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Superoxide: a key player in hypertension

SALVATORE CUZZOCREA, EMANUELA MAZZON^*, LAURA DUGO, ROSANNA DI PAOLA, ACHILLE P. CAPUTI and D. SALVEMINI^,1

Institute of Pharmacology, University of Messina;
^* Department of Biomorphology, School of Medicine, University of Messina, Italy; and
Department of Biological and Pharmacological Research, MetaPhore Pharmaceuticals, St. Louis, Missouri, USA

¹ Correspondence: MetaPhore Pharmaceuticals, 1910 Innerbelt Business Center Dr., St. Louis, MO 63114, USA. E-mail: dsalvemini{at}metaphore.com

Superoxide is increased in the vessel wall of spontaneously hypertensive rats (SHR) where, if "blocked," potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of superoxide anion in hypertension and its interaction with nitric oxide (NO). For this purpose we used a low molecular weight synthetic superoxide dismutase mimetic (M40403), known to remove selectively superoxide anion. Baseline mean arterial pressure (MAP) was significantly elevated in the SHR compared with its normal counterpart, Wistar Kyoto (WKY). M40403 at a dose (2 mg·kg^–1·h^–1), which had no effect in the WKY, significantly decreased MAP in SHR rats. To determine whether superoxide anion increases MAP by inactivating NO, NO synthesis was blocked with N^G nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), a nonselective nitric oxide synthase inhibitor. L-NAME (3 mg/kg, i.v) blocked the anti-hypertensive effect of M40403 (2 mg/kg over 30 min). When used at a dose that yielded similar increases in MAP, norepinephrine (2.1 µg/kg) failed to alter the anti-hypertensive effects of M40403 in the SHR. To investigate whether the anti-hypertensive effect of M40403 was associated with an improvement of the alterations in vascular reactivity, a separate group of experiments was carried out ex vivo. Endothelium-dependent vasorelaxation to acetylcholine (10 nM–10 µM), an index of endothelial function, was reduced in aortic rings taken from SHR rats when compared with WKY rats. In vivo treatment with M40403 caused an improvement of the degree of the endothelial dysfunction in SHR rats. Furthermore, immunohistochemical analysis for nitrotyrosine (the product formed from the interaction of nitric oxide with superoxide) revealed a positive staining in aorta from SHR rats. The degree of staining for nitrotyrosine was markedly reduced in tissue sections obtained from SHR rats treated with M40403. Our data suggest that overt production of superoxide in SHR couples with nitric oxide, reducing its function and leading to a loss of blood vessel tone and hypertension. Another important effect appears to be at the level of endothelial cellular integrity, where by interacting with nitric oxide, superoxide anion forms peroxynitrite and subsequent endothelial cell dysfunction. By removing superoxide, M40403 restores blood pressure to near-to-normal values.—Cuzzocrea, S., Mazzon, E., Dugo, L., Di Paola, R., Caputi, A. P., Salvemini, D. Superoxide: a key player in hypertension.

Key Words: superoxide dismutase • M40403 • F₂-isoprostane

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