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

This study determined if altered vascular prostacyclin ([PGI.sub.2]) and/or thromboxane [A.sub.2] (Tx[A.sub.2]) production with reduced [Po.sub.2] 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 [Po.sub.2] 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 [Po.sub.2]. 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 [PGI.sub.2] production with reduced [Po.sub.2] was similar between strains, although Tx[A.sub.2] production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of [PGH.sub.2]/Tx[A.sub.2] 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 Tx[A.sub.2], which competes against the vasodilator influences of [PGI.sub.2]. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular Tx[A.sub.2] production and may blunt vascular sensitivity to [PGI.sub.2]. skeletal muscle microcirculation; endothelium-dependent dilation; vascular reactivity; rodent models of obesity