Oral Nitrite and Nitrate in Adults With Metabolic Syndrome and Hypertension

• Change in systolic blood pressure [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
• Change in mean arterial pressure [ Time Frame: baseline and then weekly throughout the 12 week treatment ] [ Designated as safety issue: Yes ]
• Change in diastolic blood pressure [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
• Change in methemoglobin level [ Time Frame: baseline and then weekly throughout the 12 week treatment ] [ Designated as safety issue: Yes ]

This research study is being conducted to examine the effects of daily inorganic nitrate and nitrite treatment on the cardiometabolic and hormonal disturbances observed in overweight/obese adults with the metabolic syndrome and high blood pressure. Ultimately, oral nitrate and nitrite therapy may have a major impact on the prevention and treatment of both diabetes and cardiovascular disease.

Cardiovascular disease remains the leading cause of death in the United States and worldwide. Several studies have demonstrated that fruit and vegetable rich diets significantly reduced blood pressure and reduced the risk of ischemic stroke and cardiovascular disease in general, the exact mechanisms remain poorly understood. Preclinical and clinical research over the last decade has revealed the important vasoprotective effects of nitrates and nitrites with regards to reduction in blood pressure, vascular inflammation and endothelial dysfunction. More recent findings suggest that inorganic nitrate and nitrite therapy may be involved in the regulation of glucose-insulin homeostasis.

For this reason, development of an oral formulation of nitrate and nitrite salts represents a rational avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would ensure rapid acting effects upon absorption, while the nitrate would continuously provide a slow formation of nitrite over a prolonged period of time via the enterosalivary circulation pathway. In this pathway, about 25% of circulating nitrate is concentrated in the saliva and reduced to nitrite by commensal mouth bacteria with nitrate reductase enzymes. The proposal is the first human study to investigate the inorganic nitrate or nitrite effects (in any form) on insulin sensitivity in a patient population. This will be the third human trial using orally delivered inorganic nitrate capsules in normal volunteers or subjects with hypertension and the second human trial using orally delivered nitrite (previously as aqueous solution).

• Metabolic Syndrome
• Hypertension

• Drug: 14 N Sodium Nitrite
  oral formulation of sodium nitrite 20 mg daily for 12 weeks
  Other Name: sodium nitrite
• Drug: 14 N Sodium Nitrate
  oral formulation of sodium nitrate 1,000 mg daily for 12 weeks
  Other Name: sodium nitrate

Inclusion Criteria:

• Age 18-60 years
• BMI ≥ 30 kg/m2
• Hypertension: defined as systolic blood pressure ≥130 and/or diastolic blood pressure ≥85 mm Hg
• Waist circumference: >102 cm in men, >88 cm in women

Exclusion Criteria:

• Positive urine pregnancy test or breastfeeding
• Concurrent use of medications affecting glucose or lipid metabolism (oral hypoglycemics, insulin, statins, atypical antipsychotics)
• Recent addition or change in dosing of hormonal contraceptive medications (OCP, IUD, DepoProvera)
• Current use of ≥2 anti-hypertensive agents regardless of blood pressure control or normotensive on a single agent
• Current use of PD5 inhibitors or organic nitrates
• Not stable on treatments for the prior three months or not planning to remain on current dose of medications for blood pressure, contraception, etc.
• Known chronic psychiatric or medical conditions including diabetes, liver or kidney disease or obesity syndromes
• TSH >8 mIU/mL
• Smoker