Abstract 244: Oxidative Stress via Activating Soluble Guanylate Cyclase Leads to Increased Nitric Oxide Sensitivity of Coronary Arterioles in High Fat Diet-induced Obesity
Obesity is associated with hyperdynamic circulation requiring an increased coronary blood flow. It is known that nitric oxide (NO) is an important determinant of coronary flow. The impact of obesity on NO-mediated responses of coronary microvessels, however, is poorly understood. Thus, responses to NO-donors were investigated in pressurized coronary arterioles (~100 μm) isolated from control (on normal diet) and high fat diet (60% of saturated fat)-fed, obese rats. Dilations to sodium nitroprusside (SNP) and DETA-NONOate were significantly enhanced in coronary vessels of obese rats (control: 63±6% and 51±5%, obese: 78±5% and 70±5%, respectively, at 1 μM each), whereas dilations to 8-bromo-cGMP were not different in the two groups. In the presence of soluble guanylate cyclase (sGC) inhibitor, oxadiazolo-quinoxaline, both SNP and DETA-NONOate-induced dilations were reduced equally in two groups. The protein expression of the sGCβ1 subunit was not different in the two groups, whereas the SNP-stimulated cGMP production was enhanced in coronary vessels of obese rats compared to controls, as detected by immunocytochemistry. In addition, production of xanthine oxidase-derived superoxide anion (detected by lucigenin chemiluminescence) was enhanced in vessels of obese rats, when compared to those of controls. In control arterioles incubation and presence of xanthine (0.5 mM, for 30 min) increased superoxide production and resulted in enhanced dilations to the NO donor, SNP (before: 58±7% and after: 83±4% at 1 μM). Collectively, these findings are the first to suggest that obesity (induced by high fat diet in rats) is associated with enhanced xanthine oxidase-derived superoxide production, which via activation of sGC leads to an increased sensitivity of coronary smooth muscle cells to NO. This mechanism could contribute to the early adaptation of coronary arterioles to the increased metabolic requirements of the heart in obesity.