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      Relative Contributions of Cyclooxygenase- and Cytochrome P450 ω-Hydroxylase-Dependent Pathways to Hypoxic Dilation of Skeletal Muscle Resistance Arteries

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          This study determined the contribution of prostanoids, cytochrome P450 (CP450) 4A enzyme metabolites of arachidonic acid, and other potential mediators of hypoxic dilation of isolated rat skeletal muscle resistance arteries. Gracilis arteries (GA) were viewed via television microscopy and dilator responses to hypoxia (reduction in superfusate and perfusate PO<sub>2</sub> from ∼145 to ∼40 mm Hg) were measured with a video micrometer. Hypoxic dilation of gracilis arteries was severely impaired by either endothelium removal or cyclooxygenase inhibition with indomethacin, but not by nitric oxide synthase inhibition with L-NAME. Treatment of GA with 17-octadecynoic acid (17-ODYA) alone to inhibit CP450 4A enzymes significantly reduced hypoxic dilation from control levels. Treatment of vessels with N-methylsulfonyl-6-(2-proparglyoxyphenyl)hexanoic acid (MS-PPOH) to inhibit the production of epoxyeicosatrienoic acids (EETs) did not alter hypoxic dilation, although treatment with dibromo-dodecenyl-methylsulfimide (DDMS) to inhibit 20-hydroxyeicosatetraenoic acid (20-HETE) production had similar effects as 17-ODYA. Treatment of GA with 6(Z),15(Z)-20-HEDE, a competitive antagonist of the actions of 20-HETE, mimicked the effects of 17-ODYA and DDMS treatment on hypoxic dilation. These results suggest that hypoxic dilation of skeletal muscle resistance arteries primarily represents the effects of enhanced prostanoid release from vascular endothelium, although a contribution of reduced 20-HETE production via CP450 ω-hydroxylase enzymes also regulates hypoxic dilation of these vessels.

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          Increases in oxygen tension evoke arteriolar constriction by inhibiting endothelial prostaglandin synthesis.

           G Kaley,  E Messina,  D. Sun (1994)
          In vivo and in vitro studies concerned with the role of oxygen in the regulation of blood flow have primarily investigated the response of blood vessels to decreases in oxygen tension. In this study, we examined the response of isolated rat cremaster skeletal muscle arterioles to increases in oxygen tensions. First-order arterioles with an average diameter of 90 microns were cannulated and pressurized to 65 mm Hg and studied under constant pressure in a no-flow state. Arterioles were equilibrated in a Krebs bicarbonate-buffered solution (ph 7.4) gassed with 21% O2, 5% CO2, 74% N2. Changes in arteriolar diameters were continuously measured and recorded in response to increases in bath PO2 (20 to 660 mm Hg). Arterioles were studied before and after either the removal of the endothelium or the administration of indomethacin (IND, 10(-5) M), to inhibit prostaglandin synthesis. When the bath PO2 was increased from 20 to 150 mm Hg, arteriolar diameters decreased by 37%; they then decreased an additional 14% when bath PO2 was increased from 150 to 660 mm Hg. Removal of the endothelium or administration of IND completely eliminated the arteriolar constrictions in response to increases in PO2 from 20 to 150 mm Hg, and from 150 to 660 mm Hg. These observations suggest that rat cremaster arterioles constrict to increases in oxygen tension by reduction in the synthesis of endothelium-derived dilator prostaglandins.
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            Effect of oxygen tension on regulation of arteriolar diameter in skeletal muscle in situ.

             K Klotz,  K Ley,  P Gaehtgens (1995)
            Skeletal muscle arterioles are known to constrict upon elevation of ambient PO2. While several studies have shown that the endothelium plays an important role in this response, it is not clear how this response is mediated. We examined the oxygen-induced constriction of arterioles in the rat spinotrapezius muscle. Elevation of superfusion solution PO2 from about 15 to 150 mm Hg caused arteriolar constriction by 25% (+/- 3%, n = 18). Inhibition of prostaglandin synthesis by superfusion of indomethacin (30 microM) produced vasoconstriction by 28% (+/- 9.5%, n = 5), but left the PO2 response unaffected. Blockade of the synthesis of endothelium-derived relaxing factor (EDRF) by NG-nitro-L-arginine (L-NNA, 35 mg/kg i.v.) caused arteriolar constriction by 31% (+/- 8%, n = 8). During application of L-NNA, the constrictor response to PO2 elevation was reduced to 3 +/- 2%. Administration of superoxide dismutase (SOD, 80,000 U/kg i.v.) did not affect the PO2 response. It is concluded that in small arterioles of skeletal muscle both EDRF and prostanoids sustain a significant basal dilatation. The dilatory effects of EDRF but not of prostaglandins are strongly dependent on PO2. The vasoconstriction in response to high ambient PO2 is not due to EDRF breakdown during its diffusion from endothelial to smooth muscle cells.

              Author and article information

              J Vasc Res
              Journal of Vascular Research
              S. Karger AG
              August 2001
              11 July 2001
              : 38
              : 4
              : 305-314
              aDepartment of Physiology, Medical College of Wisconsin, Milwaukee, Wisc., and bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Tex., USA
              51061 J Vasc Res 2001;38:305–314
              © 2001 S. Karger AG, Basel

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              Page count
              Figures: 8, Tables: 1, References: 29, Pages: 10
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