This page contains a Flash digital edition of a book.
Endothelin Receptor Antagonists in Diabetic Nephropathy


effects on renal and myocardial tissue? Would more selective ET receptor antagonists with a higher affinity for the ETA be equally renoprotective but induce fewer side effects?


Although we do not have the evidence-based answers to all these questions, the overwhelmingly positive findings in experimental studies are promising and should encourage the continuation of well-designed trials that take into consideration the selection of the right dose and of an appropriately subclass-specific ET receptor antagonist. Such studies should be performed in well-defined populations, excluding patients with major pre-existing cardiac problems (mainly heart failure). The study protocols should include advice on how to achieve low dietary sodium intake, possibly the


1. Kimmelstiel P, Wilson C, Benign and malignant hypertension and nephrosclerosis: a clinical and pathological study, Am J Pathol, 1936;12:45–82.3


2. Orchard TJ, Dorman JS, Maser RE, et al., Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II, Diabetes, 1990;39:1116–24.


3. Adler AI, Stevens RJ, Manley SE, et al., Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64), Kidney Int, 2003;63:225–32.


4. Wenzel RR, Renal protection in hypertensive patients: selection of antihypertensive therapy, Drugs, 2005;65(Suppl. 2):29–39.


5. Wühl E, Trivelli A, Picca S, et al., Strict blood-pressure control and progression of renal failure in children, New Eng J Med, 2009;361:1639–50.


6. Yanagisawa M, Kurihara H, Kimura S, et al., A novel potent vasoconstrictor peptide produced by vascular endothelial cells, Nature, 1988;332:411–5.


7. Wenzel RR, Zbinden S, Noll G, et al., Endothelin-1 induces vasodilation in human skin by nociceptor fibres and release of nitric oxide, Br J Clin Pharmacol, 1998;45:441–6.


8. Wenzel RR, Czyborra P, Lüscher T, Philipp T, Endothelin in cardiovascular control: the role of endothelin antagonists, Curr Hypertens Rep, 1999;1:79–87.


9. Adler AI, Managing diabetes: what to do about cardiovascular disease, Diabetes Res Clin Pract, 2003;61(Suppl. 1):S3–8.


10. Wenzel RR, Role of angiotensin-1-receptor blockers in cardiorenal disease, Current Drug Therapy, 2006;1:47–54.


11. Rubanyi GM, Polokoff MA, Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology, Pharmacol Rev, 1994;46:325–415.


12. Chen S, Evans T, Deng D, et al., Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins, Nephron, 2002;90:86–94.


co-administration of diuretics that are active in the collecting duct, and a strict weight-gain control. Beyond such indispensable clinical studies, we also need additional experimental data on the role of ET-receptor subtypes in the kidney, especially in the collecting duct.31


We are convinced that, in future, ET receptor antagonists will have a role to play in patients with renal and reno-cardiac disease. Predictably, the benefit will be greatest if these drugs are used at earlier stages of renal disease than in the above studies, mainly because, at these earlier stage, fluid retention is less of a problem. Betablockers, once contraindicated in heart failure patients because of their side effects, are now the cornerstone of therapy. Maybe one day ET receptor antagonists will know the same fate? n


13. Sorokin A, Kohan DE, Physiology and pathology of endothelin-1 in renal mesangium, Am J Physiol Renal Physiol, 2003;285:F579–89.


14. Rebibou JM, He CJ, Delarue F, et al., Functional endothelin 1 receptors on human glomerular podocytes and mesangial cells, Nephrol Dial Transplant, 1992;7:288–92.


15. Benz K, Amann K, Endothelin in diabetic renal disease, Contrib Nephrol, 2011;172:139–48.


16. Wenzel RR, Czyborra P, Luscher T, Philipp T, Endothelin in cardiovascular control: the role of endothelin antagonists, Curr Hypertens Rep, 1999;1:79–87.


17. Letizia C, Iannaccone A, Cerci S, et al., Circulating endothelin-1 in non-insulin-dependent diabetic patients with retinopathy, Horm Metab Res, 1997;29:247–51.


18. Peppa-Patrikiou M, Dracopoulou M, Dacou-Voutetakis C, Urinary endothelin in adolescents and young adults with insulin-dependent diabetes mellitus: relation to urinary albumin, blood pressure, and other factors, Metabolism, 1998;47:1408–12.


19. Hargrove GM, Dufresne J, Whiteside C, et al., Diabetes mellitus increases endothelin-1 gene transcription in rat kidney, Kidney Int, 2000;58:1534–45.


20. Packer M, McMurray J, Massie BM, et al., Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study, J Card Fail, 2005;11:12–20.


21. Kelland NF, Webb DJ, Clinical trials of endothelin antagonists in heart failure: a question of dose? Exp Biol Med (Maywood), 2006;231:696–9.


22. Barst RJ, Gibbs JS, Ghofrani HA, et al., Updated evidence- based treatment algorithm in pulmonary arterial hypertension, J Am Coll Cardiol, 2009;54:S78–84.


23. Gagliardini E, Corna D, Zoja C, et al., Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes, Am J Physiol Renal Physiol, 2009;297:F1448–56.


24. Zoja C, Cattaneo S, Fiordaliso F, et al., Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes, Am J Physiol Renal Physiol, 2011;301:F1114–23.


25. Ritz E, Wenzel R, Endothelin receptor antagonists in proteinuric renal disease: every rose has its thorn, J Am Soc Nephrol, 2010;21:392–4.


26. Wenzel RR, Littke T, Kuranoff S, et al., SPP301 (Avosentan) Endothelin Antagonist Evaluation in Diabetic Nephropathy Study Investigators, Avosentan reduces albumin excretion in diabetics with macroalbuminuria, J Am Soc Nephrol, 2009;20:655–64.


27. Mann JF, Green D, Jamerson K, et al., ASCEND Study Group, Avosentan for overt diabetic nephropathy, J Am Soc Nephrol, 2010;21:527–35.


28. Kohan DE, Pritchett Y, Molitch M, et al., Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy, J Am Soc Nephrol, 2011;22:763–72.


29. Kohan DE, Rossi NF, Inscho EW, Pollock DM, Regulation of blood pressure and salt homeostasis by endothelin, Physiol Rev, 2011;91(1):1–77.


30. Smolander J, Vogt B, Maillard M, et al., Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects, Clin Pharmacol Ther, 2009;85:628–34.


31. Ritz E, Wenzel RR, Endothelin antagonist as add-on treatment for proteinuria in diabetic nephropathy: is there light at the end of the tunnel? J Am Soc Nephrol, 2011;22:593–5.


32. Moreau P, Takase H, Kung CF, et al., Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension, Hypertension, 1997;29:763–9.


33. Weber MA, Black H, Bakris G, et al., A selective endothelin- receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial, Lancet, 2009;374:1423–31.


EUROPEAN ENDOCRINOLOGY


35


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68