Comparison of the effector mechanisms during endotoxin fever in the adult rabbit.

In unanaesthetized adult rabbits an intravenous dose of E. coli endotoxin evoked a febrile rise in colonic temperature at ambient temperatures of 9 to 31 degrees C. The rise in colonic temperature and oxygen consumption did not depend on the ambient temperature, while, among the heat loss effectors, in warmer environments only the depression of respiratory heat loss and in cooler environments only ear skin vasoconstriction contributed to the febrile rise in colonic temperature. In moderately warm environments the endotoxin first induced a maximum inhibition of respiratory frequency and this was followed by vasoconstriction. Later, a transient rise in oxygen consumption occurred. During defervescence the timing of the effectors was reversed. The results showed that a febrile response is not necessarily characterized by simultaneous changes in the thermoregulatory effector mechanisms.     

Elderly bioheat modeling: changes in physiology,thermoregulation, and blood flow circulation

A bioheat model for the elderly was developed focusing on blood flow circulatory changes that influence their thermal response in warm and cold environments to predict skin and core temperatures for different segments of the body especially the fingers. The young adult model of Karaki et al. (Int J Therm Sci 67:41–51, 2013) was modified by incorporation of the physiological thermoregulatory and vasomotor changes based on literature observations of physiological changes in the elderly compared to young adults such as lower metabolism and vasoconstriction diminished ability, skin blood flow and its minimum and maximum values, the sweating values, skin fat thickness, as well as the change in threshold parameter related to core or skin temperatures which triggers thermoregulatory action for sweating, maximum dilatation, and maximum constriction. The developed model was validated with published experimental data for elderly exposure to transient and steady hot and cold environments. Predicted finger skin temperature, mean skin temperature, and core temperature were in agreement with published experimental data at a maximum error less than 0.5 °C in the mean skin temperature. The elderly bioheat model showed an increase in finger skin temperature and a decrease in core temperature in cold exposure while it showed a decrease in finger skin temperature and an increase in core temperature in hot exposure.     

Reduction of cutaneous blood flow in cold fingers

Blood flow to fingers is reduced during cold exposure. This is generally attributed to vasoconstriction. We tested the hypothesis that increased blood viscosity, not vasoconstriction, accounts for reductions of cutaneous flow after fingers cool. Blood viscosity was higher at 10 degree C than at 27 degree C and independent of hematocrit at low shear rates. The increase of finger vascular resistance may be due to increased vascular hindrance early in cold exposure (< 15 min) and is more likely due to increased viscosity after 20-30 min, a factor that may dominate the peripheral microcirculaton during prolonged cold exposure.     

Effect of local cooling on skin temperature and blood flow of men in Antarctica

Alterations to the finger skin temperature (Tsk) and blood flow (FBF) before and after cold immersion on exposure to an Antarctic environment for 8 weeks were studied in 64 subjects. There was a significant fall in Tsk and increase in finger blood flow after 1 week of Antarctic exposure. The Tsk did not further change even after 8 weeks of stay in Antarctica but a significant increase in FBF was obtained after 8 weeks. The cold immersion test was performed at non-Antarctic and Antarctic conditions by immersing the hand for 2 min in 0–4° C cold water. In the non-Antarctic environment the Tsk and FBF dropped significantly (P < 0.001) indicating a vasoconstriction response. Interestingly after 8 weeks of stay in Antarctic conditions, the skin temperature dropped (P < 0.001) but the cold induced fall in FBF was inhibited. Based on these observations it may be hypothesized that continuous cold exposure in Antarctica results in vasodilatation, which overrides the stronger vasoactive response of acute cold exposure and thus prevents cold injuries.     

Physiological mechanism of digital vasoconstriction training

Recent work in our laboratory has shown that vasodilation produced during temperature biofeedback training is mediated through a nonneural, beta-adrenergic mechanism. Here we sought to determine if the effects of feedback training for vasoconstriction are produced through a neural or nonneural pathway and whether other measures of physiological activity are correlated with these changes. Nine normal subjects received temperature feedback vasoconstriction training in which feedback was delivered only during periods of successful performance. In a subsequent session, the nerves to one finger were blocked with a local anesthetic while finger blood flow was recorded from this and other fingers. Vasoconstriction occurred during feedback in the intact fingers but not in the nerve-blocked finger and was accompanied by increased skin conductance and heart rate. These data demonstrate that temperature feedback vasoconstriction training is mediated through an efferent, sympathetic nervous pathway. In contrast, temperature feedback vasodilation training is mediated through a nonneural, beta-adrenergic mechanism.     

Habituation of the cold pressor response in normo- and hypertensive human subjects

The changes in cardiovascular response to repeated cold-pressor test were studied in young normotensive and in young hypertensive subjects. The cold stimulus consisted of immersing one foot in cold water (4 degrees C) for 60 s. Non-invasive methods were used to record the cardiovascular responses: blood flow of the calf was measured using venous occlusion plethysmography, arterial blood pressure with sphygmomanometery, heart rate with electrocardiography. The vascular conductance level in the calf was higher in hypertensive subjects than in normotensives. The difference remained throughout the series of 6 daily experiments. In both hypertensive and normotensive groups of subjects some individuals responded to the cold stimulus with vasodilatation in the calf muscles, others with vasoconstriction. In the hypertensives blood flow increased more and habituation was only transient with a strong tendency for the vasodilatory response to recover, while in normotensives habituation was rapid and complete. Vasoconstrictor responses showed no signs of reduction. The blood pressure increases were larger in hypertensives and remained unaltered within the period of repeated tests (6 days). There was not significant difference between the heart rate changes in the two groups of subjects. It is concluded that the vasculature of the calf shows lower tone and is more labile during the early stage of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered thresholds for thermoregulatory sweating and vasodilatation in anorexia nervosa.

The changes in peripheral (hand) blood flow that occurred when deep body temperature was raised were measured in 13 patients with anorexia nervosa and 13 control subjects. The relation between blood flow and core temperature was shifted to the left in the patients with anorexia, with the onset of vasodilatation occurring at lower core and mean skin temperatures: no significant differences in the slopes of the responses were evident. The onset of thermal sweating occurred at lower core and mean skin temperatures in the patients with anorexia than in the controls. After ingestion of a high-energy liquid meal core temperature increased in the patients, and this was accompanied by a significant rise in peripheral blood flow in most cases. A similar meal in the normal subjects was followed by either no change in core temperature or a slight fall, and no consistent change in peripheral blood flow. These findings suggest that the lowering of thresholds for thermoregulatory sweating and vasodilatation may be a contributory factor to the abnormally low core temperature of patients with anorexia and may also explain some of their common complaints relating to feelings of warmth in the hands and feet after meals.     

Physiological mechanism of digital vasoconstriction training

Recent work in our laboratory has shown that vasodilation produced during temperature biofeedback training is mediated through a nonneural, beta-adrenergic mechanism. Here we sought to determine if the effects of feedback training for vasoconstriction are produced through a neural or nonneural pathway and whether other measures of physiological activity are correlated with these changes. Nine normal subjects received temperature feedback vasoconstriction training in which feedback was delivered only during periods of successful performance. In a subsequent session, the nerves to one finger were blocked with a local anesthetic while finger blood flow was recorded from this and other fingers. Vasoconstriction occurred during feedback in the intact fingers but not in the nerve-blocked finger and was accompanied by increased skin conductance and heart rate. These data demonstrate that temperature feedback vasoconstriction training is mediated through an efferent, sympathetic nervous pathway. In contrast, temperature feedback vasodilation training is mediated through a nonneural, beta-adrenergic mechanism.This work was supported by research grant HL-30604 from the National Heart, Lung, and Blood Institute.     

Peripheral blood flow during rewarming from mild hypothermia in humans

During the initial stages of rewarming from hypothermia, there is a continued cooling of the core, or after-drop in temperature, that has been attributed to the return of cold blood due to peripheral vasodilatation, thus causing a further decrease of deep body temperature. To examine this possibility more carefully, subjects were immersed in cold water (17 degrees C), and then rewarmed from a mildly hypothermic state in a warm bath (40 degrees C). Measurements of hand blood flow were made by calorimetry and of forearm, calf, and foot blood flows by straingauge venous occlusion plethysmography at rest (Ta = 22 degrees C) and during rewarming. There was a small increase in skin blood flow during the falling phase of core temperature upon rewarming in the warm bath, but none in foot blood flow upon rewarming at room air, suggesting that skin blood flow seems to contribute to the after-drop, but only minimally. Limb blood flow changes during this phase suggest that a small muscle blood flow could also have contributed to the after-drop. It was concluded that the after-drop of core temperature during rewarming from mild hypothermia does not result from a large vasodilatation in the superficial parts of the periphery, as postulated. The possible contribution of mechanisms of heat conduction, heat convection, and cessation of shivering thermogenesis were discussed.     

Heat exchanges in wet suits

Flow of water under foam neoprene wet suits could halve insulation that the suits provided, even at rest in cold water. On the trunk conductance of this flow was approximately 6.6 at rest and 11.4 W . m-2 . C-1 exercising; on the limbs, it was only 3.4 at rest and 5.8 W . m-2 . degrees C-1 exercising; but during vasoconstriction in the cold, skin temperatures on distal parts of limbs were lower than were those of the trunk, allowing adequate metabolic responses. In warm water, minor postural changes and movement made flow under suits much higher, approximately 60 on trunk and 30 W . m-2 . degrees C-1 on limbs, both at rest and at work. These changes in flow allowed for a wide range of water temperatures at which people could stabilize body temperature in any given suit, neither overheating when exercising nor cooling below 35 degrees C when still. Even thin people with 4- or 7- mm suits covering the whole body could stabilize their body temperatures in water near 10 degrees C in spite of cold vasodilatation. Equations to predict limits of water temperature for stability with various suits and fat thicknesses are given.     

Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 10(-4) mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10(-5) mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm(2) (1 dyn = 10(-5) N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.     

Infrared thermal imaging based study of localized cold stress induced thermoregulation in lower limbs: The role of age on the inversion time

Thermoregulatory control of human body temperature is of paramount importance for normal bodily functions. Exposure of the upper and lower limbs to localized cold stress can cause cold-induced injuries and often lower limbs are more susceptible to damages from cold-induced injuries. In this study, we use infrared thermal imaging to probe localized cold stress induced cutaneous vasoconstriction of lower limbs in 33 healthy subjects. The cold stress is actuated by applying ice to the plantar surfaces of the lower limbs for 180 s and after removal of the cold stress, infrared thermography is utilized to non-invasively monitor the time-dependent variations in vein pixel temperatures on the dorsal surfaces of the stimulated and non-stimulated feet. It is observed that the vein pixel temperature of the stimulated foot showed a non-monotonic variation with time, consisting of an initial decrease and the presence of an inversion time, beyond which temperature is regained. The initial decrease in vein pixel temperature of the stimulated foot is attributed to the reduced blood flow caused by the cold stress induced severe vasoconstriction. Beyond the inversion time, the vein pixel temperature is found to increase due to rewarming of the surrounding skin. Experimental findings indicate that the inversion time linearly increased with the age of the subject, indicating a reduced thermoregulatory efficiency for the aged subjects. This study provides a thermal imaging-based insight into the skin temperature re-distribution during the early stages of blood perfusion in lower limbs, after an exposure to a localized acute cold stress. Statistical analyses reveal that subject height, weight, body-mass index and gender do not influence the inversion time significantly. The experimental findings are important towards rapid evaluation of personnel fitness for deployment in extreme cold environment, treatment of cold-induced injuries and probing of thermoregulatory impairments.     

Thermoreceptor distribution in different skin layers and its significance for thermoregulation

• 1.1.|The activity pattern of 50 cold receptors of the rabbit nose back skin was investigated.
• 2.2.|The latency of the response of individual cold receptors to identical cold stimuli varied between 0.8 ± 0.3 to 29.4 ± 4.5 s; maximal firing rates are attended after 5.5 ± 0.5 to 72.2 ± 6.2 s. Characteristic phasic responses are only demonstrated by short latency receptors.
• 3.3.|The results suggest that cold receptors are distributed throughout the skin of the rabbit's nose.
• 4.4.|Changes of temperature gradients between different skin layers were measured at different ambient temperatures.
• 5.5.|It is suggested that cold receptors might indicate heat flow through the skin.

     

Physiological aspects of menopausal hot flush.

Eighteen hot flushes experimenced by eight menopausal women were studied and compared with the effects of warming in six premenopausal women. The hot flushes were associated with an acute rise in skin temperature, peripheral vasodilatation, a transient increase in heart rate, fluctuations in the electrocardiographic (ECG) baseline, and a pronounced decrease in skin resistence. Although premenopausal women had greater maximum increases in skin temperature and peripheral vasodilatation, they showed a much smaller decrease in skin resistance and no changes in heart rate or ECG baseline. These findings suggest that the onset of the hot flush is associated with a sudden and transient increase in sympathetic drive. Further investigations may lead to the development of a more specific alternative to oestrogen for relieving menopausal hot flushes.     

The effect of low ambient temperature on the febrile responses of rats to semi-purified human endogenous pyrogen

The febrile responses of Sprague-Dawley rats to semi-purified human endogenous pyrogen were studied at a thermoneutral ambient temperature (26 degrees C) and in the cold (3 degrees C). It was found that while rats developed typical monophasic febrile responses at thermoneutrality, febrile responses were absent in the cold-exposed rats. Experiments were conducted to determine whether this lack of febrile responses in cold-exposed rats was due to an inability of these animals to generate or retain heat in the cold. Thermogenesis and vasoconstriction were stimulated in cold-exposed rats by selectively cooling the hypothalamus, using chronically implanted thermodes. It was shown that, using this stimulus, metabolic rate could be increased by more than 50 percent and body temperature could be driven up at a rate of 5 degrees C/hour in rats exposed to the cold. Therefore, it was concluded that the lack of febrile responses of cold-exposed rats to pyrogen is in no way due to a physical or physiological inability to retain heat. Instead, it appears that in some manner cold exposure suppresses the sensitivity or responsiveness of the rat to pyrogenic stimuli.     

Characterization of a three-phase response in gloved cold-stressed fingers

Seven gloves were studied worn by eight sedentary subjects (six men and two women) exposed to cold–dry, C–D, (mean dry bulb temperature −17.2^∘C; mean dew point temperature ), and cold–wet, C–W, ( 0^∘C; ) conditions. Mean endurance times were 75 min for the C–D and 162 min for the C–W conditions. A three-phase response pattern of the temperature in the fingers was characterized. Phase I comprised an initial period during which finger temperature remained close to the pre-exposed level, due to delayed vasoconstriction in the finger. Phase II involved an exponential-like decrease of finger temperature indicative of the onset of vasoconstriction in the finger. Phase III manifested periodic finger temperature changes due to cold induced vasodilatation (CIVD). Mean wave patterns for phase III indicated approximately 3.5 waves · h⁻¹ in the C–D but only about 2 waves · h⁻¹ in the C–W condition. Extension of endurance time, due to CIVD, was defined as the difference in time between the actual end of the experiment and the time the finger-tip would have reached the set temperature endurance limit as extrapolated by a continued exponential drop. Three overall response patterns of fingers in the cold were characterized: type A exhibiting all 3 phases; type B₁ or B₂ exhibiting either phases I+II or phases II+III; and type C showing only phase II. Considerable inter- and intra-subject variability was found. In both test conditions the final physiological thermal states of the subjects were between comfortable and slightly uncomfortable but acceptable and thus did not correlate with the responses in the fingers. Accepted: 5 January 1998     

Quantification of conservative endurance times in thermally insulated cold-stressed digits.

The estimation of endurance times of the digits exposed to cold weather is performed by an analytical, one-dimensional cylindrical model. Blood perfusion effects are lumped into a volumetric heat-generation term. Cold-induced vasodilatation (CIVD) effects are not included in the present analysis. Endurance times, defined by a drop in cylinder tip temperature to 5 degrees C, were evaluated. Parameters included in this evaluation were 1) environmental temperatures, 2) thermal insulation applied on the cylinder, 3) length of the cylinder, and 4) diameter of the cylinder. It was found that the lower the ambient temperature, the longer the finger, and the smaller its diameter, then the shorter the endurance time for the same thermal insulation. Results of the model were compared with measured data for a subject not exhibiting CIVD response to cold stress. Conformity of results calculated for an adjusted value of the volumetric heat-generation term and measured data was very good, with a maximum deviation of less than 10% at only one particular point in time. This model facilitates the conservative estimation of lower bounds to thermally insulated fingers and toes exposed to cold stress.     

Responsiveness of microcirculation and local cold vasodilation to capsaicin in the intact and chronically denervated canine tongue

Lingual blood flow and its distribution were determined at rest and in response to local cooling of the tongue (32 degrees C) in 6 anaesthetized, paralyzed and artificially ventilated dogs before and after two intraarterial (i.a.) injections of capsaicin (2.5 mg) at an interval of about 40 min. In 3 dogs, the same protocol was performed after degeneration of the chorda-lingual and glossopharyngeal nerves due to prior transection. In general the first i.a. injection of capsaicin resulted in a marked and the second injection in a smaller decrease of lingual blood flow. Local cooling of the tongue induced significant increases in lingual blood flow before as well as after capsaicin treatment, regardless of whether sensory innervation was intact or degenerated. In both the untreated and capsaicin treated dogs the increase in lingual blood flow during local cooling of the tongue was solely due to an increase in blood flow through the arteriovenous anastomoses, while blood flow through the capillaries of the mucosa and muscles even decreased. The findings suggest that capsaicin-induced vasoconstriction of the tongue vessels is due to a direct effect on vascular receptors. It is further suggested that cold vasodilatation of the canine tongue is not mediated by axon collaterals releasing substance P. Direct thermal effects on the intramural ganglia and the postganglionic vasomotor efferents innervating the AVAs, or on AVAs basal tone itself are suggested as the underlying mechanism.     

Ca2+ sensitization during sustained hypoxic pulmonary vasoconstriction is endothelium dependent

The main aim of this study was to determine the effects of endothelium removal on tension and intracellular Ca(2+) ([Ca(2+)](i)) during hypoxic pulmonary vasoconstriction (HPV) in rat isolated intrapulmonary arteries (IPA). Rat IPA and mesenteric arteries (MA) were mounted on myographs and loaded with the Ca(2+)-sensitive fluorophore fura PE-3. Arteries were precontracted with prostaglandin F(2alpha), and the effects of hypoxia were examined. HPV in isolated IPA consisted of a transient constriction superimposed on a second sustained phase. Only the latter phase was abolished by endothelial denudation. However, removal of the endothelium had no effect on [Ca(2+)](i) at any point during HPV. The endothelin-1 antagonists BQ-123 and BQ-788 did not affect HPV, although constriction induced by 100 nM endothelin-1 was abolished. In MA, hypoxia induced an initial transient rise in tension and [Ca(2+)](i), followed by vasodilatation and a fall in [Ca(2+)](i) to (but not below) prehypoxic levels. These results are consistent with sustained HPV being mediated by an endothelium-derived constrictor factor that is distinct from endothelin-1 and that elicits vasoconstriction via Ca(2+) sensitization.     

Effect of high local temperature on reflex cutaneous vasodilation

We examined the effect of high local forearm skin temperature (Tloc) on reflex cutaneous vasodilator responses to elevated whole-body skin (Tsk) and internal temperatures. One forearm was locally warmed to 42 degrees C while the other was left at ambient conditions to determine if a high Tloc could attenuate or abolish reflex vasodilation. Forearm blood flow (FBF) was monitored in both arms, increases being indicative of increases in skin blood flow (SkBF). In one protocol, Tsk was raised to 39-40 degrees C 30 min after Tloc in one arm had been raised to 42 degrees C. In a second protocol, Tsk and Tloc were elevated simultaneously. In protocol 1, the locally warmed arm showed little or no change in blood flow in response to increasing Tsk and esophageal temperature (average rise = 0.76 +/- 1.18 ml X 100 ml-1 X min-1), whereas FBF in the normothermic arm rose by an average of 8.84 +/- 3.85 ml X 100 ml-1 X min-1. In protocol 2, FBF in the normothermic arm converged with that in the warmed arm in three of four cases but did not surpass it. We conclude that local warming to 42 degrees C for 35-55 min prevents reflex forearm cutaneous vasodilator responses to whole-body heat stress. The data strongly suggest that this attenuation is via reduction or abolition of basal tone in the cutaneous arteriolar smooth muscle and that at a Tloc of 42 degrees C a maximum forearm SkBF has been achieved. Implicit in this conclusion is that local warming has been applied for a duration sufficient to achieve a plateau in FBF.