Impaired functional vasodilation in obese Zucker rats: role of insulin resistance and inflammation

Abstract

Obesity is characterized by insulin resistance (IR) and chronic inflammation, which may alter cyclooxygenase‐2 (COX‐2) activity and thus arachidonic acid (AA) metabolism. The obese Zucker rat (OZR) is a model of IR with increased inflammatory markers. We have shown an impaired functional vasodilation (FD) in the OZR due to altered arachidonic acid (AA) metabolism and increased thromboxane receptor (TP) activation. We hypothesize that IR alters AA metabolism via stimulation of COX‐2, resulting in impaired FD. Male lean (LZR) and OZR were treated with rosiglitazone (ROZ, 5mg/kg/day, rat chow) for 2 wks. The arteriolar diameters were measured in spinotrapezius muscle following muscle stimulation without and with the selective COX‐2 inhibitor NS‐398 or the TP antagonist SQ 29548 (SQ). Compared to LZR, untreated OZR exhibited an impaired oral glucose tolerance test and a two fold COX‐2 expression, both of which were normalized by ROZ treatment. The impaired FD in OZR was improved by 88% after acute treatment with NS‐398 and by 50% after chronic treatment with ROZ. SQ improved the vasodilatory responses by 58% in untreated OZR with no effect in lean or ROZ treated OZR. These results suggest that the increased TP activation and impaired FD in OZR is due to IR‐stimulated increase in COX‐2 activity. (Supported by AHA 55841, 53952, HL 51971)