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(Circulation Research. 2005;97:e104.)
© 2005 American Heart Association, Inc.

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Carbon Monoxide From Heme Oxygenase-2 Is a Tonic Regulator Against NO-Dependent Vasodilatation in the Adult Rat Cerebral Microcirculation

Mami Ishikawa^*, Mayumi Kajimura^*, Takeshi Adachi, Kayo Maruyama, Nobuya Makino, Nobuhito Goda, Tokio Yamaguchi, Eiichi Sekizuka, Makoto Suematsu

From the Department of Biochemistry and Integrative Medical Biology (M.I., M.K., T.A., K.M., N.M., N.G., M.S.) and Department of Neurosurgery (M.I.), School of Medicine, Keio University, Tokyo, Japan; Department of Molecular Genetics and Biochemistry (T.Y.), Tokyo Medical and Dental University, Japan; and Department of Internal Medicine (M.I., E.S.), Saitama National Hospital, Japan.

Correspondence to Makoto Suematsu, MD, PhD, Professor and Chair, Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan. E-mail msuem{at}sc.itc.keio.ac.jp

Although the brain generates NO and carbon monoxide (CO), it is unknown how these gases and their enzyme systems interact with each other to regulate cerebrovascular function. We examined whether CO produced by heme oxygenase (HO) modulates generation and action of constitutive NO in the rat pial microcirculation. Immunohistochemical analyses indicated that HO-2 occurred in neurons and arachnoid trabecular cells, where NO synthase 1 (NOS1) was detectable, and also in vascular endothelium–expressing NOS3, suggesting colocalization of CO- and NO-generating sites. Intravital microscopy using a closed cranial window preparation revealed that blockade of the HO activity by zinc protoporphyrin IX significantly dilates arterioles. This vasodilatation depended on local NOS activities and was abolished by CO supplementation, suggesting that the gas derived from HO-2 tonically regulates NO-mediated vasodilatory response. Bioimaging of NO by laser-confocal microfluorography of diaminofluorescein indicated detectable amounts of NO at the microvascular wall, the subdural mesothelial cells, and arachnoid trabecular cells, which express NOS in and around the pial microvasculature. On CO inhibition by the HO inhibitor, regional NO formation was augmented in these cells. Such a pattern of accelerated NO formation depended on NOS activities and was again attenuated by the local CO supplementation. Studies using cultured porcine aortic endothelial cells suggested that the inhibitory action of CO on NOS could result from the photo-reversible gas binding to the prosthetic heme. Collectively, CO derived from HO-2 appears to serve as a tonic vasoregulator antagonizing NO-mediated vasodilatation in the rat cerebral microcirculation.

Key Words: carbon monoxide • heme oxygenase • diaminofluorescein • nitric oxide • NO synthase • vascular tone

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