Apocynin normalizes hyperreactivity to phenylephrine in mesenteric arteries from cholesterol-fed mice by improving endothelium-derived hyperpolarizing factor response

• Published in: Free radical biology & medicine 2006-10, Vol.41 (8), p.1289-1303
• Main Authors: Matsumoto, Takayuki, Miyamori, Kiyoto, Kobayashi, Tsuneo, Kamata, Katsuo
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Acetylcholine - pharmacology; Adrenergic alpha-Agonists - pharmacology; Animals; Apocynin; Biological Factors - physiology; Cholesterol, Dietary - administration & dosage; Contraction; Dinoprost - analogs & derivatives; Dinoprost - blood; EDHF; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Enzyme Inhibitors - pharmacology; Free radicals; Hypercholesterolemia; Hypercholesterolemia - drug therapy; Hypercholesterolemia - physiopathology; Male; Mesenteric Arteries - drug effects; Mesenteric Arteries - physiology; Mesentery; Mice; Mice, Inbred ICR; NADPH Oxidases - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III; Nitroprusside - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Phenylephrine - pharmacology; Potassium - pharmacology; Signal Transduction - drug effects; Superoxides - metabolism; Vasoconstriction - drug effects
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2006.07.012

We studied the relationship among endothelial function, oxidative stress, and phenylephrine (PE; α 1-adrenoceptor agonist)-induced contraction in mesenteric arteries from high-cholesterol (HC)-diet-fed mice. In HC mice (vs age-matched normal-diet-fed mice): (1) PE-induced contraction in endothelium-intact rings was enhanced (endothelial denudation increased contraction in “normal-diet” rings, but did not enhance it further in “HC” rings); (2) the enhanced PE-induced contraction was further enhanced in the presence of N G-nitro- l-arginine (L-NNA; nitric oxide synthase inhibitor) or L-NNA plus indomethacin (cyclooxygenase inhibitor) [to preserve endothelium-derived hyperpolarizing factor (EDHF)], but unchanged in the presence of charybdotoxin plus apamin (to block EDHF); (3) ACh-induced EDHF-type relaxation was reduced; and (4) oxidative stress [indicated by the plasma 8-isoprostane level (reliable systemic marker) and aortic superoxide production] was greater. In HC mice, PE-induced contraction was normalized by apocynin [NAD(P)H oxidase inhibitor] or tempol (superoxide dismutase mimetic), but enhanced by NADH [NAD(P)H oxidase substrate]. Oral dietary supplementation with apocynin (30 mg/kg/day for 4 weeks) corrected the above abnormalities. Hence: (1) PE-induced contraction is modulated by the endothelium, and the enhanced contractility in HC mice results from defective EDHF signaling and elevated oxidative stress, and (2) apocynin normalizes PE-induced contraction in HC mice by improving EDHF signaling.