Shim_2014_Am.J.Physiol.Endocrinol.Metab__ajpendo 00216 2014

Skeletal muscle microvascular blood flow (MBF) increases in response to physiologic hyperinsulinemia. This vascular action of insulin may facilitate glucose uptake. We hypothesized that epoxyeicosatrienoic acids (EETs), a family of arachadonic acid-derived endothelium-derived hyperpolarizing factors, is a mediator of insulin's microvascular effects. Contrast-enhanced ultrasound (CEU) was performed to quantify skeletal muscle capillary blood volume (CBV) and MBF in wild-type and obese insulin-resistant (db/db) mice after administration of vehicle or tAUCB, an inhibitor of soluble epoxide hydrolase which converts EETs to less active dihydroxyeicosatrienoic acids. Similar studies were performed in rats pre-treated with L-NAME. CEU was also performed in rats undergoing a euglycemic hyperinsulinemic clamp, half of which were pre-treated with the epoxygenase inhibitor MS-PPOH to inhibit EET synthesis. In both wild type and db/db mice, intravenous tAUCB produced an increase in CBV (65-100% increase at 30 min, p<0.05) and in MBF. In db/db/ mice tAUCB also reduced plasma glucose by approximately 15%. In rats pretreated with L-NAME, tAUCB after produced a significant approximately 20% increase in CBV indicating a component of vascular response independent of nitric oxide (NO) production. Hyperinsulinemic clamp produced a time-dependent increase in MBF (19+/-36 and 76+/-49% at 90 min, p=0.026) mediated in part by an increase in CBV. Insulin-mediated changes in both CBV and MBF during the clamp were entirely blocked MS-PPOH. We conclude that EETs are a mediator of insulin-mediated augmentation in skeletal muscle perfusion and are involved in regulating changes in CBV during hyperinsulinemia.