Mechanisms of hydrogen-peroxide-induced biphasic response in rat mesenteric artery

1. In phenylephrine (PHE) (1 muM)-precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H2O2, 10-100 muM) caused only contraction, while high concentration of H2O2 (0.3-1 mm) caused a biphasic response: a transient contraction followed by a relaxation response. 2 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. 3 KCl at 40mm 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 40mm KCl. Iberiotoxin, apamin, or barium chloride did not inhibit the relaxation response. 4 H2O2 at I 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. 5 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 A(2); (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.705147.