Original ContributionDifferential involvement of various sources of reactive oxygen species in thyroxin-induced hemodynamic changes and contractile dysfunction of the heart and diaphragm muscles
Section snippets
Animals
Male FVB/N mice (7–9 months of age) were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) and kept at the Research Animal Facility of The Ohio State University. The experimental procedures and protocols used in this study were approved by the Animal Care and Use Committee of The Ohio State University, conforming to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85–23, revised 1996).
Antioxidant and T4 treatments
All drugs were freshly
Results
First, we investigated BP after 2 weeks of treatment in all groups. T4-treated mice exhibited significant increases in systolic (108±4 mm Hg; p<0.01), diastolic (77±3 mm Hg; p<0.05), and mean arterial pressure (MAP) (87±4 mm Hg; p<0.01) compared to control (systolic, 90±3 mm Hg; diastolic, 62±3 mm Hg; and MAP, 70±3 mm Hg; Figs. 1A–C), as we illustrated before [16]. Surprisingly, L-NIO resulted in a significant decrease in T4-induced increases in diastolic pressure (63±4 mm Hg; p<0.05) and MAP (73±4 mm
Discussion
The goal of the current study was to test the hypothesis that T4 may produce distinct hemodynamic, cardiac, and diaphragm muscle abnormalities by differentially affecting various sources of ROS. Consistent with published data [2], [9], [16], [33], [34], [35], T4 increased the BP of mice in the current study. Among all antioxidant treatments, only L-NIO, a nonspecific NOS inhibitor, attenuated T4-induced hypertension. NO is a well-known regulator of BP. Three isoforms of NOS have been
Conclusion
We have shown for the first time that T4 exerts differential effects on various sources of ROS to induce distinct cardiovascular and skeletal muscle phenotypes. Another novel finding is that T4-induced LV dysfunction seems to be independent of cardiac hypertrophy and that NADPH oxidase is a key player in this process. Furthermore, we proved the significance of both xanthine oxidase and mitochondrial ROS pathways in T4-induced fatigability of diaphragm muscles. Finally, we confirmed previous
Acknowledgments
Funding was provided in part through start-up funds to P.M.L.J. from The Ohio State University and by P30 Core Grant NINDS P30 NS045758-06 (PI: C. Beattie).
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