Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity

Abstract

Abstract-The metabolic syndrome is a common precursor of cardiovascular disease and type 2 diabetes that is characterized by the clustering of insulin resistance, dyslipidemia, and increased blood pressure. In humans, mutations in the peroxisome proliferator-activated receptor-␥ (PPAR␥) have been reported to cause the full-blown metabolic syndrome, and drugs that activate PPAR␥ have proven to be effective agents for the prevention and treatment of insulin resistance and type 2 diabetes. Here we report that telmisartan, a structurally unique angiotensin II receptor antagonist used for the treatment of hypertension, can function as a partial agonist of PPAR␥; influence the expression of PPAR␥ target genes involved in carbohydrate and lipid metabolism; and reduce glucose, insulin, and triglyceride levels in rats fed a high-fat, high-carbohydrate diet. None of the other commercially available angiotensin II receptor antagonists appeared to activate PPAR␥ when tested at concentrations typically achieved in plasma with conventional oral dosing. In contrast to ordinary antihypertensive and antidiabetic agents, molecules that can simultaneously block the angiotensin II receptor and activate PPAR␥ have the potential to treat both hemodynamic and biochemical features of the metabolic syndrome and could provide unique opportunities for the prevention and treatment of diabetes and cardiovascular disease in high-risk populations. Key Words: receptors, angiotensin II Ⅲ angiotensin II Ⅲ renin-angiotensin system Ⅲ insulin resistance Ⅲ losartan A ll currently available classes of antihypertensive drugs were developed before it was widely recognized that increased blood pressure is closely associated with insulin resistance and dyslipidemia and well before public health authorities established diagnostic criteria for the metabolic syndrome. 1-3 Thus, the antihypertensive drugs in use today were designed primarily to affect cellular and biochemical mechanisms contributing to increased blood pressure and not to address the disordered carbohydrate and lipid metabolism that often accompany hypertension as part of the metabolic syndrome. Given the major impact of the metabolic syndrome on cardiovascular disease morbidity and mortality, 4 -6 the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value.Numerous studies have demonstrated that the peroxisome proliferator-activated receptor-␥ (PPAR␥) plays an important role in regulating carbohydrate and lipid metabolism and that ligands for PPAR␥ can improve insulin sensitivity, reduce triglyceride levels, and decrease the risk for atherosclerosis. 7-15 PPAR␥ ligands also have modest antihypertensive effects related at least in part to their ability to promote peripheral vasodilation. 16 -19 Several thiazolidinedione ligands for PPAR␥ have been approved for the treatment of type 2 diabetes; however, these agents have limited capacity to reduce blood pressure and can provoke fluid retention, weight gain, edema, a...

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

“…[36][37][38][39][40] 28,30,33 and especially in elderly patients with isolated systolic hypertension. 29,31 Other mechanisms by which ARBs could reduce the incidence of new or recurrent stroke include the beneficial effects of some ARBs on blood glucose control by increasing insulin sensitivity, 49,50 their platelet antiaggregating effects, [51][52][53][54] their hypouricemic effects 66,67 and their atrial antifibrillatory effects. [69][70][71] All these actions of ARBs could add to their AII-mediated stroke protective effects.…”

“…[45][46][47][48] However, certain ARBs like telmisartan exert their beneficial effects on glucose metabolism independently of the reninangiotensin system. 49, 50 The molecule of telmisartan has a structural similarity to peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligand pioglitazone, which has been approved for the treatment of type II diabetes mellitus. These drugs play an important role in regulating carbohydrate and lipid metabolism, by increasing insulin sensitivity.…”

“…These drugs play an important role in regulating carbohydrate and lipid metabolism, by increasing insulin sensitivity. 49,50 In studies in rats fed a high carbohydrate, high-fat diet, telmisartan given in doses similar to those used for the treatment of hypertension, reduced serum levels of glucose, insulin and triglycerides. 50 Antiplatelet effects Other ARBs, like losartan exert their stroke preventive effects through their antiplatelet aggregating effects.…”

“…49,50 In studies in rats fed a high carbohydrate, high-fat diet, telmisartan given in doses similar to those used for the treatment of hypertension, reduced serum levels of glucose, insulin and triglycerides. 50 Antiplatelet effects Other ARBs, like losartan exert their stroke preventive effects through their antiplatelet aggregating effects. Increased platelet aggregation and high uric acid levels have been both associated with increased cardiovascular events and strokes.…”

Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation

“…However, the molecular mechanism for the elevation of CRP in diabetes is not fully understood. Since crosstalk between the AGE-RAGE system and angiotensin II (Ang II) has been proposed in the pathogenesis of accelerated atherosclerosis in diabetes [1], we examined here whether and how telmisartan, a unique Ang II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-γ (PPAR-γ)-modulating activity [4], could inhibit AGE-induced CRP production in a human hepatoma cell line, Hep3B cells.…”