Histamine and histamine receptors: behavioral thermoregulation in the salamander Necturus maculosus

Low doses (0.01, 0.1 mg/kg, i.p.) of histamine (HA) caused selection of significantly lower temperatures, and higher doses (0.5, 1.0 mg/kg) increased temperatures by mudpuppies in linear thermal gradients. Injection of the HA precursor, L-histidine (500 mg/kg) produced an increase in the temperatures selected. Results from injections of HA H1-receptor agonist (2-pyridylethylamine) and antagonist (pyrilamine), and H2-receptor agonist (dimaprit) and antagonist (cimetidine) had significant effects on thermoregulation; H1-receptors may mediate behavioral hyperthermia and H2-receptors behavioral hypothermia. Responses to these histaminic compounds are significantly influenced by the time of day at which the responses are measured and by season and acclimation temperature. The equivalent behavioral responses in both endotherms and ectotherms to agents which produce physiological hyperthermia and hypothermia are probably behavioral hypothermia ("cold seeking") and behavioral hyperthermia ("heat seeking"), respectively.     

Diabetes mellitus and thermoregulation

Diabetes mellitus is accompanied by a variety of alterations in metabolic, cardiovascular, and neuronal function. This paper provides a comprehensive review of the ways in which these pathophysiological aspects of diabetes may impair thermoregulatory function. The influence of diabetic neuropathy and vasculopathy on the control of peripheral blood flow is reviewed and the additional effects of changing levels of blood glucose and insulin are discussed. Both hypoglycaemia and diabetic ketoacidosis are associated with hypothermia, but the reasons for this in ketoacidosis are not clear. Impairment of heat conservation may contribute to and could be a consequence of autonomic neuropathy. The final section of the paper describes a study of our own in which metabolic stability was maintained by infusing insulin intravenously before and during the determination of the thermoregulatory responses to acute cold stress. Under these conditions, there was impairment of reflex vasoconstriction in the limbs of diabetics with neuropathy. This failure to reduce heat loss resulted in half the diabetics with neuropathy shivering in response to moderate cooling, which in some subjects was accompanied by a fall in core temperature. Diabetics without neuropathy and nondiabetics neither shivered nor dropped core temperature.     

Physiology, thermoregulation and bipedalism

It has long been recognized that the bipedal posture reduces the surface area of the body exposed to the sun. In recent years, a theory has been developed by Wheeler that bipedalism evolved in the ancestor of the Hominidae in order to help relieve thermal stress on the animals in open equatorial environments. Bipedalism was said to afford a distinct adaptive advantage over quadrupedalism by permitting hominids to remain active in the open throughout the day. The heat load of the hypothetical hominid comprises the external environment as modelled by Wheeler and the animal's internal environment (i.e., the internal heat generated by its metabolic and locomotor activities, and its evaporative and respirative cooling capacities). When these factors are integrated in the calculation of the animal's thermal budget, the putative advantage of the bipedal over the quadrupedal posture is considerably reduced. The simulations conducted in this study suggest that the increased time afforded to early hominids in the open by bipedalism was relatively short and, therefore, of little or no adaptive significance. These results suggest that thermoregulatory considerations cannot be implicated as a first cause in the evolution of bipedalism in the hominid ancestor.     

Uncoupling proteins and thermoregulation.

Energy balance in animals is a metabolic state that exists when total body energy expenditure equals dietary energy intake. Energy expenditure, or thermogenesis, can be subcategorized into groups of obligatory and facultative metabolic processes. Brown adipose tissue (BAT), through the activity of uncoupling protein 1 (UCP1), is responsible for nonshivering thermogenesis, a major component of facultative thermogenesis in newborn humans and in small mammals. UCP1, found in the mitochondrial inner membrane in BAT, uncouples energy substrate oxidation from mitochondrial ATP production and hence results in the loss of potential energy as heat. Mice that do not express UCP1 (UCP1 knockouts) are markedly cold sensitive. The recent identification of four new homologs to UCP1 expressed in BAT, muscle, white adipose tissue, brain, and other tissues has been met by tremendous scientific interest. The hypothesis that the novel UCPs may regulate thermogenesis and/or fatty acid metabolism guides investigations worldwide. Despite several hundred publications on the new UCPs, there are a number of significant controversies, and only a limited understanding of their physiological and biochemical properties has emerged. The discovery of UCP orthologs in fish, birds, insects, and even plants suggests the widespread importance of their metabolic functions. Answers to fundamental questions regarding the metabolic functions of the new UCPs are thus pending and more research is needed to elucidate their physiological functions. In this review, we discuss recent findings from mammalian studies in an effort to identify potential patterns of function for the UCPs.     

Hemodynamic physiology and thermoregulation in liposuction

Little is known about the physiology of large-volume liposuction. Patients are exposed to prolonged procedures, general anesthesia, fluid shifts, and infusion of high doses of epinephrine and lidocaine. Consequently, the authors examined the thermoregulatory and cardiovascular responses to liposuction by assessing multiple physiologic factors. The aims of their study were to serially determine hemodynamic parameters perioperatively, to quantify perioperative and postoperative plasma epinephrine levels, and to chronologically document fluctuations in core body temperature. Five female volunteers with American Society of Anesthesiologists' physical status I and II underwent moderate- to large-volume liposuction. Heart rate, blood pressure, mean pulmonary arterial pressure, cardiac index, and central venous pressure were monitored. Serum epinephrine levels and core body temperature were assessed perioperatively. The hemodynamic responses to liposuction were characterized by an increase in cardiac index (57 percent), heart rate (47 percent), and mean pulmonary arterial pressure (44 percent) (p < 0.05). Central venous pressure was not significantly altered. Maximum epinephrine levels were observed 5 to 6 hours after induction. Significant correlations between cardiac index and epinephrine concentrations were shown intraoperatively (r = 0.75). All patients developed intraoperative low body temperatures (mean 35.5 degrees C). An overall enhanced cardiac function was observed in patients subsequent to large-volume liposuction. The etiology of the altered cardiac parameters was multifactorial but may have been attributable in part to the administration of epinephrine, which counters the effects of general anesthesia and operative hypothermia. Additional explanations for raised cardiac output may be hemodilution or emergence from general anesthesia. Elevated mean pulmonary arterial pressure may be a result of subclinical fat embolism demonstrated in previous porcine studies, although fat was not observed in urine. The unchanged central venous pressure levels indicate that young healthy patients with compliant right ventricles can accommodate the fluid loads of large-volume liposuction. Overall hemodynamic parameters remained within safe limits. Within these surgical parameters, patients should be clinically screened for cardiovascular and blood pressure disorders before liposuction is undertaken, and preventative measures should be taken to limit intraoperative hypothermia.     

Hypohydration and thermoregulation in cold air

O'Brien, Catherine, Andrew J. Young, and Michael N. Sawka.Hypohydration and thermoregulation in cold air.J. Appl. Physiol. 84(1): 185-189, 1998.This study examined the effects of hypohydration onthermoregulation during cold exposure. In addition, the independentinfluences of hypohydration-associated hypertonicity and hypovolemiawere investigated. Nine male volunteers were monitored for 30 min at25°C, then for 120 min at 7°C, under three counterbalancedconditions: euhydration (Eu), hypertonic hypohydration (HH), andisotonic hypohydration (IH). Hypohydration was achieved 12 h beforecold exposure by inducing sweating (HH) or by ingestion of furosemide(IH). Body weight decrease (4.1 ± 0.2%) caused by hypohydrationwas similar for HH and IH, but differences(P < 0.05) were found between HH andIH in plasma osmolality (292 ± 1 vs. 284 ± 1 mosmol/kgH₂O) andplasma volume reduction (8 ± 2 vs. 18 ± 3%).Heat debt (349 ± 14 among) did not differ(P > 0.05) among trials. Mean skintemperature decreased throughout cold exposure during Eu but plateauedafter 90 min during HH and IH. Forearm-fingertemperature gradient tended (P = 0.06)to be greater during Eu (10.0 ± 0.7°C) than during HH or IH(8.9 ± 0.7°C). This suggests weaker vasoconstrictor tone duringhypohydration than during Eu. Final mean skin temperature was higherfor HH than for Eu or IH (23.5 ± 0.3, 22.6 ± 0.4, and 22.9 ± 0.3°C, respectively), and insulation was lower on HH than onIH (0.13 ± 0.01 vs. 0.15 ± 0.01°C · W¹ · m²,respectively), but not with Eu (0.14 ± 0.01°C · W¹ · m²).This provides some evidence that hypertonicity impairs the vasoconstrictor response to cold. Although mild hypohydration did notaffect body heat balance during 2-h whole body exposure to moderatecold, hypohydration-associated hypertonicity may have subtle effects onvasoconstriction that could become important during a more severe coldexposure.

     

Hypothalamic mechanisms in thermoregulation

Certain preoptic and rostral hypothalamic neurons are sensitive to changes in local preoptic temperature (Tpo). These neurons also receive much afferent input from peripheral thermoreceptors and control a variety of thermoregulatory responses. In thermode-implanted animals, preoptic warming increases the firing rate in warm-sensitive neurons and elicits heat loss responses such as panting and sweating. Preoptic cooling increases the firing rate in cold-sensitive neurons and elicits, first, heat retention responses (e.g., cutaneous vasoconstriction and thermoregulatory behavior), then heat production responses (e.g., shivering and nonshivering thermogenesis). It is likely that the preoptic thermosensitive neurons control these thermoregulatory responses because both respond similarly to changes in Tpo and skin temperature. Specifically, skin warming not only increases panting, skin blood flow, and the firing rate of warm-sensitive neurons, but also decreases the sensitivity of all these responses to Tpo changes. Skin cooling not only increases metabolic heat production, heat retention behavior, and the firing rate of cold-sensitive neurons, but also increases the hypothalamic thermosensitivity of all these responses. Low-firing warm-sensitive neurons receive little afferent input and are most sensitive to high Tpo. Many of these low-firing neurons probably serve in controlling heat loss responses. High-firing warm-sensitive neurons receive much excitatory afferent input and are usually sensitive only to low Tpo. These neurons probably exert their greatest influence on heat production responses, possibly by inhibiting and, thus, determining the thermosensitive characteristics of nearby cold-sensitive neurons.     

Behavioral thermoregulation in mammals and birds

Thermoregulation in homoiotherms is achieved by physiological and behavioural adjustments which involve the musculature, skin, sensory capacities, hypothalamus and endocrine glands. Under thermal stress animals exhibit anorexia, body extension, gasping, languor, lethargy, excessive drinking, bathing, decreased locomotor activities, group dispersion, and shade seeking. When exposed to cold, animals show body flexure, huddling, hyperphagia, extra locomotor activities, depressed respiration and nest building. Species and breed differences in the behavioural adjustments to unfavourable climates are related to habitat, morphological characteristics of body covering, degree of physiological adaptability, degree of physiological immaturity at birth or hatching, and the number of young.     

Exertion-induced fatigue and thermoregulation in the cold

Cold exposure facilitates body heat loss which can reduce body temperature, unless mitigated by enhanced heat conservation or increased heat production. When behavioral strategies inadequately defend body temperature, vasomotor and thermogenic responses are elicited, both of which are modulated if not mediated by sympathetic nervous activation. Both exercise and shivering increase metabolic heat production which helps offset body heat losses in the cold. However, exercise also increases peripheral blood flow, in turn facilitating heat loss, an effect that can persist for some time after exercise ceases. Whether exercise alleviates or exacerbates heat debt during cold exposure depends on the heat transfer coefficient of the environment, mode of activity and exercise intensity. Prolonged exhaustive exercise leading to energy substrate depletion could compromise maintenance of thermal balance in the cold simply by precluding continuation of further exercise and the associated thermogenesis. Hypoglycemia impairs shivering, but this appears to be centrally mediated, rather than a limitation to peripheral energy metabolism. Research is equivocal regarding the importance of muscle glycogen depletion in explaining shivering impairments. Recent research suggests that when acute exercise leads to fatigue without depleting energy stores, vasoconstrictor responses to cold are impaired, thus body heat conservation becomes degraded. Fatigue that was induced by chronic overexertion sustained over many weeks, appeared to delay the onset of shivering until body temperature fell lower than when subjects were rested, as well as impair vasoconstrictor responses. When heavy physical activity is coupled with underfeeding for prolonged periods, the resulting negative energy balance leads to loss of body mass, and the corresponding reduction in tissue insulation, in turn, compromises thermal balance by facilitating conductive transfer of body heat from core to shell. The possibility that impairments in thermoregulatory responses to cold associated with exertional fatigue are mediated by blunted sympathetic nervous responsiveness to cold is suggested by some experimental observations and merits further study.