title: Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume.
abstract: Skeletal muscle microvascular blood flow (MBF) increases in response to physiological 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, are mediators 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 trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (t-AUCB), an inhibitor of soluble epoxide hydrolase that converts EETs to less active dihydroxyeicosatrienoic acids. Similar studies were performed in rats pretreated with l-NAME. CEU was also performed in rats undergoing a euglycemic hyperinsulinemic clamp, half of which were pretreated with the epoxygenase inhibitor MS-PPOH to inhibit EET synthesis. In both wild-type and db/db mice, intravenous t-AUCB produced an increase in CBV (65-100% increase at 30 min, P < 0.05) and in MBF. In db/db mice, t-AUCB also reduced plasma glucose by ∼15%. In rats pretreated with l-NAME, t-AUCB after produced a significant ≈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) that was mediated in part by an increase in CBV. Insulin-mediated changes in both CBV and MBF during the clamp were blocked entirely by 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.
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Chi Young
authors.initials: CY
authors.lastname: Shim
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Sajeevani
authors.initials: S
authors.lastname: Kim
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Scott
authors.initials: S
authors.lastname: Chadderdon
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Melinda
authors.initials: M
authors.lastname: Wu
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Aris
authors.initials: A
authors.lastname: Xie
authors.affiliation: Knight Cardiovascular Institute and Department of Anesthesia and Peri-operative Medicine, Oregon Health and Science University, Portland, Oregon.
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.affiliation: Knight Cardiovascular Institute and.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Davidson
authors.affiliation: Knight Cardiovascular Institute and lindnerj@ohsu.edu.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001810:Blood Volume / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006946:Hyperinsulinism / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D007328:Insulin; D014508:Urea; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid
keywords: contrast ultrasound; epoxyeicosatrienoic acids; insulin; muscle blood flow