Irbesartan-mediated reduction of renal and cardiac damage in insulin resistant JCR : LA-cp rats

Background and purpose: Angiotensin II receptor antagonists (ARBs), originally developed for antihypertensive properties, have pleiotropic effects including direct vascular actions. We tested the hypothesis that the ARB irbesartan would be effective against micro- and macrovascular complications of the prediabetic metabolic syndrome using the obese, insulin-resistant JCR : LA-cp rat that exhibits micro- and macrovascular disease with ischaemic myocardial lesions and renal disease. Experimental approach: Obese male rats were treated with irbesartan (30 mg center dot kg-1 center dot day-1, incorporated into chow) from 12 to 25 weeks of age. Key results: Irbesartan treatment caused no change in food intake or body weight. Fasting glycaemic control of the JCR : LA-cp rats was marginally improved, at the expense of increased plasma insulin levels (similar to 50%). Fasting plasma triglycerides were marginally reduced (similar to 25%), while cholesterol concentrations were unchanged. Elevated concentrations of adiponectin, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1 were reduced along with severity of glomerular sclerosis. Macrovascular dysfunction (aortic hypercontractile response to noradrenergic stimulus and reduced endothelium-dependent relaxation) was improved and frequency of ischaemic myocardial lesions reduced (62%). Conclusions and implications: Irbesartan reduces markers of inflammation and prothombotic status, improves macrovascular function and reduces glomerular sclerosis and myocardial lesions in a model of the metabolic syndrome. Unlike pharmaceutical agents targeted on metabolic dysfunction, irbesartan reduced end-stage disease without major reduction of plasma lipids or insulin. The protective effects appear to be secondary to unknown intracellular mechanisms, probably involving signal transduction pathways. Understanding these would offer novel pharmaceutical approaches to protection against cardiovascular disease.