Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome

Abstract

Xiang, Lusha, Jay S. Naik, Benjamin L. Hodnett, and Robert L. Hester. Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 290: R134 -R138, 2006. First published September 15, 2005 doi:10.1152/ajpregu.00295.2005.-These studies tested the hypothesis that in obese Zucker rats (OZRs), a model of metabolic syndrome, the impaired functional vasodilation is due to increased thromboxane receptor (TP)-mediated vasoconstriction and/or decreased prostacyclin-induced vasodilation. Spinotrapezius arcade arterioles from 12-wk-old lean (LZR) and OZR were chosen for microcirculatory observation. Arteriolar diameter (5 LZR and 6 OZR) was measured after 2 min of muscle stimulation in the absence or presence of 1 M SQ-29548 (TP antagonist). Additionally, arteriolar diameter (6 for each group) was measured after application of iloprost (prostacyclin analog; 0.28, 2.8, and 28 M), arachidonic acid (10 M), and sodium nitroprusside (0.1, 1, and 10 M) in the absence or presence of 1 M SQ-29548. A 10 M concentration of adenosine was used to induce a maximal dilation. Basal diameters were not different between LZRs and OZRs. Functional hyperemia and arachidonic acid-mediated vasodilations were significantly attenuated in OZR compared with LZR, and treatment with 1 M SQ-29548 significantly enhanced the dilations in OZRs, although it had no effect in LZRs. Vasodilatory responses to iloprost and sodium nitroprusside (1 and 10 M) were significantly reduced in OZR. Adenosine-mediated vasodilation was not different between groups. These results suggest that the impaired functional dilation in the OZR is due to an increased TP-mediated vasoconstriction and a decreased PGI2-induced vasodilation.obese Zucker rat; prostacyclin; thromboxane; vasoconstriction IT IS WELL ESTABLISHED THAT, during periods of increased skeletal muscle metabolism (such as during exercise), blood flow to the muscle increases (functional hyperemia) because of dilation of local arterioles (functional dilation), and this vasodilatory response is dependent, in some part, on endothelial function (22). However, in patients and animals with metabolic syndrome, endothelial dysfunction may occur early in the pathology of this syndrome (4), possibly contributing to the impaired functional hyperemia seen in metabolic syndrome. For example, patients with type 2 diabetes exhibit an impaired endothelial-dependent vasodilatory response to ACh and a significant impairment of the functional hyperemic response to leg cycle ergometer exercise (14). Our laboratory and others (8,32) have demonstrated that the obese Zucker rat (OZR), a model of metabolic syndrome, have both an attenuated functional and ACh-induced vasodilation in skeletal muscle arterioles. Although the mechanism(s) responsible for the impaired functional dilation remains unclear, these studies reveal a possible relationship between the endothelial dysfunction and the impaired functional vasodilation.The determination of the mechanism(s) responsible...

Obesity and vascular dysfunction

“…Thus the decreased levels of NO noted in obesity may primarily reflect an increased scavenging via reactive oxygen species, resulting in the production of substances such as peroxynitrite [71,74]. When arachidonic acid is introduced to the system, vasodilatory responses are attenuated in both gracilis and spinotrapezious arterioles of the OZR in comparison to the LZR [73,75]. The impaired responses appear to operate partially via an elevation in oxidant stress, but additional signaling pathways independent of acute alterations in oxidant tone appear to also be involved.…”

“…More recently, increased levels of vasoconstrictor prostanoids have also been suggested as a possible mechanism for the decreased vascular perfusion and dilator reactivity within obesity and the metabolic syndrome [88]. In the OZR, an increase in vasodilation was noted when the prostaglandin H2/thromboxane A2 receptor antagonist SQ-29548 was administered, suggesting that a chronic basal vasoconstrictor influence, mediated via the PGH2/TxA2 receptor may contribute to impairments in organ perfusion and dilator reactivity [75]. These changes to endothelial vasoconstrictor response with obesity may show an initial effect, while neurological mechanisms may show a longer lasting systemic role [89].…”

Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome

“…Additionally, the cremaster muscle was stimulated to contract for 3 min at both 1-and 3-Hz contractions by using electrodes placed on opposite sides of the muscle (Grass SD9). Stimulation parameters followed those established previously for transilluminated, striated muscle preparations (34,36), and assessments of both mechanical and perfusion responses were determined immediately following cessation of the electrical stimulation. All procedures were performed under control conditions in LZR and OZR, and following treatment of the in situ cremaster muscle with Tempol (10 Ϫ3 M), SQ-29548 (10 Ϫ4 M), and/or phentolamine (10 Ϫ5 M) within the superfusate solution.…”

“…With continued hyperphagia, OZR become progressively insulin-resistant, dyslipidemic (hypercholesterolemia and severe hypertriglyceridemia) and moderately hypertensive (5, 18). As such, the OZR represents a complete model of the metabolic syndrome and, owing to the origin in a chronic excess caloric intake, an appropriate and relevant model for the human condition.Previous study from our laboratory and by others has demonstrated that multiple relevant pathways of both dilator and constrictor reactivity are altered in OZR with development of the metabolic syndrome, and this can contribute to an impaired ability to effectively match skeletal muscle perfusion with metabolic demand (10,11,34,35,36). Among these impacted pathways are those of endothelium-dependent origin, such as wall shear rate (3, 15), reduced PO 2 (16,17), and an array of pharmacological challenges, including acetylcholine (15) and arachidonic acid (17,(35)(36)(37).…”

“…Among these impacted pathways are those of endothelium-dependent origin, such as wall shear rate (3, 15), reduced PO 2 (16,17), and an array of pharmacological challenges, including acetylcholine (15) and arachidonic acid (17,(35)(36)(37). From the perspective of constrictor reactivity, previous studies suggest that adrenergic constriction (10, 20) or signaling mechanisms contributing to adrenergic constriction (26, 32) may be enhanced in arterioles of OZR, as well as myogenic (i.e., pressure-induced) activation (13) and responses to thromboxane A 2 (17,35,36). However, despite the presence of this growing body of knowledge, how these myriad stimuli interact to determine vessel dimension, and ultimately tissue perfusion, remains completely unknown.…”