Oral Nitrite and Nitrate in Adults With Metabolic Syndrome and Hypertension

• Change in insulin sensitivity (i.e. insulin stimulated glucose disposal) [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
  obtained by hyperinsulinemic euglycemic clamp
  
  

• 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 ]
  

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

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).