title: Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes.
abstract: Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Sara
authors.initials: S
authors.lastname: Cattaneo
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zambelli
authors.forename: Monica
authors.initials: M
authors.lastname: Salio
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Chiara
authors.initials: C
authors.lastname: Pagani
authors.forename: Daniela
authors.initials: D
authors.lastname: Rottoli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bisighini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002452:Cell Count; D024061:Collagen Type III / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology*; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D032342:Muscle Cells / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D011924:Rats, Zucker; D060888:Real-Time Polymerase Chain Reaction; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013534:Survival; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D024061:Collagen Type III; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D042461:Vascular Endothelial Growth Factor A; C002744:3-nitrotyrosine; D014443:Tyrosine; D040262:Receptors, Vascular Endothelial Growth Factor