Diabetic nephropathy is associated with cardiovascular morbidity. 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 ACE inhibitor and ETA 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 months with: vehicle; ramipril (1mg/kg); sitaxsentan (60mg/kg); 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 MCP-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 re-established 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 ETA 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 ETA receptor antagonist through the action of VEGF.
DISTINCT CARDIAC AND RENAL EFFECTS OF ETA RECEPTOR ANTAGONIST AND ACE INHIBITOR IN EXPERIMENTAL TYPE 2 DIABETES
LIONETTI, Vincenzo;
2011-01-01
Abstract
Diabetic nephropathy is associated with cardiovascular morbidity. 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 ACE inhibitor and ETA 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 months with: vehicle; ramipril (1mg/kg); sitaxsentan (60mg/kg); 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 MCP-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 re-established 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 ETA 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 ETA receptor antagonist through the action of VEGF.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
