Abstract
AimsThe molecular mechanisms of the vasoconstrictor responses evoked by hydrogen peroxide (H2O2) have not been clearly elucidated in skeletal muscle arterioles.Methods and ResultsChanges in diameter of isolated, cannulated and pressurized gracilis muscle arterioles (GAs) of Wistar-Kyoto rats were determined under various test conditions. H2O2 (10–100 µM) evoked concentration-dependent constrictions in the GAs, which were inhibited by endothelium removal, or by antagonists of phospholipase A (PLA; 100 µM 7,7-dimethyl-(5Z,8Z)-eicosadienoic acid), protein kinase C (PKC; 10 µM chelerythrine), phospholipase C (PLC; 10 µM U-73122), or Src family tyrosine kinase (Src kinase; 1 µM Src Inhibitor-1). Antagonists of thromboxane A2 (TXA2; 1 µM SQ-29548) or the non-specific cyclooxygenase (COX) inhibitor indomethacin (10 µM) converted constrictions to dilations. The COX-1 inhibitor (SC-560, 1 µM) demonstrated a greater reduction in constriction and conversion to dilation than that of COX-2 (celecoxib, 3 µM). H2O2 did not elicit significant changes in arteriolar Ca2+ levels measured with Fura-2.ConclusionsThese data suggest that H2O2 activates the endothelial Src kinase/PLC/PKC/PLA pathway, ultimately leading to the synthesis and release of TXA2 by COX-1, thereby increasing the Ca2+ sensitivity of the vascular smooth muscle cells and eliciting constriction in rat skeletal muscle arterioles.
Highlights
Among its many important roles, H2O2 is involved as a signalling molecule in the physiological regulation of the vascular diameter
These data suggest that H2O2 activates the endothelial Src kinase/phospholipase C (PLC)/protein kinase C (PKC)/phospholipase A (PLA) pathway, leading to the synthesis and release of thromboxane A2 (TXA2) by COX-1, thereby increasing the Ca2+ sensitivity of the vascular smooth muscle cells and eliciting constriction in rat skeletal muscle arterioles
We investigated the acute effects of H2O2 on the diameter of arterioles isolated from rat skeletal muscle and rat coronaries, the signal transduction pathway initiating H2O2-evoked vasoconstriction, and the changes in vascular smooth muscle intracellular Ca2+ concentrations induced by H2O2
Summary
Among its many important roles, H2O2 is involved as a signalling molecule in the physiological regulation of the vascular diameter. The vascular signalling pathways mobilized by H2O2 have not been fully elucidated. H2O2 can be produced by endothelial cells, smooth muscle cells and fibroblasts [6,7], under both physiological and pathological conditions. Significant amounts of H2O2 are released by activated leukocytes under inflammatory conditions [8]. Numerous enzyme systems, including NAD(P)H oxidase [9,10], the mitochondrial respiratory chain, xanthine oxidase, uncoupled endothelial nitric oxide (NO) synthase, cytochrome P-450 enzymes, lipoxygenase and the cyclooxigenases [11,12,13,14,15,16], can generate the superoxide anion (O22), which is reduced to H2O2. There can be a great variation in the extracellular concentration of H2O2, but it can probably reach 0.3 mM [8,17,18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
