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Abstract
In humans, short-term supplementation with nitrate is hypotensive and inhibits platelet aggregation via an nitric oxide (NO)-dependent mechanism. In the present work, we analyzed whether short-term treatment with nitrate induces antithrombotic effects in rats and mice. Arterial thrombosis was evoked electrically in a rat model in which renovascular hypertension was induced by partial ligation of the left renal artery. In mice expressing green fluorescent protein, laser-induced thrombosis was analyzed intravitally by using confocal microscope. Sodium nitrate (NaNO3) or sodium nitrite (NaNO2) was administered orally at a dose of 0.17 mmol/kg, twice per day for 3 days. Short-term nitrate treatment did not modify thrombus formation in either rats or mice, while nitrite administration led to pronounced antithrombotic activity. In hypertensive rats, nitrite treatment resulted in a significant decrease in thrombus weight (0.50 ± 0.08 mg vs. VEH 0.96 ± 0.09 mg; p < 0.01). In addition, nitrite inhibited ex vivo platelet aggregation and thromboxane B2 (TxB2) generation and prolonged prothrombin time. These effects were accompanied by significant increases in blood NOHb concentration and plasma nitrite concentration. In contrast, nitrate did not affect ex vivo platelet aggregation or prothrombin time and led to only slightly elevated nitrite plasma concentration. In mice, nitrate was also ineffective, while nitrite led to decreased platelet accumulation in the area of laser-induced endothelial injury. In conclusion, although nitrite induced profound NO-dependent antithrombotic effects in vivo, conversion of nitrates to nitrite in rats and mice over short-term 3-day treatment was not sufficient to elicit NO-dependent antiplatelet or antithrombotic effects.
Highlights
Nitrites (NO2−) and nitrates (NO3−) were thought to be stable end-products of nitric oxide (NO) produced by NO synthase (NOS) (Bryan 2006)
We demonstrated for the first time that a low dose of nitrate (0.17 mmol/kg, p.o., bid), given as a shortterm 3-day treatment, did not display antithrombotic effects in rats and in mice
We found that nitrite, but not nitrate, decreased fibrin generation
Summary
Nitrites (NO2−) and nitrates (NO3−) were thought to be stable end-products of nitric oxide (NO) produced by NO synthase (NOS) (Bryan 2006). A reductive NO3−-NO2−-NO pathway has been proposed as a backup system that acts to maintain NO generation (Kapil 2013). Compatible with the importance of the reductive pathway for NO production in vivo, even short-term (3 days) supplementation with NaNO3 (0.1 mmol/kg daily) was shown to result in a significant increase in plasma NO2− concentration in healthy humans and a subsequent fall in diastolic blood pressure (Larsen 2006). Short-term (3 days) supplementation with dietary nitrate, given in the form of beetroot juice to healthy volunteers, reduced systolic and diastolic blood pressure and improved endothelial function and significantly attenuated ex vivo collagen-induced and ADP-induced platelet aggregation (Webb 2008). Nitrateinduced effects on blood pressure and platelet aggregation were correlated with an increase in plasma nitrite concentration. Kapil et al (2010) demonstrated that inorganic nitrate given as a single dose (12 or 24 mmol) or in one shot of beetroot juice (containing 5.5 mmol of nitrate) lowered
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