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

ABSTRACT

1. In phenylephrine (PHE) (1 micro M)-precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H(2)O(2), 10-100 micro M) caused only contraction, while high concentration of H(2)O(2) (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 40 mM inhibited the relaxation response to H(2)O(2) 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. 4. H(2)O(2) at 1 mM hyperpolarized membrane potential and reversibly augmented K(+) current in smooth muscle cells of mesenteric artery. These effects of H(2)O(2) were attenuated significantly by 4-AP. 5. In summary, in PHE-precontracted rat mesenteric artery (1) the response to H(2)O(2) shifted qualitatively from contraction to a biphasic response as H(2)O(2) 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 H(2)O(2) is independent of phospholipase A(2), cyclooxygenase, lipoxygenase, cytochrome P450 monooxygenase, adenylate or guanylate cyclase.