Type 2 Diabetes Alters Nitric Oxide Signaling in the Rat Aorta

Abstract

We tested the hypotheses that type 2 diabetes (T2D) and a Western diet, high in fat, sucrose and cholesterol (HFSC), would impair endothelial and vascular smooth muscle function. Eight week old rats were divided into the following groups: T2D (n=10; Otsuka Long-Evans Tokushima Fatty rats, hyperphagic rodent model of T2D), lean control (LC; n=10; Long-Evans Tokushima Otsuka, non-hyperphagic control), T2D+HFSC (n=10) and LC+HFSC (n=10). At thirty-two weeks old, rats were euthanized, their aortas were harvested and aortic function was measured using an isometric wire myograph. Aortic rings were pre-constricted with phenylephrine and dose response curves for ACh and SNP were examined under the following conditions: untreated, NOS inhibition (L-NAME), COX inhibition (indomethacin) and combined NOS+COX inhibition. ACh-induced vasorelaxation was greater in LC+HFSC vs. all other groups (P<0.05). During L-NAME inhibition, ACh-induced vasorelaxation was greater in T2D vs. LC and LC+HFSC (P<0.05). SNP-induced vasorelaxation was greater in LC and LC+HFSD vs. T2D and T2D+HFSC (P<0.05). The aforementioned trend was consistent across conditions (NOS, COX and NOS+COX inhibition). In contrast to the hypotheses, rats with T2D and rats fed the HFSC did not display gross endothelial and vascular smooth muscle dysfunction. However, vascular smooth muscle responsiveness to SNP was attenuated in T2D and T2D+HFSC rats. T2D rats displayed augmented vasorelaxation to ACh during NOS inhibition and impaired vasorelaxation to SNP, implicating an alternative vasodilatory pathway compensates for altered NO signaling in the vascular smooth muscle. Support: HL036088(MHL) and VHA-CDA2 1299-03(RSR)