• Vascular endothelial cells produce a number of important vasodilator and constrictor substances.• Prostacyclin and nitric oxide (NO) are potent vasodilators secreted by vascular endothelium.• The isolation of endothelium-derived vasodilators initiated a search for counterbalancing constricting factors (or EDCFs).• A long-acting vasoconstrictor substance was isolated from porcine aortic endothelial cells in 1988, and named endothelin.
• Most potent and long lasting vasoconstricter• Endothelin = 100 (noradrenaline)• Autocrine & Paracrine• Affects multiple system
• 21- amino acid peptide• Three forms : Type Source Endothelin 1 vascular endothelial and smooth muscle cells, airway epithelial cells, macrophages, fibroblasts, cardiac myocytes, brain neurons, and pancreatic islets Endothelin 2 Ovary Intestinal epithelial cells Endothelin 3 endothelial cells, brain neurons, renal tubular epithelial cells, intestinal epithelial cells
SYSTEMIC VASCULAR BED Dose-dependent vasoconstriction in most vascular beds Intravenous ET-1 : a rapid and transient decrease in arterial blood pressure followed by a prolonged increase The depressor response : prostacyclin and nitric oxide from the vascular endothelium (ET B ) The pressor response : direct contraction of vascular smooth muscle (ET A ET B ) Mitogenic effect on vascular smooth muscle cell
PULMONARY VASCULAR BEDVasoconstriction through vascular smooth muscle cell (ET A ,ET B )Remodeling of smooth muslcle cells
CARDIACPositive chronotropic and inotropic effects in vitro.Decreases cardiac output in vivo, due to increased afterload and a baroreceptor mediated decrease in heart rate.Mitogenic effect on cardiac myocytes and coronary vascular smooth muscle cells
RENALConstriction of afferent and efferent arterioles decrease in renal plasma flow and glomerular filtration rate (ETA)Preventing tubular reabsorbtion of sodium and water (ETB) Mitogenic effect on human mesangial cells
ENDOCRINEStimulates ACE and aldosterone release
• endothelial injuryET-1 induced • vascular smooth muscleETA - dependent proliferation • vasoconstriction of pulmonary resistance vesselsSelective ETA-receptor antagonists and nonselective ET receptor blockadeHigher pulmonary arterial versus venous plasma level of ET 1
•Increasing vascular tone Hemangioendothelioma+•Activating the sympathetic ET-1 +hypertension nervous system & RAS OPERATED•Increasing mitogenesis Normal ET1 & PressureAlmost all studies animal models of hypertension,hypercholesterolemia,or atherosclerosis was shown chronic treatmentwith ETA-receptor antagonists was associated with improvedendothelium-dependent, NO-mediated vasodilation.
Impaired cardiac functionPulmonary hypertension ↓Coronary artery disease Pulmonary congestion ↓ChronotropyInotropy Increased level of ET1 & big ET1 ↓ArrhythmiaContractile function of myocyte Further worsoning ofRemodeling cardiac function
Regulation of blood flow One of the most sensetive vascular bedWater and sodium transport contracting to endothelin in picomolarAcid base balance range Podocyte damage ↓Glomerulosclerosis Production of endothelin inProteinuria podocyteSalt sensetive hypertension ↓ Reorganization of Actin cytoskeleton ↓ Glomerular injury
•Lymphocyte and Leukocyte•Stimulates formation of cytokines:-Interleukins-Tumor necrosis factor (TNF)•Play imortant role in connective tissue disorder •Lupus erythematosus •Systemic sclerosis •Sjoegren’s Syndrom •Scleroderma•Acute and Chronic Rejection after solid organ transplantation ↓•Graft atherosclerosis, fibrosis, glomerulosclerosis
The pharmaceutical industry has extensively studied pulmonary hypertension as a clinical target for ET antagonism Randomized clinical trials have demonstrated clear benefits regarding symptoms and quality of life compared with placebo The first endothelin receptor antagonist to receive US FDA approval - Bosentan
Selective antagonist (ET- A) also used in PAH It is unclear whether selective antagonists are superior to nonselective ones in terms of clinical improvement, side effects, and survival in PAH patients Clinical trials are needed, and ongoing trials include combination therapy of endothelin antagonists with other pulmonary vasodilators, such as sildenafil or prostacyclin
Preclinical data on hypertension have been underscored by clinical studies in humans with essential hypertension Nonselective ET-receptor antagonist bosentan or selective ETA-receptor antagonist darusentan substantially reduces arterial blood pressure in patients with essential or resistant essential hypertension It currently remains unclear whether selective antagonists provide an advantage over nonselective compounds
In animals : benefit of chronic endothelin blockade on survival and left ventricular remodelling after myocardial infarction Currently no evidence for a protective effect of chronic endothelin antagonism in humans with heart failure All long-term clinical trials investigating chronic treatment with endothelin receptor antagonists in patients with acute or chronic congestive heartfailure have been negative
A large number of experimental prevention studies have investigated the effects of chronic endothelin blockade on the development of glomerulosclerosis Studies found pronounced nephroprotective effects Only relatively few studies have investigated the effects of endothelin receptor blockade in conditions in which renal disease was already established
Studies have investigated the antiproteinuric effect of endothelin receptor antagonists in normotensive or severely hypertensive animal Models In these studies, treatment not only reversed proteinuria but also lead to a healing of the previously injured glomeruli and podocytes Renal disease is a particularly relevant area for the clinical application of endothelin receptor blockers with the potential to reverse established disease
Connective tissue diseases show activation of the endothelin system and are frequently associated with the development of pulmonary hypertension Patients with connective tissue disease are likely to receive an endothelin receptor antagonist at some point in their life Endothelin blockade alleviates other symptoms including digital ulcers and Raynaud’s syndrome Corresponding clinical trials are underway
Endothelin blockade has been successful in partially preventing the systemic and cardiorenal changes seen in preclinical models of connective tissue Disease Also improved conditions related to other autoimmune disorders, such as type 1 diabetes
Treatment with endothelin receptor antagonists effectively interferes with the development of graft atherosclerosis or the development of fibrosis or glomerulosclerosis related to solid organ transplantation No clinical studies have been performed to investigate the therapeutic potential of endothelin receptor antagonists in transplantation medicine
• INDICATION• Pulmonary arterial hypertension in patients with WHO Class II to IV symptoms to improve exercise capacity and decrease clinical worsening• DOSE: Initiate at 62.5 mg twice daily with or without food for 4 weeks, and then increase to 125 mg twice daily
• ADVERSE DRUG REACTION – Elevations of liver aminotransferases (ALT, AST) and liver failure• PRECAUTIONS – Pre-existing hepatic impairment: Avoid use in moderate and severe impairment. Use with caution in mild impairment – Fluid retention: May require intervention – Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter
• INDICATION : pulmonary hypertension• DOSE : 5-10 mg once a daily with or without food• ADR : Elevations of liver aminotransferases
• SITAXENTAN: withdrawn by pfizer• ATRASENTAN : experimental drug for cancer : block endothelin proliferation• ZIBOTENTAN :experimental drug : anticancer• DARUSENTAN : experimetnal drug : uncontrolled hypertension• BQ-123 : biochemical tool in the study of endothelin receptor function.
• Endothelin is not merely a vasoconstrictor, but a multifunctional peptide• Initial clinical indications such as heart failure have been shown not to benefit from endothelin receptor blockade on top of standard treatment and are unlikely to ever become an indication for this new form of treatment.• Pulmonary arterial hypertension, has become the first clinical indications
• Basic science studies suggest that diseaseas such as – proteinuric renal disease – Cancer – connective tissue diseases – chronic allograft rejections will be indications for endothelin antagonist therapy in the near future.• Well-designed clinical studies are warranted to test and verify the therapeutic potential of this new class of drugs for cardiovascular medicine, nephrology, oncology, and related medical fields.
• Barton M, Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can. J. Physiol. Pharmacol. July 2008;86:485-98.• Alexei VA, William GH. Role of endothelin in cardiovascular disease. Jraas. 2002;3:1-15.• Deborah YC, Thomas M. Pharmacology of Vascular Tone. In: David Golan, editor. Principles of Pharmacology, The Pathophysiological Basis of Drug Therapy, 3rd ed. Philadelphia: Lippincott Williams and Wilkins Publications; 2012.p.357-67.• Ian AR. Vasoactive Peptides. In: Bertram G Katzung, editor. Basic and Clinical Pharmacolgoy, 11th ed. New Delhi: Tata McGraw-Hill Education Private Limited; 2010.p.303-04.