TCT-434 Vascular Protective Actions Of A Novel Sustained Release Nitrite Formulation In Obese Swine With Metabolic Syndrome

Abstract

Background: Metabolic syndrome (MetS) results in vascular dysfunction and decreased nitric oxide (NO) generation via endothelial nitric oxide synthase (eNOS). Following eNOS dysfunction blood and tissue nitrite (NO2-) stores are converted to NO to compensate and maintain NO signaling, but are rapidly depleted. We investigated the effects of a novel sustained release sodium nitrite formulation (SR-Nitrite, Theravasc, Inc.) on NO bioavailability, myocardial oxidative stress, and coronary vascular function in a clinically relevant model of MetS. Methods: MetS was generated in Ossabaw miniswine (6 mos. of age) fed a high fat, high carbohydrate diet for 6 mos. SR-Nitrite (80 mg/kg b.i.d.; n=5) or placebo (n=6) was administered orally for 3 wks. Plasma and myocardial NO2- and nitrosothiol (RSNO) levels were measured as an index of NO bioavailability. Cardiac oxidative stress was assessed by protein carbonyl levels. Myocardial expression of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPX) was also determined using Western blots. Coronary artery rings were isolated, suspended in organ chambers, and equilibrated to physiological tension. Following pre-constriction with PGF2α, vascular relaxation curves were generated using sodium nitroprusside (10-9 to 10-5 M) and maximum vasorelaxation was measured. Results: SR-Nitrite significantly (p Conclusions: These data demonstrate that a novel, SR-Nitrite formulation increases NO bioavailability, attenuates myocardial oxidative stress, and improves coronary vascular reactivity in the setting of obesity and MetS.