Role of the nitric oxide pathway in hypoxia-induced hypothermia of rats

Abstract

Hypothermia is a response to hypoxia that occurs in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Recently, the NO pathway has been suggested to be involved in thermoregulation. In the present study, we assessed the participation of nitric oxide in hypoxia-induced hypothermia by means of NO synthase inhibition using NG-nitro-L-arginine methyl ester (L-NAME). The rectal temperature of awake, unrestrained rats was measured before and after hypoxia or L-NAME injection or both treatments together. Control animals received saline injections of the same volume. We observed a significant (P < 0.05) reduction in body temperature of 1.32 +/- 0.36 degrees C after hypoxia (7% inspired O2) and of 0.96 +/- 0.42 degree C after L-NAME (30 mg/kg body wt) injected intravenously. When the two treatments were combined, no significant difference in body temperature was observed. To assess the role of central thermo-regulatory mechanisms, a smaller dose of L-NAME (1 mg/kg) was injected into the third cerebral ventricle or intravenously. Intracerebroventricular injection of L-NAME caused an increase in body temperature, but when L-NAME was combined with hypoxia (7% inspired O2) no change in body temperature was observed. Intravenous injection of 1 mg/kg L-NAME had no effect. The data indicate that NO plays a major role in hypoxia-induced hypothermia at central rather than peripheral sites.

Role of nitric oxide in hypoxia inhibition of fever

“…In the present study, the rise in T b produced in conscious rats by LPS administration was prevented when the animals breathed 10 or 7% O 2 , in agreement with previous reports (9,12,26). Moreover, hypoxia is known to stimulate the NO pathway in the CNS (4).…”

“…Besides these peripheral effects, the NOS blocker may influence the central thermoregulatory mechanism. However, intracerebroventricular injection of NO blocker was reported to have little effect on T b (4,18) or even to enhance T b and oxygen consumption (8). Such opposite effects on T b of NOS inhibitors given intracerebroventricularly or systemically may be confusing.…”

“…This response should be adaptive because it decreases O 2 demand when availability of oxygen is limited (22), promotes a leftward shift of the oxyhemoglobin dissociation curve, and blunts the energetically costly response to hypoxia, e.g., increased cardiac output and ventilation (32). Moreover, hypoxia leads to activation of the NO-guanosine 3Ј,5Ј-cyclic monophosphate pathway in the CNS (4), and central NO is known to cause a reduction in T b (4,8).Previous studies have established that, during fever produced by endotoxin injection, the increase in T b is markedly reduced by hypoxia (9,12,26). Thus the aim of the present study was to test the hypothesis that hypoxia inhibition of fever would be mediated by NO.…”

“…Recently, it has been reported that NO also plays an important role in thermoregulation. It has been shown that NO is required for the production of fever (27) and that the L-arginine-NO pathway in the central nervous system (CNS) is necessary to produce hypoxia-induced hypothermia (4). The family of NO synthases (NOS), the enzymes that produce NO in vivo, consists of two different classes, i.e., the inducible and constitutive forms (5) that can be blocked by arginine analogs such as N -nitro-L-arginine (L-NNA) (21).…”

“…This response should be adaptive because it decreases O 2 demand when availability of oxygen is limited (22), promotes a leftward shift of the oxyhemoglobin dissociation curve, and blunts the energetically costly response to hypoxia, e.g., increased cardiac output and ventilation (32). Moreover, hypoxia leads to activation of the NO-guanosine 3Ј,5Ј-cyclic monophosphate pathway in the CNS (4), and central NO is known to cause a reduction in T b (4,8).…”