Myeloperoxidase evokes substantial vasomotor responses in isolated skeletal muscle arterioles of the rat


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Abstract

Aims:Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses.Methods:Following exposure to MPO (1.92 mU mL−1) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored.Results:Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 μm), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 μm), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 μm) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 μm) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca2+] levels in SMAs.Conclusion:These data showed that H2O2-derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca2+ sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2O2-evoked vasoconstrictions. Nevertheless, inhibition of the HOCl–COX–TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.

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