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


METHODS
Obese male rats were treated with irbesartan (30 mg.kg(-1).day(-1), incorporated into chow) from 12 to 25 weeks of age.


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 ( approximately 50%). Fasting plasma triglycerides were marginally reduced ( approximately 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
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.
Russell
J C
JC
Alberta Institute for Human Nutrition, University of Alberta, Edmonton, Canada. jim.russell@ualberta.ca
Kelly
S E
SE
Vine
D F
DF
Proctor
S D
SD
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D000077405:Irbesartan; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000187:drug effects / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000503:physiopathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000209:etiology / Q000517:prevention & control; D009765:Obesity / Q000150:complications*; D051381:Rats; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D007328:Insulin; D013777:Tetrazoles; D014280:Triglycerides; D000077405:Irbesartan