NMDA receptor-mediated modulation of ventilation in obese Zucker rats.
BACKGROUND
Ventilation in response to hypoxia is reduced in some obese humans and is believed to represent part of the pathogenesis of obesity hypoventilation syndrome (OHS). Ventilation in response to hypoxic exposure is closely related to the release of excitatory neurotransmitters, in particular glutamate, acting specifically on N-methyl-D-aspartate (NMDA) receptors.


OBJECTIVE
The aim of the present study was to investigate whether NMDA receptor-mediated mechanisms are responsible for the altered ventilatory response to sustained hypoxia observed in obese Zucker (Z) rats.


METHODS
Seven lean and seven 15-week-old obese male Z rats were studied.


METHODS
Ventilation ([V](E)) at rest and during 30 min sustained hypoxic (10% O(2)) exposure was measured by the barometric method. [V](E) was assessed following the blinded-random administration of equal volumes of either saline (vehicle) or dextromethorphan (DM, 10 mg/kg), a non-competitive glutamate NMDA receptor antagonist.


RESULTS
DM had no effects on resting [V(E) in both lean and obese rats during room air breathing. Lean rats treated with DM exhibited a significant (P<0.05) depression in [V](E), V(T), and V(T)/T(I) during either the early (5 min) or the late phase (30 min) of ventilatory response to sustained hypoxia. In contrast, DM administration in obese rats did not change [V(E), V(T), or V(T)/T(I) during the early phase of ventilatory response to hypoxia. During the late phase of ventilatory response to hypoxia. obese rats treated with DM exhibited a similar depression in [V](E) and V(T) as observed in lean rats, but had no significant change in V(T)/T(I) during the 30 min hypoxic exposure.


CONCLUSIONS
Our findings indicate that altered glutamatergic mechanisms acting on NMDA receptors are partially responsible for a blunted early phase of ventilatory response to hypoxia noted in obese rats and also contribute to their reduced neural respiratory drive.
Lee
S D
SD
Department of Physical Therapy, Exercise, and Nutrition Science, University at Buffalo, The State University of New York, Buffalo, New York 14214-3079, USA.
Nakano
H
H
Farkas
G A
GA
D000818:Animals; D003915:Dextromethorphan / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D051381:Rats; D011924:Rats, Zucker; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D003915:Dextromethorphan