Antihypertensive inorganic nitrate and nitrite: what is the underlying mechanism?

Antihypertensive Inorganic Nitrate and Nitrite: What Is the Underlying Mechanism? To the Editor: l-Arginine, organic nitrates such as nitroglycerin, inorganic nitrate (NO3 −), and inorganic nitrite (NO2 −) are precursors of nitric oxide (NO), a potent vasodilator and blood pressure–lowering molecule. How NO is released from nitroglycerin,1 NO3 −, and NO2 − is incompletely understood. Ghosh et al2 reported that erythrocytic xanthine oxidoreductase (XOR) plays a crucial role in lowering blood pressure in hypertensives on oral administration of NO3 − by reducing NO3 −-derived NO2 − to NO. But because NO2 − reduction to NO by XOR requires anaerobic conditions, XOR is unlikely to generate NO from NO2 − in erythrocytes. Allopurinol is frequently used to support XOR involvement in various processes. Yet, the action of allopurinol is not restricted to XOR. Allopurinol decreases significantly the concentration of circulating asymmetrical dimethylarginine (ADMA),3 an endogenous inhibitor of NO synthase. Thus, allopurinol may normalize endothelial dysfunction4 by abolishing the inhibitory action of ADMA on NO synthase activity. Reduction of oxidative stress by allopurinol has been proposed as a mechanism explaining the decrease of circulating ADMA seen on allopurinol administration.3 Yet, allantoin is not a reliable oxidative stress biomarker, because allopurinol inhibits XORinduced formation of uric acid,5 the precursor of allantoin. In plasma and urine of patients with peripheral arterial occlusive disease, we did not find any correlation between ADMA and the oxidative stress biomarkers malondialdehyde and 15(S)-8-iso-prostaglandin F2α (Figure). This suggests that allopurinol is unlikely to reduce circulating ADMA concentration by decreasing oxidative stress. NO3 − and NO2 − are emerging experimental drugs for the treatment of NO-related dysfunctions. The mechanisms by which NO3 −, NO2 −, and nitroglycerin are reduced to NO are unresolved, and their resolution provides a challenging task.