Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates

• Published in: International Journal of Obesity 2016-10, Vol.40 (10), p.1600-1603
• Main Authors: Chadderdon, S M, Belcik, J T, Bader, L, Kievit, P, Grove, K L, Lindner, J R
• Format: Article
• Language: English
• Subjects: 59; 631/443/1338/2729; 631/443/319/1642; 631/45/287/1183; 692/699/2743/2037; 692/699/2743/393; 692/699/75; Acids; Animals; Biological activity; Blood flow; Blood glucose; Blood volume; Blood Volume - drug effects; Capillaries - drug effects; Complications and side effects; Correlation; Cytochrome; Cytochrome P-450 Enzyme System - metabolism; Development and progression; Disease Models, Animal; Eicosanoids; Enzymes; Epidemiology; Epoxide hydrolase; Genetic aspects; Glucose; Glucose metabolism; Glucose tolerance; Glucose Tolerance Test; Health aspects; Health Promotion and Disease Prevention; Hydroxyeicosatetraenoic Acids - pharmacology; Insulin; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Intravenous administration; Laboratory animals; Macaca mulatta; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Metabolites; Microcirculation - drug effects; Microcirculation disorders; Microvasculature; Monkeys & apes; Muscle, Skeletal - blood supply; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Nitric oxide; Obesity; Primates; Public Health; Regional Blood Flow - drug effects; Risk factors; short-communication; Skeletal muscle; Ultrasonic imaging; Vasoactive agents; Vasoconstriction; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2016.117

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.