Abstract 221: Pharmacokinetics and Brain Bioavailability of Nitrite Therapy After Ventricular Fibrillation Cardiac Arrest in Rats
Introduction: Nitrite (NO2-) reduces neurological damage and myocardial dysfunction after cardiac arrest (CA), likely through a nitric oxide (NO) or S-nitrosothiol mechanism. The pharmacokinetics (PK) and blood brain barrier (BBB) penetration and elimination of nitrite therapy after CA are unknown but have important implications for clinical translation. Prior reports support optimal cytoprotection at blood levels of 10-20 μM. We tested the hypothesis that exogenous nitrite rapidly crosses the BBB and is taken up by tissues, increasing levels in cerebrospinal fluid (CSF), brain and heart.
Methods: Rats (total n=23) were subjected to 5 min VF CA followed by 1.5 min CPR/defibrillation. Rats received either 1 ml placebo or nitrite (8μM) intravenously between 5-10 min resuscitation time (RT). Shams (n=6) with or without nitrite treatment were also analyzed. Nitrite blood levels were measured at various times up to 60 min. At 16 min RT (n=13), CSF was obtained, animals perfused with nitrite-free saline and brain, and heart removed. Separate placebo-controlled experiments (n=6) measured blood nitrite clearance during the initial hour RT. Tissue nitrite concentrations were calculated based on wet tissue weight.
Results: Blood nitrite levels were 57.14±10.82 μM at 11 min RT in the nitrite groups, respectively, vs. 0.94±0.58 μM in placebo (p<0.001). Blood nitrite rapidly declined in the initial 2 min after dosing (distribution) reaching 73% of peak values with a more gradual elimination (beta t½ = 25 min) subsequently. Nitrite rapidly crossed the BBB and was present in CSF at 17.1±1.1 min RT in levels comparable to plasma. Heart and brain had more modest 2-3 fold increases.
Conclusions: Nitrite given after CA rapidly crosses the BBB and the PK data suggest significant tissue uptake. These data provide a biological basis for potential cytoprotection including the brain and will inform clinical trials regarding optimal dosing.
- © 2013 by American Heart Association, Inc.