Mechanisms of hydrogen peroxide-induced contraction of rat aorta

• Published in: European journal of pharmacology Vol. 344; no. 2; pp. 169 - 181
• Main Authors: Yang, Zhi-wei, Zheng, Tao, Zhang, Aimin, Altura, Bella T, Burton M. Altura
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.03.1998; Elsevier
• Subjects: Animals; Aorta - drug effects; Aorta - physiology; Aorta, rat; Biological and medical sciences; Blood vessels and receptors; Ca 2; Calcium - physiology; Cytochrome P450 product; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Fundamental and applied biological sciences. Psychology; Hydrogen peroxide (H 2O 2); Hydrogen Peroxide - pharmacology; In Vitro Techniques; Male; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Oxidants - pharmacology; Prostaglandin; Protein kinase C; Rats; Rats, Wistar; Vasoconstriction - physiology; Vertebrates: cardiovascular system; Protein kinase C; Cytochrome P450 product; Prostaglandin; Hydrogen peroxide (H 2O 2); Aorta, rat; Ca 2; Rat; Enzyme; Transferases; Cytochrome P450; Rodentia; Vasoconstriction; Smooth muscle; In vitro; Artery; Endothelium; Vertebrata; Hyperoxides; Mammalia; Calcium ion; Blood vessel; Aorta; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(97)01576-8

It has been suggested that reactive oxygen species may be involved in the regulation of vascular tone. However, the underlying mechanisms remain to be elucidated. The present studies were designed to investigate the contractile effects of hydrogen peroxide (H 2O 2), one of the reactive oxygen species, on isolated ring segments of rat aorta with and without endothelium. H 2O 2 induced an endothelium-independent contraction in isolated rat aorta ring segments in a concentration-dependent manner at concentrations from 5×10 −6 to 5×10 −3 M. H 2O 2-induced contractions of denuded rat aorta rings were stronger than those on intact rat aorta segments. The contractile effects of H 2O 2 were inhibited completely by 1200 u/ml catalase. The presence of 1.0 μM Fe 2+ or 10 μM proadifen, a cytochrome P450 monooxygenase inhibitor, potentiated the contractile effect of H 2O 2 on isolated rat aorta segments. 1 mM deferoxamine (a Fe 2+ chelator) or 100 μM dimethyl sulfoxide (a hydroxyl radical scavenger) significantly attenuated the vessel contractions induced by hydrogen peroxide plus Fe 2+ or hydrogen peroxide itself. Removal of extracellular Ca 2+ ([Ca 2+] 0), addition of 5 μM verapamil, administration of a protein kinase C inhibitor (staurosporine), treatment with an inhibitor of protein tyrosine phosphorylation (genistein) or employment of 5.0 μM indomethacin resulted in a significant attenuation of the contractile responses of the vessels to H 2O 2. Pharmacological antagonists (e.g. a muscarinic acetylcholine receptor antagonist (atropine), an antagonist of histamine H 1 receptors (diphenhydramine), an antagonist of histamine H 2 receptors (cimetidine), an α-adrenoceptor antagonist (phentolamine), a β-adrenoceptor antagonist (propranolol) and an antagonist of serotonin receptor (methysergide)) did not inhibit or attenuate the contractions induced by H 2O 2. Exposure of primary aortic smooth muscle cells to H 2O 2 (5×10 −6 to 5×10 −3 M) produced significant rises of intracellular Ca 2+ ([Ca 2+] i) within 20 s. Employment of 1.0 μM Fe 2+ markedly enhanced the increment in [Ca 2+] i in the smooth muscle cells. 10 μM proadifen treatment failed to alter the hydrogen peroxide-induced increment in [Ca 2+] i of the smooth muscle cells. However, the presence of 5 μM indomethacin significantly attenuated the rise in [Ca 2+] i in smooth muscle cells. The present results suggest that H 2O 2 can induce contractions of rat aorta segments, at pathophysiological concentrations, which are Ca 2+-dependent. Hydroxyl radicals ( · OH ), cyclooxygenase products, protein kinase C and products of protein tyrosine phosphorylation appear to play some role in hydrogen peroxide-induced contractions. Metabolites catalyzed by cytochrome P450-dependent enzymes (upon treatment with hydrogen peroxide) appear to exert a vasodilator effect on rat aorta segments. Lastly, some unidentified mediators, produced by a cytochrome P450 inhibitor (proadifen), during hydrogen peroxide treatment, appear to play some role in contraction of vascular smooth muscle of rat aorta segments in vitro.