Effects of GABA receptor blockade on the ventilatory response to hypoxia in hypothermic newborn piglets

Abstract

Hypothermic newborn piglets have a depressed ventilatory response to hypoxia, and this may be due to an increase in CNS γ-aminobutyric acid (GABA) levels. To evaluate the effects of GABA(A) receptor blockade on the ventilatory response to hypoxia in hypothermic piglets, 31 anesthetized paralyzed mechanically ventilated newborn piglets (2-7 d) were studied at a brain temperature of 38.5 ± 0.5°C [normothermia (NT), n = 15] or 34 ± 0.5°C [hypothermia (HT), n = 16]. The central respiratory output was evaluated by measuring burst frequency and moving time average area of phrenic nerve activity. Measurements of minute phrenic output (MPO), arterial blood pressure, heart rate, oxygen consumption, and arterial blood gases were obtained at room air and during 20 min of isocapnic hypoxia [fraction of expired oxygen (Fio2) = 0.10]. After 10 min of hypoxia, a bolus injection of 20 μL of bicuculline methiodide (BM; 10 μg) or Ringer's solution was administered into the cisterna magna over a 1-min period, and the piglets remained in hypoxia for an additional 10 min. There was an initial increase of 50 ± 6% in MPO during the first minute of hypoxia followed by a decrease to values 24 ± 8% above baseline at 10 min in the NT group. In contrast, in the HT group, the initial increase in MPO with hypoxia was eliminated, and, at 10 min, there was a decrease to a mean value 35 ± 4% below baseline level (NT versus HT, p < 0.03). After administration of BM, a significant increase in MPO with hypoxia was observed in both groups compared with their placebo groups (p < 0.002 in NT-BM group, p < 0.0001 in HT-BM group). However, the magnitude of the increase in MPO during hypoxia was significantly greater in the HT group after administration of BM (NT versus HT, p < 0.0001). Changes in oxygen consumption, arterial blood pressure, heart rate, pH, partial pressure of oxygen (Pao2), and base excess with hypoxia were not different between NT and HT groups before and after the administration of BM. The cardiorespiratory response to hypoxia was not modified after administration of Ringer's solution to NT and HT placebo groups. These data suggest that the depression in hypoxic ventilatory response produced by HT is in part modulated by an increased CNS GABA concentration.