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects. Evidence for increased production of endothelin in pulmonary circulation. Circulation 84, 2280-2285. 

Several studies have shown that the extent of coronary artery stenosis due to atherosclerotic plaque formation and expansion into the arterial lumen is not sufficient to explain the incidence of clinical events associated with atherosclerosis [183]. It appears that the generation of clinical events involves plaque mpture, resulting in thrombus formation and arterial occlusion. This mpture is induced by vasomotor disturbances in which oxidized low-density lipoproteins may be involved. Resveratrol is able to regulate vasomotion, which is impaired in atherosclerosis. The key regulators of the vasomotor function are the vasodilator NO and the vasoconstrictor endothelin-1 [167]. A number of in vitro and in vivo studies have shown improved vascular function in response to resveratrol [184, 185]. Resveratrol enhances expression and activity of endothelial nitric oxide synthase [186] and inhibits endothelin-1 secretion and endothelin-1 gene expression in human umbilical vein endothelial cells [187]. Intragastric administration of resveratrol for 12 weeks to hypercholesterolemic rabbits improved the endothelial function, reduced plasma endothelin-1 levels, and induced... 

The ECE isoforms show different subcellular distributions and enzymatic characteristics (Table 2). ECE-la and ECE-lc are mainly expressed at the cell surface, whereas ECE-lb, ECE-Id and ECE-2 are expressed intracellularly. Plasma membrane-bound ECE cleaves big-ET-1 circulating in the blood, whereas intracellular ECE isoforms are involved in the generation of mature endothelins. In addition, ECEs (as well as NEP and the insulin-degrading enzyme) contribute to the degradation of amyloid (3 (A 3) peptide. 

B8. Beishuizen, A, Gotz, J. M., Kip, L Haanen, C., and Vermes, I Elevated plasma levels of endothelin are associated with the severity of sepsis and presence of shock in contrast to the levels of atrial natriuretic peptide. Med. Inflam. 1,419-423 (1992). 

PI. Pacher, R Stanek, B., HUlsmann, M Koller-Strametz, J Berger, R., Schuller, M., Hartter, E Ogris, E., Frey, B., Heinz, G., and Maurer, G Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure. J. Am. Coll. Cardiol. 27,633-641 (1996). 

Tl. Takakuwa, T., Endo, S Nakae, H., Suzuki, T Inada, K., Yoshida, M Ogawa, M., and Uchi-da, K Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Res. Commun. Chem. Pathol. Pharmacol. 84,271-281 (1994). 

V4. Vermes, I., Beishuizen, A., Hampsink, R. M and Haanen, C., Dissociation of plasma adreno-corticotropin and cortisol levels in critically ill patients Possible role of endothelin and atrial natriuretic hormone. J. Clin. Endocrinol. Metab. 80, 1238-1242 (1995). 

Rybicki AC, Benjamin LJ. Increased levels of endothelin-1 in plasma of sickle cell anemia patients [letter]. Blood 1998 92 2594-2596. 

Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, D Anna R, Lasco A, Squadrito G, Gaudio A, Cancellieri F, Arcoraci V, Squadrito F (2001) Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma no concentrations, endothelin-1 levels, and endothelium-dependent vasodilation in postmenopausal women. Arterioscler Thromb Vase Biol 21 1512-1519... 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

Mechanism of Action An antihypertensive that blocks endothelin-l, the neurohormone that constricts pulmonary arteries. Therapeutic Effect Improves exercise ability and slows clinical worsening of pulmonary arterial hypertension (PAH). Pharmacokinetics Highlybound to plasma proteins, mainlyalbumin. Metabolized in the liver. Eliminated by biliary excretion. Half-life Approximately 5 hr. 

The most important stimulus to the release of ANP from the heart is atrial stretch via mechanosensitive ion channels. ANP release is also increased by volume expansion, changing from the standing to the supine position, and exercise. ANP release can also be increased by sympathetic stimulation via aiA-adrenoceptors, endothelins via the -receptor subtype (see below), glucocorticoids, and vasopressin. Plasma ANP concentration increases in various pathologic states, including heart failure, primary aldosteronism, chronic renal failure, and inappropriate ADH secretion syndrome. 

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