Impact of systemic lupus erythematosus on oral health-related quality of life.

Oral symptoms in systemic lupus erythematosus (SLE) patients are often unexplored and affect the health-related quality of life. The aims of this study were: (a) to evaluate the oral health condition of SLE patients compared to control subjects without rheumatic diseases; (b) to determine the consequences of oral health condition in the quality of life of these two groups. Individuals with SLE ( n = 75) and without SLE ( n = 78) (control group), paired for gender and age, underwent complete oral examination. Sociodemographic and clinical information was obtained, and interviews were conducted using the Brazilian version of the oral health impact profile. The activity and damage of SLE disease were assessed, respectively, by the systemic lupus erythematosus disease activity index 2000 and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. When we analysed the oral health condition and hygiene habits of the participants, SLE patients exhibited an increased number of missing teeth despite their higher frequency of tooth brushing. No significant differences were verified in other habits and clinical parameters evaluated such as smoking, flossing, salivary flux, periodontitis, decayed and filled teeth. Patients with SLE presented with worse oral health-related quality of life than controls ( P = 0.011). The significant difference was on individuals' physical disability ( P = 0.002). The determinant of the negative impact on the oral health-related quality of life was prosthesis wearing ( P < 0.05). Overall, the oral health impact profile score was higher in individuals with moderate SLE damage compared to SLE individuals with no damage ( P = 0.043). Patients with SLE had a negative impact of oral condition on their quality of life. The evaluation of the oral health-related quality of life might be useful to monitor the effects of SLE on oral condition.

Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial.

BACKGROUND: As novel treatments carry substantial price tags and are mostly cost-prohibitive in low- and middle-income countries, there is an urgent need to develop alternatives, such as off-patent drugs. Megestrol acetate (MA) has a longstanding history in the treatment of breast cancer, but recently it is being used less often due to the advent of newer agents. PATIENTS AND METHODS: This two-stage phase II trial evaluated the antitumor activity and toxicity of MA in postmenopausal women with hormone-sensitive advanced breast cancer who had experienced disease progression on a third-generation nonsteroidal aromatase inhibitor (NSAI). Eligible patients had metastatic breast cancer treated with a NSAI with at least 6-month progression-free survival (PFS), or relapse after ≥1 year on adjuvant NSAI. Patients received MA at a single daily oral dose of 160 mg. Primary end point was clinical benefit rate (CBR). RESULTS: Forty-eight patients were enrolled. The CBR was 40% [95% confidence interval (CI) 25% to 55%], and the median duration of clinical benefit was 10.0 (95% CI 8.0-14.2) months. The median PFS was 3.9 (95% CI 3.0-4.8) months. The most common grade 3 adverse events were anemia (2%), dyspnea (2%), fatigue (2%), musculoskeletal pain (4%), deep vein thrombosis (10%), and weight gain (2%). CONCLUSIONS: This is the first study to prospectively evaluate the efficacy and safety of MA in postmenopausal women with hormone-sensitive disease progressing on a NSAI. MA has demonstrated activity and acceptable tolerability in this setting, and therefore remains a reasonable treatment option in a cost-sensitive environment. These results also provide the background for further evaluation of progestins in the treatment of breast cancer. CLINICAL TRIALS: local trial number, related to the approval by the IRB: CEP 108/06.

Central NO-cGMP pathway in thermoregulation and survival rate during polymicrobial sepsis.

Sepsis induces production of inflammatory mediators such as nitric oxide (NO) and causes physiological alterations, including changes in body temperature (Tb). We evaluated the involvement of the central NO-cGMP pathway in thermoregulation during sepsis induced by cecal ligation and puncture (CLP), and analyzed its effect on survival rate. Male Wistar rats with a Tb probe inserted in their abdomen were intracerebroventricularly injected with 1 microL NG-nitro-L-arginine methyl ester (L-NAME, 250 microg), a nonselective NO synthase (NOS) inhibitor; or aminoguanidine (250 microg), an inducible NOS inhibitor; or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 0.25 microg), a guanylate cyclase inhibitor. Thirty minutes after injection, sepsis was induced by cecal ligation and puncture (CLP), or the rats were sham operated. The animals were divided into 2 groups for determination of Tb for 24 h and assessment of survival during 3 days. The drop in Tb seen in the CLP group was attenuated by pretreatment with the NOS inhibitors (p < 0.05) and blocked with ODQ. CLP rats pretreated with either of the inhibitors showed higher survival rates than vehicle injected groups (p < 0.05), and were even higher in the ODQ pretreated group. Our results showed that the effect of NOS inhibition on the hypothermic response to CLP is consistent with the role of nitrergic pathways in thermoregulation.

Experimental sepsis induces sustained inflammation and acetylcholinesterase activity impairment in the hypothalamus.

Sepsis is one of the leading causes of mortality in intensive care units besides causing profound alterations in the brain. One of the structures notably affected during sepsis is the hypothalamus, resulting in important physiopathological consequences. Recently, we provided evidence that the presence of neuroinflammation, oxidative stress, and apoptosis in the hypothalamus of septic rats, is accompanied by impairment of arginine vasopressin (AVP) secretion. We had also demonstrated that sepsis survivor animals present attenuated AVP secretion after osmotic challenge, suggesting a persistent inflammation in the hypothalamus. However, the long-term course of inflammation in the hypothalamus remains unclear. Thus, we induced sepsis by cecal ligation and puncture (CLP) in Wistar rats and, five days after sepsis induction, the hypothalamus of each animal was collected for analysis. Nonmanipulated animals (naive) were used as controls. We found that CLP-induced morphological alterations in microglial cells are accompanied by an increase in Iba-1 immunoreactivity. Moreover, we observed enhanced expression of NF-κB and CREB transcription factors, which are well known to modulate the immune response. Additionally, we found that phosphorylation of GSK3α/ß (a kinase upstream to the CREB signaling pathway) was increased, as well as COX-2, iNOS, and IL-6 that are canonic inflammatory proteins. Thus, our results indicated the presence of sustained activation of resident glial cells that may result in neuroinflammation and cholinergic neurotransmission disruptions in the hypothalamus.

Activation of locus coeruleus heme oxygenase-carbon monoxide pathway promoted an anxiolytic-like effect in rats.

The heme oxygenase-carbon monoxide pathway has been shown to play an important role in many physiological processes and is capable of altering nociception modulation in the nervous system by stimulating soluble guanylate cyclase (sGC). In the central nervous system, the locus coeruleus (LC) is known to be a region that expresses the heme oxygenase enzyme (HO), which catalyzes the metabolism of heme to carbon monoxide (CO). Additionally, several lines of evidence have suggested that the LC can be involved in the modulation of emotional states such as fear and anxiety. The purpose of this investigation was to evaluate the activation of the heme oxygenase-carbon monoxide pathway in the LC in the modulation of anxiety by using the elevated plus maze test (EPM) and light-dark box test (LDB) in rats. Experiments were performed on adult male Wistar rats weighing 250-300 g (n=182). The results showed that the intra-LC microinjection of heme-lysinate (600 nmol), a substrate for the enzyme HO, increased the number of entries into the open arms and the percentage of time spent in open arms in the elevated plus maze test, indicating a decrease in anxiety. Additionally, in the LDB test, intra-LC administration of heme-lysinate promoted an increase on time spent in the light compartment of the box. The intracerebroventricular microinjection of guanylate cyclase, an sGC inhibitor followed by the intra-LC microinjection of the heme-lysinate blocked the anxiolytic-like reaction on the EPM test and LDB test. It can therefore be concluded that CO in the LC produced by the HO pathway and acting via cGMP plays an anxiolytic-like role in the LC of rats.

Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity.

The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO), a biologically active molecule which exerts most of its effects via activation of soluble guanylate cyclase (sGC). In the present study, we tested the hypothesis that endogenous CO could modulate inflammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical nociceptor hypersensitivity in rats. The intra-plantar (i.pl.) administration of the HO inhibitor, ZnDPBG (Zinc deuteroporphyrin 2,4-bis glycol), potentiated in a dose-dependent manner the mechanical nociceptor hypersensitivity evoked by i.pl. administration of carrageenan. The mechanical hypersensitivity evoked by i.pl. injection of interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha), but not interleukin-8 (IL-8), prostaglandin E(2) (PGE(2)) or dopamine, was also enhanced by ZNDPBG: Moreover, the haeme (HO substrate) injection in the paws reduced the hypersensitivity evoked by IL-1beta, but not PGE(2). Furthermore, i.pl. administration of the gas CO reduced the hypersensitivity elicited by PGE(2). The inhibitory effect of haeme and CO upon mechanical nociceptor hypersensitivity were counteracted by a soluble guanylate cyclase (sGC) inhibitor, ODQ (1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one), suggesting that this effect of CO is mediated via cyclic GMP. Finally, the inhibitory effect of CO upon mechanical nociceptor hypersensitivity was prevented by the NO synthase blocker, L-NMMA (N(G)-monomethyl L-arginine), suggesting that the impairment of mechanical hypersensitivity elicited by CO depends on the integrity of the NO pathway. In conclusion, the results presented in this paper imply that endogenously CO produced by HO plays an anti-hyperalgesic role in inflamed paws, probably by increasing the intracellular levels of cyclic GMP in the primary afferent neurone.

Role of central adenosine in the respiratory and thermoregulatory responses to hypoxia.

No reports are available about the role of central adenosine in the respiratory and thermoregulatory responses to hypoxia in conscious rats. We therefore measured ventilation (VE) and body temperature (Tb) before and after intracerebroventricular injection of saline or aminophylline (adenosine antagonist), followed by a 30-min period of hypoxia exposure. Aminophylline did not change VE or Tb during normoxia; however, during hypoxia, it caused a significant increase in VE, and significantly attenuated hypoxic hypothermia. The present data indicate that central adenosine has an inhibitory effect on hypoxic hyperventilation and partially causes hypoxic hypothermia, suggesting that the ventilatory and metabolic interaction during hypoxia does not involve opposing mechanisms.

Role of nitric oxide in 2-deoxy-D-glucose-induced hypothermia in rats.

The present study was designed to test the hypothesis that nitric oxide (NO) plays a role in 2-deoxy-D-glucose (2-DG)-induced hypothermia. The body temperature of awake, unrestrained rats was measured before and after the administration of 2-DG, or N(G)-nitro-L-arginine methyl ester (L-NAME; a non-selective NOS inhibitor) or both treatments together. We observed a significant reduction in body temperature after 2-DG injection. L-NAME alone caused no significant change in body temperature. When the two treatments were combined, a reduction in the magnitude of 2-DG-induced hypothermia was observed. The neuronal NOS inhibitor 7-nitroindazole also inhibited 2-DG-induced hypothermia. The data indicate that NO, probably produced by neuronal NOS, plays a role in 2-DG-induced hypothermia.

Role of nitric oxide in rat locus coeruleus in hypoxia-induced hyperventilation and hypothermia.

The locus coeruleus modulates the ventilatory and thermoregulatory response to hypoxia and contains nitric oxide synthase. Therefore, we examined the effects of L-NAME unilaterally microinjected into the locus coeruleus on hypoxic hyperventilation and hypothermia. Ventilation and body temperature were measured before and after microinjection of L-NAME (100 nmol/0.5 microl) into the locus coeruleus, followed by hypoxia. Control rats received microinjection of D-NAME (an inactive enantiomer of L-NAME). Under normoxia, L-NAME treatment did not affect ventilation or body temperature. D-NAME did not affect hypoxia-induced hyperventilation and hypothermia. L-NAME treatment reduced the ventilatory response to hypoxia but did not affect hypoxia-induced hypothermia. These data suggest that nitric oxide in the locus coeruleus is involved in the ventilatory response to hypoxia, exercising an inhibitory modulation on the locus coeruleus neurons, but plays no role in hypoxia-induced hypothermia.

Tolerance to lipopolysaccharide is related to the nitric oxide pathway.

Repeated administration of lipopolysaccharide (LPS) induces a refractory state to its usual pyrogenic effects which is called endotoxin tolerance. We tested the hypothesis that nitric oxide (NO) participates in the endotoxin tolerance. Single injection of LPS resulted in an elevation in body temperature (Tb), whereas a significant reduction of the thermoregulatory response to LPS was observed to repeated administration of LPS (administered at 48 h intervals). Intracerebroventricular (i.c.v.) injection of L-NAME (a non-selective NO inhibitor of nitric oxide synthesis) markedly enhanced the febrile response to LPS in tolerant rats. The data suggest that NO pathway in the central nervous system plays a role in endotoxin tolerance.

Effect of nitric oxide synthase inhibition on hypercapnia-induced hypothermia and hyperventilation.

Hypercapnia elicits hypothermia in a number of vertebrates, but the mechanisms involved are not well understood. In the present study, we assessed the participation of the nitric oxide (NO) pathway in hypercapnia-induced hypothermia and hyperventilation by means of NO synthase inhibition by using Nomega-nitro-L-arginine (L-NNA). Measurements of ventilation, body temperature, and oxygen consumption were performed in awake unrestrained rats before and after L-NNA injection (intraperitoneally) and L-NNA injection followed by hypercapnia (5% CO2). Control animals received saline injections. L-NNA altered the breathing pattern during the control situation but not during hypercapnia. A significant (P < 0.05) drop in body temperature was measured after both L-NNA (40 mg/kg) and 5% inspired CO2, with a drop in oxygen consumption in the first situation but not in the second. Hypercapnia had no effect on L-NNA-induced hypothermia. The ventilatory response to hypercapnia was not changed by L-NNA, even though L-NNA caused a drop in body temperature. The present data indicate that the two responses elicited by hypercapnia, i.e., hyperventilation and hypothermia, do not share NO as a common mediator. However, the L-arginine-NO pathway participates, although in an unrelated way, in respiratory function and thermoregulation.

Central CO-heme oxygenase pathway raises body temperature by a prostaglandin-independent way.

Recently, the carbon monoxide (CO)-heme oxygenase pathway has been shown to play an important role in fever generation by acting on the central nervous system, but the mechanisms involved have not been assessed. Thus the present study was designed to determine whether prostagandins participate in the rise in body temperature (T(b)) observed after induction of the CO-heme oxygenase pathway in the central nervous system. Intracerebroventricular (ICV) injection of heme-lysinate (152 nmol/4 microl), which is known to induce the CO-heme oxygenase pathway, caused an increase in T(b) [thermal index (TI) = 5.3 +/- 0.5 degrees C. h], which was attenuated by ICV administration of the heme oxygenase inhibitor ZnDPBG (200 nmol/4 microl; TI = 2.5 +/- 1.7 degrees C. h; P < 0.05). No change in T(b) was observed after intraperitoneal injection of the cyclooxygenase inhibitor indomethacin (5 mg/kg), whereas indomethacin at the same dose attenuated the fever induced by ICV administration of lipopolysaccharide (LPS) (10 ng/2 microl) (vehicle/LPS: TI = 4.5 +/- 0.5 degrees C. h; indomethacin/LPS: TI = 1.7 +/- 1.0 degrees C. h; P < 0.05). Interestingly, indomethacin did not affect the rise in T(b) induced by heme-lysinate (152 nmol/4 microl) ICV injection (vehicle/heme: TI = 4.5 +/- 1.4 degrees C. h; indomethacin/heme: TI = 4.2 +/- 1.0 degrees C. h). Finally, PGE(2) (200 ng/2 microl) injected ICV evoked a rise in T(b) that lasted 1.5 h. The heme oxygenase inhibitor ZnDPBG (200 nmol/4 microl) failed to alter PGE(2)-induced fever. Taken together, these results indicate that the central CO-heme oxygenase pathway increases T(b) independently of prostaglandins.

Role of neuronal nitric oxide synthase in hypoxia-induced anapyrexia in rats.

Anapyrexia (a regulated decrease in body temperature) is a response to hypoxia that occurs in organisms ranging from protozoans to mammals, but very little is known about the mechanisms involved. Recently, it has been shown that the NO pathway plays a major role in hypoxia-induced anapyrexia. However, very little is known about which of the three different nitric oxide synthase isoforms (neuronal, endothelial, or inducible) is involved. The present study was designed to test the hypothesis that neuronal nitric oxide synthase (nNOS) plays a role in hypoxia-induced anapyrexia. Body core temperature (T(c)) of awake, unrestrained rats was measured continuously using biotelemetry. Rats were submitted to hypoxia, 7-nitroindazole (7-NI; a selective nNOS inhibitor) injection, or both treatments together. Control animals received vehicle injections of the same volume. We observed a significant (P < 0.05) reduction in T(c) of approximately 2.8 degrees C after hypoxia (7% inspired O(2)), whereas intraperitoneal injection of 7-NI at 25 mg/kg caused no significant change in T(c). 7-NI at 30 mg/kg elicited a reduction in T(c) and was abandoned in further experiments. When the two treatments were combined (25 mg/kg of 7-NI and 7% inspired O(2)), we observed a significant attenuation of hypoxia-induced anapyrexia. The data indicate that nNOS plays a role in hypoxia-induced anapyrexia.

Role of nitric oxide in hypoxia inhibition of fever.

Hypoxia causes a regulated decrease in body temperature (T(b)), and nitric oxide (NO) is now known to participate in hypoxia-induced hypothermia. Hypoxia also inhibits lipopolysaccharide (LPS)-induced fever. We tested the hypothesis that NO may participate in the hypoxia inhibition of fever. The rectal temperature of awake, unrestrained rats was measured before and after injection of LPS, with or without concomitant exposure to hypoxia, in an experimental group treated with N(omega)-nitro-L-arginine (L-NNA) for 4 consecutive days before the experiment and in a saline-treated group (control). L-NNA is a nonspecific NO synthase inhibitor that blocks NO production. LPS caused a dose-dependent typical biphasic rise in T(b) that was completely prevented by hypoxia (7% inspired oxygen). L-NNA caused a significant drop in T(b) during days 2-4 of treatment. When LPS was injected into L-NNA-treated rats, inhibition of fever was observed. Moreover, the effect of hypoxia during fever was significantly reduced. The data indicate that the NO pathway plays a role in hypoxia inhibition of fever.

Indomethacin impairs LPS-induced behavioral fever in toads.

We tested the hypothesis that PGs mediate lipopolysaccharide (LPS)-induced behavioral fever in the toad Bufo paracnemis. Measurements of preferred body temperature (T(b)) were performed with a thermal gradient. Toads were injected intraperitoneally with the cyclooxygenase inhibitor indomethacin (5 mg/kg), which inhibits PG biosynthesis, or its vehicle (Tris) followed 30 min later by LPS (0.2 and 2 mg/kg) into the lymph sac. LPS at the dose of 0.2 mg/kg caused a significant increase in T(b) from 7 to 10 h after injection, and then T(b) returned toward baseline values. LPS at the dose of 2 mg/kg produced a different pattern of response, with a longer latency to the onset of fever (10th h) and a longer duration (until the end of the experiment at the 15th h). Tris significantly attenuated the fever induced by LPS at 0.2 mg/kg, but not at 2 mg/kg. Moreover, indomethacin completely blocked the fever evoked by LPS (2 mg/kg). These results indicate that the behavioral fever induced by LPS in toads requires the activation of the COX pathway, suggesting that the involvement of PG in fever has an ancient phylogenetic history and that endogenous PGs raise the thermoregulatory set point to produce fever, because behavioral thermoregulation seems to be related to changes in the thermoregulatory set point.

A new function for lactate in the toad Bufo marinus.

In the amphibian Bufo marinus, progressive hypoxia below a critical PO2 elicits a transient 50% increase in O2 consumption that coincides with the onset of lactate formation. The present study was designed to test the hypothesis that lactate causes the observed rise in metabolic rate. Arterial bolus infusions of pH-neutral sodium lactate solutions (4 mmol/kg body wt) in toads maintained under hypoxia actually elicit a similar increase in metabolic rate. The application of adrenergic antagonists (bretylium tosylate, phentolamine, propranolol, and reserpine) inhibits this response, suggesting that catecholamines are involved. Moreover, animals injected with lactate move to a cooler environment (behavioral hypothermia), a behavioral response that is beneficial during hypoxia. We hypothesize that, in accordance with Cannon's concept of an emergency response, lactate may function as an alarm signal during hypoxia. However, the signal function of lactate is observed in animals both under hypoxia and under normoxia and should thus be considered in future studies whenever elevated lactate levels are present, e.g., during and after exercise.

Hypoxic metabolic response of the golden-mantled ground squirrel.

We examined the magnitude of the hypoxic metabolic response in golden-mantled ground squirrels to determine whether the shift in thermoregulatory set point (T(set)) and subsequent fall in body temperature (T(b)) and metabolic rate observed in small mammals were greater in a species that routinely experiences hypoxic burrows and hibernates. We measured the effects of changing ambient temperature (T(a); 6--29 degrees C) on metabolism (O(2) consumption and CO(2) production), T(b), ventilation, and heart rate in normoxia and hypoxia (7% O(2)). The magnitude of the hypoxia-induced falls in T(b) and metabolism of the squirrels was larger than that of other rodents. Metabolic rate was not simply suppressed but was regulated to assist the initial fall in T(b) and then acted to slow this fall and stabilize T(b) at a new, lower level. When T(a) was reduced during 7% O(2), animals were able to maintain or elevate their metabolic rates, suggesting that O(2) was not limiting. The slope of the relationship between temperature-corrected O(2) consumption and T(a) extrapolated to a T(set) in hypoxia equals the actual T(b). The data suggest that T(set) was proportionately related to T(a) in hypoxia and that there was a shift from increasing ventilation to increasing O(2) extraction as the primary strategy employed to meet increasing metabolic demands under hypoxia. The animals were neither hypothermic nor hypometabolic, as T(b) and metabolic rate appeared to be tightly regulated at new but lower levels as a result of a coordinated hypoxic metabolic response.

Endogenous vasopressin does not mediate hypoxia-induced anapyrexia in rats.

The present study was designed to test the hypothesis that arginine vasopressin (AVP) mediates hypoxia-induced anapyrexia. The rectal temperature of awake, unrestrained rats was measured before and after hypoxic hypoxia, AVP-blocker injection, or a combination of the two. Control animals received saline injections of the same volume. Basal body temperature was 36.52 +/- 0.29 degreesC. We observed a significant (P < 0.05) reduction in body temperature of 1. 45 +/- 0.33 degreesC after hypoxia (7% inspired O2), whereas systemic and central injections of AVP V1- and AVP V2-receptor blockers caused no change in body temperature. When intravenous injection of AVP blockers was combined with hypoxia, we observed a reduction in body temperature of 1.49 +/- 0.41 degreesC (V1-receptor blocker) and of 1.30 +/- 0.13 degreesC (V2-receptor blocker), similar to that obtained by application of hypoxia only. Similar results were observed when the blockers were injected intracerebroventricularly. The data indicate that endogenous AVP does not mediate hypoxia-induced anapyrexia in rats.

Inhibition of the central heme oxygenase-carbon monoxide pathway increases 2-deoxy-D-glucose-induced hypothermia in rats.

The present study was designed to test the hypothesis that carbon monoxide (CO) plays a role in 2-deoxy-D-glucose (2-DG)-induced hypothermia. The body temperature (T(b)) of awake, unrestrained rats was measured before and after systemic administration of 2-DG (50 mg/kg) and intracerebroventricular administration of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG, a heme-oxygenase inhibitor, 200 nmol/4 microl). We observed a significant reduction in body temperature after 2-DG injection. ZnDPBG alone caused no significant change in body temperature. When the two treatments were combined, 2-DG-induced hypothermia was significantly increased. The data indicate that heme oxygenase-carbon monoxide pathway plays a key role in 2-DG-induced hypothermia, inhibiting 2-DG-induced hypothermia.

Role of nitric oxide in insulin-induced hypothermia in rats.

Hypothermia is a well-known phenomenon which accompanies hypoglycemia in mammals. The present study was designed to test the hypothesis that nitric oxide (NO) plays a role in insulin-induced hypothermia. The body temperature (Tb) of awake, unrestrained rats was measured before and after systemic infusion of insulin (2U x kg(-1) x h(-1)), and intracerebroventricular administration of NG-nitro-(L)-arginine methyl ester (L-NAME, a nonselective NO synthase inhibitor, 200 microg/1 microl). We observed a significant reduction in body temperature after insulin infusion. L-NAME alone caused no significant change in body temperature. When the two treatments were combined, no change in Tb was observed. The data indicate that NO plays a key role in insulin-induced hypothermia.