Comparision of secretagogue effects of rosiglitazone and telmisartan on ANP secretion in rats

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear transcription factor, is a key regulator of insulin signaling, and glucose and fat metabolism. In this study, we evaluated the direct effect of PPAR-γ ligand on the secretion of atrial natriuretic peptide (ANP). The isolated perfused beating atria were used and rosiglitazone (0.01, 0.3 and 1μM) or telmisartan was perfused into atria with and without inhibitors. High frequency stimulation caused a decreased atrial contractility by 40% and an increased ANP secretion by 80%. Rosiglitazone augmented high frequency-induced ANP secretion and concentration in a dose-dependent manner. Rosiglitazone-induced ANP secretion was attenuated by the pretreatment with PPAR-γ antagonist (GW 9662), or inhibitor for phosphoinositol 3-kinase (PI3-kinase, wortmannin), Akt (API-2) or nitric oxide synthase (l-NAME). Telmisartan, a partial agonist of PPAR-γ with angiotensin II type 1 receptor (AT1R) blocker, also stimulated ANP secretion, which was more potent than rosiglitazone or losartan. Infusion of rosiglitazone or telmisartan in anesthetized rats tended to decrease mean arterial pressure and to increase pulse pressure without difference. A plasma ANP level was increased by telmisartan more than by rosiglitazone. In diabetic rats, an increased plasma ANP level was more prominent than sham rats. Therefore, we suggest that rosiglitazone stimulates high frequency-induced ANP secretion through the PPAR-γ receptor-PI3-kinase-Akt-eNOS pathway and telmisartan shows synergistic effect on ANP secretion.