Selective peroxisome proliferator activated receptor-y modulation in the treatment of hypertension and metabolic syndrome. Role of angiotensin II receptor blockers.

Metabolic syndrome is a cluster of many risk factors that lead to an increase in the risk of cardiovascular disease and type 2 diabetes mellitus. In patients with metabolic syndrome, the use of the older antihypertensive agents such as thiazide diuretics and β-blockers (β-adrenoceptor antagonists) results in potentially adverse effects on glucose and lipid metabolism and may even exacerbate metabolic syndrome and increase the risk of new-onset type 2 diabetes mellitus. Conversely, recent evidence suggests a favourable role for lifestyle changes (physical exercise, dietary approach) and for the use of agents that inhibit the renin-angiotensin system (RAS). In particular, some angiotensin II receptor blockers (ARBs) are capable of stimulating the intracellular peroxisome proliferator-activated receptor (PPAR)-γ system, which affects the expression of key target genes that mediate beneficial effects on glucose and lipid metabolism. In addition to blood pressure control, this may remarkably improve the cardiovascular risk profile of patients with hypertension and metabolic syndrome treated with these PPAR-γ-stimulating ARBs. The dose-adjusted capacity of activating PPAR-γ receptors is well documented for ARBs such as irbesartan and, in particular, telmisartan, and recently a PPAR-γ receptor-activating property has also been demonstrated for the EXP 3179 metabolite of losartan. EXP 3179 acts like a selective PPAR-γ modulator and behaves similarly to telmisartan and irbesartan in its effect on differentiation assays, adipocytic gene regulation and transactivation assays, leading to a favourable metabolic profile. In addition, EXP 3179 potently inhibits the expression of endothelial cyclo-oxygenase (COX)-2, thereby exerting a potent anti-inflammatory action that could contribute to the antiatherogenic effect described in animal models treated with losartan and, probably, to the large benefit observed in the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial in patients undergoing losartan administration. Treatment with ARBs with PPAR-γ-stimulating properties is an interesting area for future research for the treatment of patients with hypertension and metabolic syndrom