physiology, pathophysiology, antiendothelins

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

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”

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

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

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

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.