Hydrogen peroxide modulates coronary arteriolar function : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2003]
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| Subjects: |
| Abstract: | ABSTRACT: Hydrogen peroxide (H₂O₂) is not only involved in the pathogenesis of coronary dysfunction in many cardiovascular diseases, but also serves as an endogenous mediator regulating coronary vascular tone. To address the effects of H₂O₂ on coronary microvascular function, porcine subepicardial vessels (50-100 microm) were isolated, cannulated, and pressurized without flow for in vitro study. The effects of H₂O₂ on endothelial function were investigated by luminal exposure of microvessels to H₂O₂ (100 micromol/L, 60 minutes). Luminal incubation of the vessels with H₂O₂ did not alter basal tone but inhibited the vasodilatory response to adenosine in a manner similar to that by L-NAME, a nitric oxide (NO) synthase inhibitor. In contrast with the NO-mediated response, endothelium-dependent dilations to the cyclooxygenase activator arachidonic acid, the cytochrome P450 monooxygenase activator bradykinin, and endothelium-independent vasodilation to sodium nitroprusside, were not altered by H₂O₂. However, H₂O₂-induced inhibition was reversed by L-arginine, a NO precursor, suggesting a reduction in the availability of L-arginine for NO synthesis. Inhibition of arginase by α-difluoromethylornithine restored the vasodilatory function in response to adenosine indicating an involvement of endothelial arginase. Furthermore, we also found that arginase I protein and mRNA in coronary arterioles were upregulated after incubation with H₂O₂. Together, these results indicate that luminal H₂O₂ specifically impairs endothelium-dependent NO-mediated dilation of coronary microvessels by induction of endothelial arginase. The effects of H₂O₂ on vasomotor tone of coronary microvessels were also investigated. Disruption of endothelium and inhibition of cyclooxygenase (COX) by indomethacin (10 micromol/L) produced identical attenuation of vasodilation to albuminal H₂O₂. In contrast, the vasodilation to H₂O₂ was not affected by L-NAME and miconazole. Prostaglandin E₂(PGE₂) production was significantly increased by H₂O₂. Furthermore, inhibition of PGE₂ receptors with AH6809 attenuated coronary arteriolar dilation to H₂O₂ similar to that produced by indomethacin, indicating the involvement of PGE₂ in H₂O₂-induced vasodilation. Inhibition of calcium-activated potassium channels (Kca) by iberiotoxin and a high concentration of extraluminal KC1 further attenuated vasodilation of denuded vessels to H₂O₂. Together, these results suggest that H₂O₂ induces endothelium-dependent vasodilation through COX-mediated release of PGE₂ and also directly relaxes smooth muscle by opening Kca channels. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2003." Approved as to style and content by: Lih Kuo, Janet L. Parker, Theresa W. Fossum, Emily Wilson, Harris J. Granger. |
| Physical Description: | xii, 128 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 100-127). |