title: Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates.
abstract: The inability to augment capillary blood volume (CBV) in response to insulin or glucose is thought to contribute to insulin resistance (IR) by limiting glucose uptake in key storage sites. Understanding the mechanisms that contribute to impaired CBV augmentation early in the onset of IR may lead to new future therapies. We hypothesized that inactivity alters the balance of vasoactive eicosanoids and contributes to microvascular IR. In ten activity-restricted (AR) and six normal activity adult male rhesus macaques, contrast-enhanced ultrasound of skeletal muscle blood flow and CBV was performed at baseline and during intravenous glucose tolerance test (IVGTT). Plasma was analyzed for vasoconstrictor hydroxyeicosatetraenoic acids (HETEs) and the ratio of vasodilatory epoxyeicosatrienoic acids (EETs) to their less biologically active dihydroxyeicosatrienoic acids (DHETs) as an indirect measure of soluble epoxide hydrolase activity. AR primates were IR during IVGTT and had a 45% lower glucose-stimulated CBV response. Vasoconstrictor 18-HETE and 19-HETE and the DHET/EET ratio were markedly elevated in the AR group and correlated inversely with the CBV response. In addition, levels of 18-HETE and 19-HETE correlated directly with microvascular IR. We conclude that a shift toward increased eicosanoid vasoconstrictor tone correlates with abnormal skeletal muscle vascular recruitment and may contribute to IR.
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Chadderdon
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Belcik
authors.affiliation: The Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bader
authors.affiliation: The Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kievit
authors.affiliation: The Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Grove
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Lindner
mesh_terms: D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D014662:Vasoconstrictor Agents; C061444:18-hydroxy-5,8,11,14-eicosatetraenoic acid; C055986:19-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System