dextromethorphan and Obesity

Arterial baroreflex, an important physiological regulatory system for buffering systemic blood pressure, is impaired in obesity. This study investigated whether the blunted baroreflex function in obesity is attributed to the altered nitroxidergic or N-methyl--aspartate (NMDA) mechanism. Baroreflex bradycardia responses, blood pressure and heart rate in 30 lean and 30 obese anesthetized Zucker rats (8-12 weeks of age) were assessed after injecting phenylephrine with intravenous preadministration of saline (control), dextromethorphan (DXM, NMDA receptor antagonist, 10 mg kg(-1)) or N(G)-nitro-L-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 100 mg kg(-1)). Compared with lean rats (-2.00+/-0.29 b.p.m. mm Hg(-1)), the baroreflex sensitivity (BRS) in obese rats (-0.43+/-0.05 b.p.m. mm Hg(-1)) was significantly blunted. The BRS was significantly suppressed by DXM in lean rats but not in obese rats. After administration of L-NAME, BRS was significantly suppressed in lean Zucker rats but not in obese Zucker rats. The normal BRS was significantly suppressed in lean rats after administration of both DXM and L-NAME, and the blunted BRS in obesity was significantly blocked to nearly no BRS after administration of both DXM and L-NAME. This study suggests that BRS is blunted in obese rats and that blunted baroreflex is, at least in part, attributed to altered nitroxidergic or NMDA receptor-mediated modulation.

Topics: Animals; Baroreflex; Blood Pressure; Dextromethorphan; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Heart Rate; Male; NG-Nitroarginine Methyl Ester; Nitrergic Neurons; Nitric Oxide; Obesity; Phenylephrine; Rats; Rats, Zucker; Receptors, N-Methyl-D-Aspartate; Sympathomimetics

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

Topics: Animals; Dextromethorphan; Excitatory Amino Acid Antagonists; Hypoxia; Male; Obesity; Rats; Rats, Zucker; Receptors, N-Methyl-D-Aspartate; Respiratory Mechanics