Macro- and Microvascular Disease in an Insulin-Resistant Pre-Diabetic Animal Model

Russell, James C.; Proctor, Spencer

doi:10.1007/978-1-60327-116-5_8

Cited by 1 publication

(2 citation statements)

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“…A variety of pharmaceutical interventions have been studied in the cp/cp rat. ACE inhibitors, endopeptidase inhibitors, insulin sensitizers and ethanol have all been shown to reduce hyperinsulinaemia, hypertriglyceridaemia, vascular dysfunction and myocardial lesions (Russell and Proctor, 2008). Recently, we have shown that these substances also reduce renal microvascular dysfunction and damage (Russell et al.…”

Section: Discussionmentioning

confidence: 99%

“…, 1999). These include advanced intimal (atherosclerotic) lesions, myocardial ischaemic lesions and microvascular renal dysfunction (Russell and Proctor, 2008), but the animals are not hypertensive (Russell and Amy, 1986). Vascular dysfunction, at the macrovascular level, includes increased contractility and reduced endothelium‐mediated vascular relaxation, and at the microvascular level is evident in albuminuria and glomerular sclerosis.…”

Section: Introductionmentioning

confidence: 99%

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

Russell

Kelly

Vine

et al. 2009

British J Pharmacology

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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·kg, 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 (~50%). Fasting plasma triglycerides were marginally reduced (~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 endotheliumdependent 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%