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.
        
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Shim CY, Kim S, Chadderdon S, Wu M, Qi Y, Xie A, Alkayed N, Davidson BP, Lindner JR (2014) Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume American Journal of Physiology Endocrinol Metab
Shim CY, Kim S, Chadderdon S, Wu M, Qi Y, Xie A, Alkayed N, Davidson BP, Lindner JR (2014) American Journal of Physiology Endocrinol Metab