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The thermal responses of rats which were pretreated with 5,7-dihydroxytryptamine to deplete hypothalamic 5-hydroxytryptamine, 6-hydroxydopamine to deplete hypothalamic catecholamines, phentolamine and propranolol to inhibit adrenergic receptors, haloperidol to inhibit dopamine receptors, or atropine to inhibit cholinergic receptors, to intrahypothalamic administration of bombesin were compared with those of control rats. The bombesin-induced hypothermia was attenuated by pretreatment of the rats with either hypothalamic dopamine depletion or receptor blockade, or hypothalamic cholinergic receptor blockade. The reduction in the bombesin-induced hypothermia in the treated rats was due to the reduction of metabolic and vasomotor response. The data indicate that bombesin may act on hypothalamic dopamine and/or cholinergic receptor mechanisms to induce hypothermia by promoting a reduction in metabolic heat production and an enhancement in heat loss in rats.

Highlights • Mild heat preconditioning up-regulated HSP72 expression in cultured hypothalamic cells. • siRNA-HSP72 pretreatment down-regulated HSP72 expression. • Mild heat preconditioning attenuated heat-induced cell loss. • siRNA-HSP72 pre-treatment exacerbated heat-induced cell loss. • A positive correlation between HSP72 expression and heat tolerance might exist in hypothalamic cells., Heat shock protein (HSP) 72 in serum was decreased to a greater degree in patients with serious heat stroke than in those with mild heat stroke. Thus, increased levels of HSP72 appeared to correlate with a better outcome for the patient. Nevertheless, the function of HSP72 in the heat-induced hypothalamic cell death has not been assessed. In this study, we found that increasing HSP72 levels with mild heat preconditioning or decreasing HSP72 levels with pSUPER plasmid expressing HSP72 small interfering RNA significantly attenuated or exacerbated heat-induced cell death in cultured primary hypothalamic cells, respectively. Our findings suggest that HSP72 plays a pivotal role in heat-induced cell death and may be associated with heat tolerance.

✓ To assess thermoregulatory sweating in palmar hyperhidrosis, the authors determined the responses of three groups of normal, hyperhidrotic, and denervated subjects to a variety of ambient temperatures (TA's), 22°, 28°, and 41° C. The normal group had no hyperhidrosis, with intact T2–3 ganglia, the hyperhidrotic group had palm hyperhidrosis with intact T2–3 ganglia, and the denervated group had hyperhydrosis treated with T2–3 ganglionectomy. Both groups of hyperhidrotic and denervated subjects maintained oral and mean skin temperatures within normal limits displayed by the normal group over a wide range of TA's tested. The local sweating rate (LSR) of both the palms and the soles of the feet in the hyperhidrotic group was decreased to a minimal level by either the T2–3 ganglionectomy or the subcutaneous administration of atropine sulfate. Furthermore, the denervated group had a significantly lower LSR of both the forehead and the upper chest regions, but showed a higher LSR of both the ventral thigh and the lateral lumbar regions at a TA of 41° C when compared to the LSR of either the normal or the unoperated hyperhidrotic group. The data demonstrate that the surgical removal of both the T-2 and the T-3 ganglia, although producing no alterations in the thermal balance, does produce abnormalities in quantitative distribution of thermoregulatory sweating in man.

The effects of depleting the tissue catecholamines with alpha-methyl-p-tyrosine (AMPT, an inhibitor of catecholamine synthesis) on the splenic NK cell cytotoxic activity were assessed both in vivo and in vitro. Treatment with i.p. doses of AMPT (3-500 mg/kg) produced a dose-related suppression in the splenic NK cytotoxic activity in many mouse strains. For an i.p. dose of 300 mg/kg of AMPT, the splenic NK cell activity began to fall 1 h after AMPT injection. The splenic NK cell activity reached its maximal level at 3 h, accompanied by a severe depletion of norepinephrine contents in the spleen. Both the NK activity and the splenic norepinephrine content returned to their control levels at 24 h. Direct addition of AMPT (up to 2500 micrograms/ml) to the cultured mouse spleen cells in vitro resulted in no NK suppression. However, when the serum obtained from the AMPT-treated mice was added to the cultured mouse spleen cells of the AMPT-untreated mice, the splenic NK cytotoxic activity was greatly suppressed. In addition, natural killing by spleen cells from AMPT-untreated mice was not reduced by the addition of spleen cells from AMPT-treated mice. No evidence of AMPT-induced cellular suppressors of natural killing could be detected. It was also found that both the splenic NK cell activity and the effector-target cell conjugation activity were suppressed by treatment with AMPT. These observations indicate that depleting the tissue catecholamines with AMPT results in the release of certain humoral factors which can suppress both the effector-target cell conjugation activity and the splenic NK cell activity in mice.

The thermoregulatory responses induced by alterations in hypothalamic temperature (Thy) were measured in three groups of rabbits: untreated controls, treated with 5,7-dihydroxytryptamine (a serotonin depletor), and treated with 6-hydroxydopamine (a catecholamine depletor) at ambient temperatures (Ta) of 2 or 22°C. In the cold (2°C), changes in metabolic rate (MR) occurring in response to alterations in Thy were used to delineate thermosensitivity. Rabbits after diencephalic serotonin (5-HT) depletion displayed a greater sensitivity of the MR that did control animals. In contrast, animals after diencephalic norepinephrine (NE) depletion had a lesser sensitivity of the MR than did the control animals. At room temperature (22°C), the changes in respiratory evaporative heat loss (Eres) and in ear blood flow (EBF) occurring in response to alterations in Thy were used as the measure of thermosensitivity. In 5-HT-depleted animals, the Thy threshold for the onset of vasodilation and panting was greatly decreased. In contrast, the Thy threshold for the onset of vasodilation and panting was greatly increased in NE-depleted animals. The data indicate that diencephalic 5-HT and NE depletions alter, in an apparently reciprocal fashion, the thermoregulatory responses to different hypothalamic temperatures.

In the first series of experiments, the effects of administration of insulin (0.04-0.12 IU/microliter) into the preoptic anterior hypothalamic area on thermoregulatory responses were assessed in unanesthetized rats at various ambient temperatures (Ta). Intrahypothalamic administration of insulin induced a dose-dependent rise in rectal temperature. At Ta = 8 degrees C, the hyperthermia in response to insulin was due to increased metabolism, whereas at Ta = 30 degrees C, the hyperthermia was due to cutaneous vasoconstriction. However, at Ta = 22 degrees C, the insulin-induced hyperthermia was due to both increased metabolism and cutaneous vasoconstriction. In the second series of experiments, the effects of intracerebroventricular administration of insulin on 35 hypothalamic units classified as cold-responsive, warm-responsive, or thermally unresponsive were assessed in 35 rats anesthetized with urethane. It was found that the majority (80%) of the warm-responsive units were depressed by insulin, whereas the majority (70%) of the cold-responsive units were excited by insulin. The data indicate that insulin acts on the hypothalamic thermally responsive neurons to induce hyperthermia by promoting an increase in heat production and/or vasoconstriction.

We exposed rat pheochromocytoma PC12 cells to hyperthermia or high dosage of dopamine and examined the direct effects of mild hypothermia or dopamine D(2) receptor agonist. At a hyperthermia of 42-43 degrees C for 120 min there was approximately 50% loss of cell viability accompanied by dopamine overproduction. The model of cell death due to hyperthermia in PC12 cells belonged to the necrotic and late apoptotic population. At each temperature examined below 37 degrees C, significant decrease in cytotoxicity, the percentage of necrotic and late apoptotic cells, and dopamine overproduction were observed. Cytotoxicity could also be induced by high dosages of dopamine. Both hyperthermia and dopamine induced cytotoxicity in PC12 cells could also be reduced by dopamine D(2) agonists. These results indicate the dopamine is important in hyperthermic situations. The results also indicate that mild hypothermia and dopamine D(2) receptor agonists are neuroprotective against hyperthermia-induced brain injury.