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1 Department of Clinical Pharmacology, The University of Tokushima, Institute of Health Biosciences, Tokushima, Japan
2 Department of Pharmacology, The University of Tokushima School of Medicine, Tokushima, Japan
3 Department of Pharmacokinetics and Biopharmaceutics, The University of Tokushima, Institute of Health Biosciences, Tokushima, Japan
4 Department of Pediatrics, The University of Tokushima School of Medicine, Tokushima, Japan
* To whom correspondence should be addressed. E-mail: tamaki{at}basic.med.tokushima-u.ac.jp.
In this paper, we investigated whether orally administered nitrite is changed to NO, and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of 15N-nitrite (15NO2-) as a source of nitrite in order to distinguish between endogenous nitrite and the exogenously administered one and measured hemoglobin(Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (Az=23.4 Gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 ± 0.52 and 10.58 ± 0.40 µM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 ± 9.23 µM). In addition, co-administration of nitrite (100 mg/liter drinking water) with L-NAME (1 g/liter) for three weeks significantly attenuated the L-NAME-induced hypertension (149 ± 10 mmHg) compared to L-NAME alone (170 ± 13 mmHg). Further, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo, and may explain, at least in part, the mechanism of the nitrite-nitrate rich DASH (Dietary Approaches to Stop Hypertension) diet-induced hypotensive effects.
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