Effects of short‐term therapy with high dose nutritional inorganic nitrite and nitrate on vascular dysfunction, oxidative damage and epigenetic regulation in experimental arterial hypertension

Abstract

BackgroundArterial hypertension is one of the major risk factors leading to highly relevant diseases like coronary artery disease, stroke or peripheral artery disease. Even short‐term application of angiotensin‐II (AT‐II) in animal models of arterial hypertension is leading to vascular dysfunction, enhanced production of reactive oxygen species (ROS) and modification of epigenetic processes. Nitric oxide (NO) represents an important opponent to AT‐II induced vasoconstriction and high blood pressure. Dietary uptake (e.g. vegetables) of inorganic nitrite (NO2−) and nitrate (NO3−) leads to enhanced NO bioavailability and provides antihypertensive effects. The present study aims to understand the underlying vasoprotective effects of nutritional NO2− and NO3− co‐therapy in hypertensive mice.Methods and resultsHigh‐dose AT‐II (1mg/kg/d for 1 week) was used to induce arterial hypertension in male C57BL/6 mice. In parallel high dose inorganic nitrite (7.5mg/kg/d) and inorganic nitrate (150mg/kg/d) was administered via drinking water. Hemodynamic effects were evaluated by blood pressure measurements and isometric tension studies. To elucidate underlying epigenetic regulation processes gene expression analyses and quantification of ROS formation were performed.Administration of AT‐II induced hypertension, cardiac hypertrophy and impaired endothelial function. Co‐therapy with high dose inorganic nitrite, but not with nitrate, normalised vascular function and arterial hypertension. In addition, oxidative stress markers and inflammatory pathways were enhanced in hypertensive mice and mostly normalized by nitrite therapy. We observed hypertension induced changes, at least by trend, of epigenetic proteins like histone deacetylase 2 or lysine demethylase 3A in cardiac tissue, which were mostly normalized by nitrite therapy.ConclusionNutritional nitric oxide precursors represent complementary therapy to classical antihypertensive drugs, representing a dietary treatment applicable to the general population (e.g. by eating certain vegetables). Short‐term therapy with inorganic nitrite showed beneficial effects on vascular function, oxidative stress and epigenetic regulation in experimental hypertension, which were less pronounced with inorganic nitrate. The observed differences may rely on superior bioconversion of nitrite to NO or intoxication through methaemoglobinaemia because of high dose inorganic nitrate therapy. Therefore, in particular inorganic nitrite seems to represent a cost‐efficient, drug‐free, alternative in antihypertensive therapy. Further clinical research is necessary to further support these preclinical findings and to demonstrate whether the incidence and severity of hypertension in particular and cardiovascular outcome in general can be influenced by inorganic nitrite therapy.Support or Funding InformationWe gratefully acknowledge the financial support by Stiftung Mainzer Herz (to M.O. and A.D.).