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Dr Syed
Pulau Pinang

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  1. 1. Endothelins?
  2. 2. “ Sorry, I don’t speak Greek”
  3. 4. Endothelin, one of the most potent vasoconstrictors Was first discovered by Yanagisawa and co-workers in 1988….. (Yanagisawa M, Kurihara H, Kimura S et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-5 .) It was first isolated, characterised, and cloned in porcine aortic endothelial cells
  4. 5. Endothelin <ul><li>A 21-amino acid peptide </li></ul><ul><li>It has a molecular weight of 2,492 daltons </li></ul><ul><li>Free carboxyl and amino terminal </li></ul><ul><li>Has two intramolecular disulfide bonds. </li></ul><ul><li>It is present in many mammalian animals </li></ul>
  5. 6. Endothelin <ul><li>Endothelin is secreted in vascular smooth muscle cells, renal tubular epithelial cells, epithelial cells from breasts, glomerular mesangial cells, glial cells, marcophages, mast cells, primary pituitary cells and tumour explants </li></ul><ul><li>Predominant expression is in vascular tissues </li></ul><ul><li>Alteration of ETs may be involved in diseases affecting both micro- and macrovasculature. </li></ul>
  6. 7. Endothelins and the kidney <ul><li>In the kidney,endothelins have a wide variety of biologic actions. </li></ul><ul><li>Most importantly are : </li></ul><ul><li>Regulation of vascular resistance </li></ul><ul><li>Modulation of fluid and electrolyte transport </li></ul><ul><li>Regulation of cell proliferation and extracellular matrix accumulation. </li></ul>
  7. 8. Pathophysiology Of Endothelins <ul><li>Renal haemodynamics </li></ul><ul><li>Diabetic complications </li></ul><ul><li>Renal disease </li></ul><ul><li>Hypertension </li></ul><ul><li>Heart failure </li></ul>
  8. 9. <ul><li>Ischaemic heart disease </li></ul><ul><li>Variant angina </li></ul><ul><li>Primary pulmonary hypertension </li></ul><ul><li>Subarachnoid haemorrhage (SAH) </li></ul><ul><li>Migraine </li></ul>Pathophysiology Of Endothelins
  9. 10. Synthesis And Secretion Of Endothelin
  10. 11. NO diffuses to smooth muscle cells and initiates (cGMP) by activating soluble cytosolic guanylyl cyclase. Elevation of cGMP levels causes vasodilation by decreasing intracellular calcium in smooth muscle cells Activation of ETA receptors results in calcium influx via phospholipase C (PLC) mediated diacylglycerol (DAG) and inositol trisphosphate (IP3) production. DAG activates protein kinase C (PKC), which, alongside increased intracellular calcium, causes phosphorylation of myosin kinase and smooth muscle cell contraction .
  11. 12. Pathophysiology Of Endothelins <ul><li>Endothellin A receptors are primarily localized on vascular smooth muscle cells </li></ul><ul><li>Regulate potent vasoconstriction </li></ul><ul><li>Whether Endothelin A or B receptor stimulated depend on types of stimulant, receptor affinity, number of receptors activated, types of receptors activated, and the tissue involved. </li></ul>
  12. 13. Pathophysiology Of Endothelins <ul><li>ET-B receptors primarily localized in endotelial cells secrete Nitric Oxide </li></ul><ul><li>Endothelial-derived NO plays a major role in maintaining arteriolar dilation and mesangial cell tone </li></ul><ul><li>Chronic systemic blockade of NO bioactivity in rats induced by pharmacologic inhibition of NOS enzyme activity results in significant glomerular capillary hypertension </li></ul><ul><li>In some clinical settings however enhanced eNOS activity may be deleterious </li></ul><ul><li>Contribute to the renal vasodilation and glomerular hyperfiltration observed in diabetic nephropathy. </li></ul>
  13. 14. Pathophysiology Of Endothelins In Renal Disease <ul><li>ETs are released in substantial amounts by renal endothelial cells when a prolonged and severe decrease in renal blood flow occurs. </li></ul><ul><li>This may be appropriate, as in marked prerenal states, in an attempt to maintain coronary and cerebral perfusion </li></ul><ul><li>However can also be injurious such as following ischemic renal injury or after renal exposure to nephrotoxins (such as cyclosporine, radiocontrast media, endotoxin, amphotericin B ) </li></ul>
  14. 15. Pathophysiology Of Endothelins In Hypertension <ul><li>Endothelin causes potent vasoconstriction and prolonged elevation of blood pressure in experimental models </li></ul>
  15. 16. <ul><li>Plasma endothelin levels are increased in unstable angina and acute myocardial infarction </li></ul><ul><li>Patients with stable angina do not have increased endothelin levels </li></ul><ul><li>It has been shown that plasma endothelin levels on the third day after myocardial infarction are significantly related to the mortality </li></ul><ul><li>Plasma endothelin levels at nine weeks after hospitalisation with unstable angina or non-q wave myocardial infarction are related to the incidence of further cardiovascular events </li></ul>Pathophysiology Of Endothelins In Ischaemic heart disease
  16. 17. <ul><li>Plasma endothelin levels are increased in animal models of CHF and in patients with CHF </li></ul><ul><li>In patients, increased plasma endothelin levels correlate closely with the degree of haemodynamic and functional impairment, with higher levels predicting a greater likelihood of death or need for cardiac transplantation </li></ul>Pathophysiology Of Endothelins In Heart Failure
  17. 18. <ul><li>In primary pulmonary hypertension there is proliferation of pulmonary arterial smooth muscle and endothelial injury </li></ul><ul><li>Endothelins contract pulmonary vascular rings and increase pulmonary vascular resistance </li></ul><ul><li>Endothelin also stimulates DNA synthesis and proliferation of pulmonary artery smooth muscle cells </li></ul>Pathophysiology Of Endothelins In Primary Pulmonary Hypertension
  18. 19. Pathophysiology Of Endothelins In Subarachnoid haemorrhage <ul><li>Endothelin-1 has a causative role in mediating SAH induced vasospasm. </li></ul><ul><li>Plasma and CSF endothelin levels are significantly increased in patients after SAH and plasma levels of endothelins are highest in those who develop vasospasm. </li></ul>
  19. 20. Endothelins regulates cell proliferation and extracellular matrix accumulation <ul><li>Cell proliferation and extracellular matrix accumulation are altered by the endothelins. It regulates: </li></ul><ul><li>The release of tissue inhibitor of metalloproteinase </li></ul><ul><li>The release of cytokines that stimulate matrix accumulation </li></ul><ul><li>The production of renal cell fibronectin and collagen </li></ul>
  20. 21. <ul><li>Therefore, endothelins have a role in the gradual progression of glomerular sclerosis and interstitial fibrosis that occurs with irreversible renal injury. </li></ul><ul><li>This can be the pathophysiology of glomerulosceloris in FSGS or Diabetic Nephropathy </li></ul>
  21. 22. Evidence of Endothelins in pathophysiology of Diabetic Nephropathy <ul><li>In the kidneys of diabetic rats, increased ET-1 mRNA and upregulation of ETA receptors has been demonstrated </li></ul><ul><li>It has been demonstrated that diabetes-induced increased expression of glomerular collagen a1(I), a1(III), a1(IV), laminin B1 and B2, tumor necrosis factor-α, PDGF, transforming growth factor-β, and bFGF can be completely prevented by treatment with an ETA receptor antagonist </li></ul>
  22. 23. Are you still with me?
  23. 24. Role Of Endothelin Antagonism in Kidney diseases Given the role of Endothelins in several processes that lead to progression of chronic kidney disease, the possibility that Endothelin antagonism may be beneficial has been studied
  24. 25. Endothelin-A receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure: a comparison of selective and combined endothelin receptor blockade . Goddard, J, Johnston, NR, Hand, MF, et al. Circulation 2004; 109:1186.
  25. 26. The differences between selective Endothelin A, selective Endothelin B, and combined ETA/B receptor blockade was examined <ul><li>A randomized, placebo-controlled, double-blind, 4-way crossover study comparing : </li></ul><ul><li>Selective Endothelin A receptor antagonists (BQ-123) </li></ul><ul><li>Selective Endothelin B receptor antagonist ( BQ-788 ) </li></ul><ul><li>Given alone and in combination, </li></ul><ul><li>In acute studies in 8 hypertensive CRF patients and 8 matched healthy controls </li></ul>
  26. 27. Results: <ul><li>BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone </li></ul><ul><li>BQ-123 substantially increased renal blood flow and reduced renal vascular resistance when given alone but not when combined with BQ-788. </li></ul><ul><li>BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls </li></ul><ul><li>BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls </li></ul>
  27. 28. Interpretation of the results <ul><li>ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension </li></ul><ul><li>Because it has the ability to increase renal blood flow and reduce renal vascular resistence it has renoprotective effect beyond the control of B/P </li></ul><ul><li>Because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits. </li></ul>
  28. 29. ASCENT Trial Avosentan on Doubling of Serum Creatinine, End Stage Renal Disease and Death in Diabetic Nephropathy
  29. 30. <ul><li>A Randomised, Double Blind, Placebo Controlled, Parallel Group Study to Assess the Effect of the Endothelin Receptor Antagonist Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death in Patients With Type 2 Diabetes Mellitus and Diabetic Nephropathy </li></ul><ul><li>Patients will be randomized to receive either 25 mg or 50 mg of Avosentan once daily plus standard therapy, or standard therapy alone. </li></ul><ul><li>This study is currently recruiting patients </li></ul><ul><li>Study start: July 2005;  </li></ul><ul><li>Expected completion: March 2009 </li></ul><ul><li>Expected Total Enrollment:  2364 patients </li></ul>
  30. 31. Health Authority: Bulgaria: Bulgarian Drug Agency; Canada: Health Canada; China: State Food and Drug Administration; Columbia: Republica de Colombia, Ministerio de la Proteccion Social; Croatia:Ministry of Health; Czech Republic: State Institute for Drug Control; Estonia: The State Agency of Medicine; Finland: National Agency for Medicines; Germany: Federal Institute for Drugs and Medical Devices; Hungary: National Institute of Pharmacy; India: The Drugs Controller General; Indonesia: Badan Pom (NA-DFC); Italy: Ministry of Health; Israel: The Ministry of Health, Pharmaceutical Department; Korea: Korea Food and Drug Administration; Latvia: State Agency of Medicines; Lithuania: State Medicine Control Agency - : National Pharmaceutical Bureau Control; Mexico: Federal Commission for Protection against Health Hazards; Peru: Instituto Nacional de Salud; Philippines: Bureau of Food and Drugs; Poland: Ministry of Health; Romania: State Institute for Drug Control; Russia: Federal Services for Supervision in the area of Healthcare and Social Development; Singapore: Health Sciences Authority; Slovakia: State Institute for Drug Control; South Africa: Medicines Control Council; Spain: Agencia del Medicamento y Productos Sanitaros; Sweden: Medical Products Agency; Thailand: Ministry of Publich Health; Head of Thai Drug Control Division; Taiwan: Bureau of Pharmaceutical, Department of Health; Turkey: Ministry of Health; United Kingdom: Medicines and Healthcare Products Regulatory Agency; United States: Food and Drug Administration Ministry of Health; Malaysia
  31. 32. <ul><li>Primary Outcomes: To determine the effect of each dose of avosentan on time to doubling of serum creatinine, end stage renal disease (ESRD) or death when administered on top of standard treatment in subjects with type 2 diabetes mellitus and diabetic nephropathy. </li></ul><ul><li>Secondary Outcomes: To determine the effect of each dose of avosentan on: cardiovascular mortality; non-cardiovascular mortality; coronary or peripheral vascular revascularisations including amputations (except where due to trauma); non-fatal acute myocardial infarction; stroke; congestive heart failure; unstable angina </li></ul>
  32. 33. Role of ET-A receptor antagonism in Heart Failure Love MP, Haynes WG, Gary GA et al. Vasodilator effects of endothelin-converting enzyme inhibition and ET-A receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996; 94: 2131-7.
  33. 34. <ul><li>It has been shown that short term oral endothelin receptor blockade with bosentan (a mixed ETA/ETB receptor antagonist) resulted in improved haemodynamics without neurohormonal stimulation in patients who were symptomatic despite triple drug chronic heart failure therapy including an ACE inhibitor, diuretic, and digoxin </li></ul><ul><li>ERB cause venous, pulmonary artery, and arterial vasodilatation when acting alone or when combined with ACE inhibitors </li></ul><ul><li>Pulmonary vascular resistance, which was elevated despite chronic ACE inhibition, was markedly reduced by bosentan. </li></ul>
  34. 35. Role of ET-A receptor antagonism in Cerebral Vasospasm <ul><li>Willette RN, Zahang H, Mitchell MP et al. </li></ul><ul><li>Non-peptide endothelin antagonist: cerebral vasospasm characterization and effects on delayed cerebral vasospasm. </li></ul><ul><li>Stroke 1994; 25: 2450-6. </li></ul>
  35. 36. <ul><li>It has been demonstrated that bosentan, a non-peptide mixed endothelin receptor antagonist partially reversed the vasospasm in cerebral haemorrage </li></ul><ul><li>Similarly, inhibition of enzymatic conversion of proendothelin-1 to endothelin-1 by phosphoramidon reduces the vasospasm seen in dog model of subarachnoid hemorrhage, as does administration of monoclonal antibodies to endothelin </li></ul>
  36. 37. <ul><li>Willette RN, Ohlstin EH, Mitchell MP et al. </li></ul><ul><li>Nonpeptide endothelin receptor antagonists can attenuate acute hypoxia induced pulmonary hypertension in the dog. </li></ul><ul><li>J Pharmacol Experiments and Therapeutics 1997; 280: 695-701. </li></ul>Role of ET-A receptor antagonism in Pulmonary Hypertension
  37. 38. <ul><li>The over-production of endothelin-1 contributes to the accelerated growth of pulmonary artery smooth muscle cells </li></ul><ul><li>Infusion of endothelin receptor blockers reduces progression of pulmonary hypertension and right ventricular hypertrophy and prevents thickening of pulmonary artery </li></ul>
  38. 39. Bosentan (Tracleer®) <ul><li>Bosentan is an oral medication used to treat pulmonary arterial hypertension (PAH). </li></ul><ul><li>It was approved by the Food and Drug Administration (FDA) in 2001 for the treatment of pulmonary arterial hypertension </li></ul><ul><li>Bosentan is a pill that is taken orally twice a day. The initial dose for most patients is 62.5 mg twice a day. If there are no problems or side effects after one month, the dose is increased to 125 mg twice a day </li></ul>
  39. 40. Side effects?/ Safety profile?
  40. 41. <ul><li>Does endothelin antagonism causing endothelin deficiency bear any side effects? </li></ul><ul><li>Experimental mutations in mouse endothelin B receptor gene have resulted in aganglionic megacolon, a phenotype overlapping with that of patients with Hirschprung's disease </li></ul><ul><li>Mice homozygous for endothelin-1 mutations have cardiovascular malformations and abnormalities of cranio-facial organs derived from the pharyngeal arch, indicating that endothelins are essential to normal embryonic development </li></ul>
  41. 42. <ul><li>Bosentan is generally well tolerated by patients with minimal side effects. </li></ul><ul><li>Reported side effects include nasal congestion, headache, flushing, and lower extremity swelling. </li></ul><ul><li>The major potential side effect of bosentan is damage to the liver. in The development of abnormal liver function tests (LFTs), measured in blood samples to greater than 3 times the upper limit of normal is observed in about 10% of patients receiving this medication </li></ul>
  42. 43. <ul><li>Bosentan has been shown to be harmful to the growing fetus in rats. Therefore, pregnancy should be avoided in women treated with bosentan </li></ul><ul><li>Bosentan may lower sperm counts and decrease the ability to father children; this may be irreversible. </li></ul>