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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1522    most recent 00596.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Goodwill, A. G. Articles by Frisbee, J. C. PubMed PubMed Citation Articles by Goodwill, A. G. Articles by Frisbee, J. C.

Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension

Center for Interdisciplinary Research in Cardiovascular Sciences, Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia

Submitted 7 June 2008 ; accepted in final form 1 August 2008

This study determined if altered vascular prostacyclin (PGI₂) and/or thromboxane A₂ (TxA₂) production with reduced PO₂ contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in PO₂ under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced PO₂. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI₂ production with reduced PO₂ was similar between strains, although TxA₂ production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH₂/TxA₂ receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA₂, which competes against the vasodilator influences of PGI₂. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA₂ production and may blunt vascular sensitivity to PGI₂.

skeletal muscle microcirculation; endothelium-dependent dilation; vascular reactivity; rodent models of obesity