Oral Nitrite Trial for Hypertension and Metabolic Syndrome

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 nitrite salt represents a rational avenue of exploration for the treatment of cardiovascular diseases, whereby nitrite would ensure rapid acting effects upon absorption. Nitrite could then be oxidized to nitrate 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 will investigate the inorganic nitrite effects (in any form) on insulin sensitivity in a targeted population of overweight/obese adults with metabolic syndrome and hypertension, at risk for insulin resistance and endothelial dysfunction. This will be the third human trial using orally delivered nitrite (previously as aqueous solution).

• 14 Nitrogen (N) Sodium Nitrite (Drug), also known as sodium nitrite: oral formulation of sodium nitrite 40 mg three times daily for 12 weeks
• Placebo (Drug): oral formulation of matching placebo three times daily for 12 weeks

Primary outcomes

• Change in insulin sensitivity (i.e. insulin stimulated glucose disposal) [baseline and 12 weeks]: obtained by hyperinsulinemic euglycemic clamp

Secondary outcomes

• Change in systolic blood pressure [baseline and 12 weeks]: ambulatory blood pressure
• Change in mean arterial pressure [baseline and then biweekly throughout the 12 week treatment]: ambulatory blood pressure
• Change in diastolic blood pressure [baseline and 12 weeks]: ambulatory blood pressure
• Change in methemoglobin level [baseline and then biweekly throughout the 12 week treatment]: by co-oximetry

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Age 18-60 years
* Body mass index (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 metabolism (oral hypoglycemics, insulin, atypical antipsychotics)
* Recent addition or change in dosing of hormonal contraceptive medications (Oral Contraceptive Pill (OCP), Intra Uterine Device (IUD), DepoProvera shot)
* Current use of ≥3 anti-hypertensive agents regardless of blood pressure control or normotensive on a single or double agent
* Current use of phosphodiesterase-5 (PD) inhibitors or organic nitrates. We will not exclude for dietary sources of nitrate/nitrite.
* 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
* Thyroid Stimulating Hormone (TSH) >8 milli-International unit/mL
* Smoker
* Anemia (central lab hemoglobin < 11g/dL)
* Active periodontal disease

• Kara S Hughan, MD, Principal investigator, University of Pittsburgh
• Mark Gladwin, MD, Study director, University of Pittsburgh