Mechanisms of hydrogen‐peroxide‐induced biphasic response in rat mesenteric artery
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abstract
In phenylephrine (PHE) (1 μM)‐precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H2O2, 10–100 μM) caused only contraction, while high concentration of H2O2 (0.3–1 mM) caused a biphasic response: a transient contraction followed by a relaxation response.Endothelium removal did not affect the biphasic response. 7,7‐Dimethyl‐(5Z,8Z)‐eicosadienoic acid, diclofenac, furegrelate, or SQ 29548 greatly inhibited the contraction but did not affect the relaxation. 17‐Octadecynoic acid, eicosatriynoic acid, ICI 198615, SQ 22536, or ODQ did not inhibit the biphasic response.KCl at 40 mM inhibited the relaxation response to H2O2 by 98±24%. 4‐Aminopyridine (4‐AP) inhibited while tetraethylammonium chloride (TEA), charybdotoxin, or glibenclamide attenuated the relaxation response. A combination of 4‐AP, TEA and glibenclamide mimicked the effects of 40 mM KCl. Iberiotoxin, apamin, or barium chloride did not inhibit the relaxation response.H2O2 at 1 mM hyperpolarized membrane potential and reversibly augmented K+ current in smooth muscle cells of mesenteric artery. These effects of H2O2 were attenuated significantly by 4‐AP.In summary, in PHE‐precontracted rat mesenteric artery: (1) the response to H2O2 shifted qualitatively from contraction to a biphasic response as H2O2 increased to 0.3 mM or higher; (2) the relaxation response is caused by the activation of K+ channels, with voltage‐dependent K+ channels playing a primary role; and the contraction is likely to be mediated by thromboxane A2; (3) the K+ channel activation by H2O2 is independent of phospholipase A2, cyclooxygenase, lipoxygenase, cytochrome P450 monooxygenase, adenylate or guanylate cyclase.British Journal of Pharmacology (2003) 138, 1085–1092. doi:10.1038/sj.bjp.0705147
