Chronic hyperglycemia impairs functional vasodilation via increasing thromboxane-receptor-mediated vasoconstriction

Abstract

Individuals with hyperglycemia exhibit impaired exercise performance and functional vasodilatory response. Based on the importance of arachidonic acid (AA) metabolites in functional vasodilation and the increased thromboxane-to-prostacyclin ratio in diabetes, we hypothesized that chronic hyperglycemia in diabetes increases thromboxane-receptor (TP)-mediated vasoconstriction, resulting in an attenuated functional vasodilation. Three groups of lean Zucker rats (8 wk) were used to test the effects of chronic hyperglycemia on endothelial function: normal, streptozotocin (STZ; 70 mg/kg ip), and STZ + insulin (2 U/day). After 4 wk of treatment, spinotrapezius arcade arterioles were chosen for microcirculatory observation. Arteriolar diameter was measured following muscle stimulation and 10 microM AA application in the absence and presence of 1 microM SQ-29548 (TP antagonist). STZ rats exhibited significantly higher fasting glucose levels and attenuated functional and AA-induced dilation compared with normal animals. SQ-29548 improved the vasodilatory responses in STZ rats but had no effect in controls. Insulin treatment normalized both the glucose levels and the vasodilatory responses, and SQ-29548 treatment had no effect on functional or AA-mediated vasodilation in STZ + insulin animals. These results suggest that the impaired functional vasodilation in diabetic rats is due to hyperglycemia-mediated increases in TP-mediated vasoconstriction.

Improved functional vasodilation in obese Zucker rats following exercise training

“…Consistent with our laboratory's previous findings, treatment with SQ-29548 only partially restored the functional and AAinduced vasodilation in the spinotrapezius muscle of the sedentary OZ (43). Our laboratory has shown that this partial restoration is due to both impaired production and response to vasodilator prostanoids, such as PGI 2 (20,21,45).…”

“…We have shown that minimizing the hyperglycemia in streptozotocin diabetic LZ increased the impaired functional vasodilation via a decreased TP-mediated vasoconstriction (43). More specifically, we have demonstrated that insulin resistance and resultant hyperglycemia in OZ contribute to the elevated TP activation and impaired functional vasodilation via increased vascular reactive oxygen species (41).…”

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

“…While this lack of a demonstrated role for the endothelium in bulk hyperemia at the organ level of resolution could reflect a compensated state wherein acute interventions cannot overcome a chronic disease condition, the present results neither support nor refute this concept. However, these results do suggest a critical importance for the vascular endothelium in maintaining perfusion distribution at higher levels of resolution, potentially through the impact of communicated responses (6,8,29), sensing of arteriolar wall shear stresses (28,29,33), or arachidonic acid metabolism (17,35,36). Clearly, this role for the endothelium would be in addition to its established involvement in other outcomes, including contributions to angiogenesis/angiostasis, antithrombotic activity, and leukocyte adhesion, among others.…”

“…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).…”