Premium
GAL‐160 increases CO 2 chemosensitivity and reverses opioid‐induced respiratory depression in rats (1092.14)
Author(s) -
Baby Santhosh,
Ideo Courtney,
Mardirosian Saro,
Peng Sean,
Golder Francis,
MacIntyre D.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1092.14
Subject(s) - chemistry , morphine , ventilation (architecture) , respiratory minute volume , respiratory system , respiration , opioid , respiratory acidosis , anesthesia , medicine , pharmacology , endocrinology , receptor , mechanical engineering , engineering , anatomy
OIRD may result, at least in part, from decreased CO 2 chemosensitivity. Previously, we reported that GAL‐021 administered IV reverses OIRD and increases CO 2 chemosensitivity in rats. GAL‐021 IV has now been shown to attenuate OIRD in humans. Here we report on GAL‐160, an orally bioavailable analog of GAL‐021. In conscious rats, OIRD was induced with morphine (10 mg/kg, IV) and was evident as respiratory acidosis and hypoxemia using arterial blood gas analysis. GAL‐160 (0.03 ‐ 0.3 mg/kg/min X 30 min IV infusion) dose‐dependently reversed the effects of morphine on breathing. The effects on CO 2 chemosensitivity were evaluated in urethane anesthetized rats following biphasic IV infusion of GAL‐160 (0.005 mg/kg/min X 15 min + 0.003 mg/kg/min X 60 min and 0.01 mg/kg/min X 15 min + 0.006 mg/kg/min X 60 min): regimens that do not stimulate ventilation. Minute volume was measured using tracheal spirometry at three levels of P aCO 2 : baseline (eucapnia), and +10 and +20 mmHg above baseline. CO 2 chemosensitivity was calculated as the slope of the hypercapnic ventilatory responses. GAL‐160 increased CO 2 chemosensitivity in the higher dose group (slope before GAL‐160: 10 ± 2; after GAL‐160: 16 ± 2 ml/min/mmHg) but not the lower dose group (before GAL‐160: 11 ± 2; after GAL‐160: 11 ± 2 ml/min/mmHg). These results demonstrate that GAL‐160 can reverse OIRD possibly by increasing CO 2 chemosensitivity.