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• 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
• G- protein coupled receptor   • G- protein coupled receptor
• Affinity : ET1, ET2 > ET 3    • Affinity : ET1= ET2 = ET 3
• Primary vasoconstrictor and   • Vasodilator ,Vasoconstrictor,
  growth promoting                inhibit cell growth
• Vascular smooth muscle        • Vascular smooth muscle
  cells                           cells & endothelial cells
                                • “Clearance receptor”
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 BED
Vasoconstriction through vascular smooth
 muscle cell (ET A ,ET B )
Remodeling of smooth muslcle cells
CARDIAC
Positive 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
RENAL
Constriction 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
ENDOCRINE
Stimulates ACE and aldosterone release
• endothelial injury
ET-1 induced                 • vascular smooth muscle
ETA - dependent               proliferation
                             • vasoconstriction of pulmonary
                              resistance vessels


Selective ETA-receptor antagonists and nonselective ET receptor blockade



Higher 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 & Pressure



Almost     all   studies      animal   models   of     hypertension,
hypercholesterolemia,or atherosclerosis was shown chronic treatment
with ETA-receptor antagonists was associated with improved
endothelium-dependent, NO-mediated vasodilation.
Impaired cardiac function
Pulmonary hypertension                            ↓
Coronary artery disease
                                          Pulmonary congestion
                                                  ↓
Chronotropy
Inotropy                          Increased level of ET1 & big ET1
                                                  ↓
Arrhythmia
Contractile function of myocyte         Further worsoning of
Remodeling                                cardiac function
Regulation of blood flow   One of the most sensetive vascular bed
Water and sodium transport contracting to endothelin in picomolar
Acid base balance          range

                                        Podocyte damage
                                                  ↓
Glomerulosclerosis
                                     Production of endothelin in
Proteinuria
                                             podocyte
Salt 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
• Bosentan     •   Ambrisentan
• Tezosentan   •   Atrasentan
               •   BQ-123
               •   Darusentan
               •   Sitaxentan
               •   Zibotentan
• 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.
Endothelin

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Endothelin

  • 1.
  • 2. • 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.
  • 3. Most potent and long lasting vasoconstricter • Endothelin = 100 (noradrenaline) • Autocrine & Paracrine • Affects multiple system
  • 4. • 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
  • 5.
  • 6. • G- protein coupled receptor • G- protein coupled receptor • Affinity : ET1, ET2 > ET 3 • Affinity : ET1= ET2 = ET 3 • Primary vasoconstrictor and • Vasodilator ,Vasoconstrictor, growth promoting inhibit cell growth • Vascular smooth muscle • Vascular smooth muscle cells cells & endothelial cells • “Clearance receptor”
  • 7.
  • 8. 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
  • 9. PULMONARY VASCULAR BED Vasoconstriction through vascular smooth muscle cell (ET A ,ET B ) Remodeling of smooth muslcle cells
  • 10. CARDIAC Positive 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
  • 11. RENAL Constriction 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
  • 12. ENDOCRINE Stimulates ACE and aldosterone release
  • 13.
  • 14.
  • 15. • endothelial injury ET-1 induced • vascular smooth muscle ETA - dependent proliferation • vasoconstriction of pulmonary resistance vessels Selective ETA-receptor antagonists and nonselective ET receptor blockade Higher pulmonary arterial versus venous plasma level of ET 1
  • 16. •Increasing vascular tone Hemangioendothelioma+ •Activating the sympathetic ET-1 +hypertension nervous system & RAS OPERATED •Increasing mitogenesis Normal ET1 & Pressure Almost all studies animal models of hypertension, hypercholesterolemia,or atherosclerosis was shown chronic treatment with ETA-receptor antagonists was associated with improved endothelium-dependent, NO-mediated vasodilation.
  • 17. Impaired cardiac function Pulmonary hypertension ↓ Coronary artery disease Pulmonary congestion ↓ Chronotropy Inotropy Increased level of ET1 & big ET1 ↓ Arrhythmia Contractile function of myocyte Further worsoning of Remodeling cardiac function
  • 18. Regulation of blood flow One of the most sensetive vascular bed Water and sodium transport contracting to endothelin in picomolar Acid base balance range Podocyte damage ↓ Glomerulosclerosis Production of endothelin in Proteinuria podocyte Salt sensetive hypertension ↓ Reorganization of Actin cytoskeleton ↓ Glomerular injury
  • 19. •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
  • 20.
  • 21.  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
  • 22.  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
  • 23.  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
  • 24.  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
  • 25.  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
  • 26.  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
  • 27.  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
  • 28.  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
  • 29.  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
  • 30.
  • 31. • Bosentan • Ambrisentan • Tezosentan • Atrasentan • BQ-123 • Darusentan • Sitaxentan • Zibotentan
  • 32. • 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
  • 33. • 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
  • 34. • INDICATION : pulmonary hypertension • DOSE : 5-10 mg once a daily with or without food • ADR : Elevations of liver aminotransferases
  • 35. • 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.
  • 36. • 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
  • 37. • 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.
  • 38. • 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.