sodium-nitrite and Peripheral-Vascular-Diseases

Ischaemic tissue damage represents the ultimate form of tissue pathophysiology due to cardiovascular disease, which is the leading cause of morbidity and mortality across the globe. A significant amount of basic research and clinical investigation has been focused on identifying cellular and molecular pathways to alleviate tissue damage and dysfunction due to ischaemia and subsequent reperfusion. Over many years, the gaseous molecule nitric oxide (NO) has emerged as an important regulator of cardiovascular health as well as protector against tissue ischaemia and reperfusion injury. However, clinical translation of NO therapy for these pathophysiological conditions has not been realized for various reasons. Work from our laboratory and several others suggests that a new form of NO-associated therapy may be possible through the use of nitrite anion (sodium nitrite), a prodrug which can be reduced to NO in ischaemic tissues. In this manner, nitrite anion serves as a highly selective NO donor in ischaemic tissues without substantially altering otherwise normal tissue. This surprising and novel discovery has reinvigorated hopes for effectively restoring NO bioavailability in vulnerable tissues while continuing to reveal the complexity of NO biology and metabolism within the cardiovascular system. However, some concerns may exist regarding the effect of nitrite on carcinogenesis. This review highlights the emergence of nitrite anion as a selective NO prodrug for ischaemic tissue disorders and discusses the potential therapeutic utility of this agent for peripheral vascular disease.

Topics: Animals; Humans; Ischemia; Neovascularization, Physiologic; Nitric Oxide; Peripheral Vascular Diseases; Prodrugs; Sodium Nitrite

Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg · kg(-1) · day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.

Topics: Animals; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Female; Heart Diseases; Male; Metabolic Syndrome; Myocardium; Nitric Oxide Synthase Type III; Obesity; Oxidation-Reduction; Oxidative Stress; Peripheral Vascular Diseases; Severity of Illness Index; Sodium Nitrite; Swine; Vasodilation

Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 mug/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.

Topics: Animals; Arteries; Cyclic N-Oxides; Cytoprotection; Disease Models, Animal; Endothelium, Vascular; Free Radical Scavengers; Hindlimb; Imidazoles; Ischemia; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nitric Oxide; Peripheral Vascular Diseases; Sodium Nitrite