Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice
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Título: | Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice |
Autor/a: | Leal, Marcos A.S. Dias, Ananda T. Porto, Marcela L. Brun, Bruna F. Gava, Agata L. Meyrelles, Silvana S. Gil-Longo, José Campos-Toimil, Manuel Pereira, Thiago M.C. Vasques, Elisardo C. |
Centro/Departamento: | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
Palabras chave: | Atherosclerosis | Endothelial dysfunction | Oxidative stress | TXA2 | ET-1 | Cyclooxygenase | |
Data: | 2018-01 |
Editor: | Karger |
Cita bibliográfica: | Leal, M., Dias, A., Porto, M., Brun, B., Gava, A., & Meyrelles, S. et al. (2017). Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE<sup>-/-</sup> Mice. Cellular Physiology And Biochemistry, 44(5), 1796-1809. http://dx.doi.org/10.1159/000485817 |
Resumo: | Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE-/- mice exhibited enhanced vasoconstriction to PE (Rmax ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE-/- mice also exhibited enhanced contractions to ET-1 (Rmax ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities |
Versión do editor: | https://doi.org/10.1159/000485817 |
URI: | http://hdl.handle.net/10347/16777 |
DOI: | 10.1159/000485817 |
ISSN: | 1015-8987 |
E-ISSN: | 1421-9778 |
Dereitos: | © 2017 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
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© 2017 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission
© 2017 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission