2015 ACVIM Forum Research Abstract Program

The purpose of this study was to determine whether oral supplementation with L-arginine could reach plasma concentrations of L-citrulline, as a surrogate of nitric oxide generation, that are associated with pulmonary vascular hemodynamic improvement in humans with pulmonary hypertension. Three clinically healthy, staff owned dogs were treated in a pilot study with 50 mg/kg q 8 hrs of L-arginine PO for one week. Plasma samples were obtained at pre-treatment baseline (BL), at steady state trough (TR) and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after dosing. Plasma Lcitrulline and L-arginine were analyzed by HPLC. Peak concentrations of both plasma L-arginine (median 404.7 uM, range 298.8-552.1) and plasma L-citrulline (median 140 uM, range 92.1-165.4) were consistently seen at 4 hours post dosing (T4 hrs). However, a 33% increase in plasma L-citrulline from BL, which is the target in humans, was not reached in any dogs (median 10.9%, range À9.5 to 25.5%). Eleven clinically healthy, staff owned dogs were then treated with 100 mg/kg q8 hrs of Larginine PO for one week. Plasma L-arginine concentrations increased from a median (range) of 160.1 uM (100. 2-231.4 ) at BL to 412.7 uM (206.5-807 .3) at T4 hrs and plasma L-citrulline concentrations increased from a median (range) of 82.1 uM (59.1-117.1) at BL to 102.2 uM (47.4-188. 3) at T4 hrs. While only 2/11 dogs showed a > 33% increase in plasma L-citrulline concentrations, all dogs dosed with L-arginine 100 mg/kg q8 hrs had plasma L-citrulline concentrations greater than those (mean 44 uM) associated with pulmonary vascular hemodynamic improvement in people. Median systemic systolic, diastolic and mean blood pressures were not significantly different between BL (SBP 150 mmHg, DBP 93 mmHg, MBP 119 mmHg, , TR (SBP 145 mmHg, DBP 85 mmHg, MBP 108 mmHg, and T4 hrs (SBP 155 mmHg, DBP 90 mmHg, MBP 115 mmHg, ) (SBP P = 0.47, DBP P = 0.163 and MBP P = 0.256). Median heart rate did not significantly change between the BL (100 bpm, 79-154), TR (112 bpm, 84-132) and T4 hrs (97 bpm, 74-144) (P = 0.163). Chemistry profiles were analyzed in 7/11 dogs and there were no changes seen at T4 hrs when compared to BL.