In this study, 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 to distinguish between endogenous nitrite and that exogenously administered 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 (A(Z) = 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 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, 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 Dietary Approaches to Stop Hypertension diet-induced hypotensive effects.

Abstract. Reactive oxygen species have been known as important contributors to ischemia / reperfusion (I / R) injury. Studies on the beneficial effect of N-acetylcysteine (NAC), a potent antioxidant, on limiting infarct size induced by I / R yielded contrasting results. The present study was undertaken to compare the effect of NAC by different administration methods on infarct size in a rat myocardial I/ R model. Rats underwent 30 min of left coronary occlusion followed by 4 h of reperfusion. Treatment with continuous infusion of NAC (150 mg / kg per hour) from 30 min before occlusion for 2 h (until 1 h after the start of reperfusion) produced a significant limitation of the infarct size as a percentage of the ischemic area (8%) compared to the non-treated control (60%). However, bolus injection of 150 mg / kg at 30 min prior to occlusion and 5 min prior to reperfusion failed to reduce it (56%) although the total dose is the same. The decreased total glutathione content and glutathione peroxidase activity in the ischemic region were recovered in the continuous infusion group, but not in the bolus injection group. The increased myeloperoxidase activity and phosphorylation of inhibitor κB after I / R were inhibited by the continuous treatment. These results indicate that the protective effect of NAC on myocardial infarction induced by I / R was different depending on the administration method. It is necessary to maintain blood concentration during the early period of reperfusion to obtain the beneficial effect of NAC.

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The responsiveness to vasoactive agents in the perfused mesenteric vascular bed of streptozocin-induced diabetic rats was examined and compared with that of propylthiouracil-induced hypothyroid rats. Diabetic rats at 4 and 8 weeks after the induction of diabetes showed a significant decrease in isoproterenol-induced vasodilatation. In addition, the contractile responses to norepinephrine and 5-hydroxytryptamine and the vasodilative response to acetylcholine were significantly decreased in 12-week-diabetic rats. The contractile response to nerve stimulation was markedly decreased at 8 and 12 weeks. On the other hand, hypothyroid rats showed a decreased response to isoproterenol, but they did not show any change in the response to nerve stimulation. A decrease in plasma thyroid hormone levels in diabetic rats at any time period was similar in extent to that in hypothyroid rats. The data indicate that the progressive changes in vascular reactivity in diabetic rats may be divided into two stages. In the early stage, the altered reactivity of vasculature is likely to be mediated by hypothyroidism, whereas in the later stage, it is induced by other factors, e.g. hyperglycemia and hypoinsulinemia. Adrenergic neuropathy is not caused by hypothyroidism.

Phase I clinical studies of 7432-S, a new oral cephalosporin, including a randomized placebo-controlled trial were conducted with 40 healthy volunteers. In single-dose studies, 7432-S was orally administered at doses of 25, 50, 100, and 200 mg. The mean plasma levels peaked at 2.1 to 3.0 hours and reached 1.9, 3.6, 5.6, and 11.6 micrograms/ml, respectively. Linear correlation was observed between plasma AUC values and doses given. The half-lives of the plasma levels were 0.88 to 2.26 hours with a mean of 1.53 +/- 0.33 hours. The mean urinary recoveries were 67.5 to 75.2% of the dose within 24 hours. 7432-S was partially metabolized to 7432-S-trans which was excreted in urine at 7.2 to 9.2% of the doses. Study of the meal effect showed that AUC values and peak levels were not altered although the time to the peak levels was slightly prolonged. In multiple-dose studies, 100 mg of 7432-S twice daily for 2 weeks and 200 mg twice daily for 1 week were administered and there was no abnormal accumulation of 7432-S in plasma throughout the study. No significant differences were observed in plasma levels and urinary recoveries between single- and multiple-dose regimens. Clinical symptoms, physical tests, laboratory parameters, and fecal levels of vitamins K1 and K2 were in normal ranges. 7432-S was concluded to be safe and well tolerated.