Effect of N-methyl-D-aspartate-receptor blockade on hypoxic ventilatory response in unanesthetized piglets

Abstract

The central excitatory amino acid (EAA) neurotransmitter glutamate has been shown to mediate the ventilatory response to hypoxia through N-methyl-D-aspartate (NMDA) receptors in anesthetized adult animals. To determine the role of the EAA glutamate in the neonatal ventilatory response to hypoxia, 19 unanesthetized chronically instrumented piglets were studied. Minute ventilation (VE), oxygen consumption (VO2), arterial blood pressure (ABP), heart rate (HR), and blood gases were measured in room air (RA) and after 1, 5, and 10 min of hypoxia (inspired oxygen fraction = 0.10) before and after an infusion of saline or CGS-19755, a competitive NMDA-receptor blocker (10 mg/kg i.v.). Nine control piglets [age 6 +/- 1 (SD) days; weight 2.02 +/- 0.40 kg] and 10 CGS-19755-treated animals (age 6 +/- 1 days; weight 1.90 +/- 0.66 kg) were studied during quiet sleep and in a thermoneutral environment. There was a marked decrease in the VE response to hypoxia after the administration of CGS-19755. The ventilatory response to hypoxia was not modified by saline infusion. Changes in ABP and arterial PO2 during hypoxia were similar between groups, whereas the decrease in arterial PCO2 was significantly less after CGS-19755 administration. The increase in HR with hypoxia was eliminated by the NMDA-receptor blocker administration. VO2 decreased with hypoxia in both groups, but this decrease was more marked after the NMDA-receptor blockade. These results suggest that the central EAA glutamate mediates, at least in part, the hypoxic hyperventilation in unanesthetized newborn piglets.

NMDA receptor-mediated modulation of ventilation in obese Zucker rats

“…The decreased ventilation was not related to metabolic rate or body temperature, since DM had no effect on either V Ç O 2 or T b in lean rats (Table 2). This is in agreement with previous reports demonstrating that the application of NMDA blockers decreased both the early and late phase of ventilatory response to hypoxia in unanesthetized piglets 11 and eliminated overall phrenic nerve output during 30 min hypoxia in anesthetized rats. 24 In contrast, DM in obese Z rats did not affect V Ç E during the early phase of ventilatory response to hypoxia but depressed V Ç E during the late phase of ventilatory response to hypoxia.…”

“…Since DM has been shown to have safer and lower toxicological effects in other species compared to MK-801, 23,30 and from our own preliminary observations in Z rats, DM was deemed a suitable agent. In the present study, the ventilatory response to hypoxia noted at a dose of 10 mgakg DM in lean Z rats was similar to responses obtained with other NMDA receptor antagonists in piglets, 11 in dogs 12 and in rats. 13,24 Resting ventilation In the present study, baseline (saline) ventilatory and metabolic variables (Table 1) for both lean and obese rats were within the range of previously published values.…”

“…These ®ndings are in agreement with previous studies noting that NMDA antagonists have no effects on f, V T , V E and V O 2 under normoxic condition in conscious animals. 11,31 Ventilatory response to hypoxia Lean Z rats exhibited an abrupt increase in ventilation in response to hypoxia (early phase) followed by a gradual decline with sustained hypoxia (late phase). Obese Z rats, however, displayed a smaller initial increase in ventilation in response to hypoxia that plateaued with sustained hypoxic exposure.…”

“…8,9 The ventilatory response to sustained hypoxia in humans and in some animals is characterized by an initial increase in ventilation (early phase), followed by a gradual decline in ventilation (late phase). 10,11 The increase in ventilation during hypoxia is closely related to the release of excitatory neurotransmitters, in particular glutamate, 11 ± 15 acting on Nmethyl-D-aspartate (NMDA) receptors located in brainstem respiratory motor neurons. 11 ± 14 Indeed, blocking NMDA receptors attenuates both the early and the late phases of ventilatory response to sustained hypoxia in conscious animals.…”

Glutamatergic neurotransmission modulates hypoxia-induced hyperventilation but not anapyrexia

“…These findings corroborate previous reports in the literature that investigated the same question. When different glutamatergic receptor antagonists are applied directly to the ventral surface of the medulla (14,17), into the nucleus tractus solitarii (13), intra-ventriculocisternally (3) or systemically (15,16), a reduction in the magnitude of the hyperventilatory response to hypoxia is observed.…”