Circulatory responses to heat after celiac ganglionectomy or adrenal demedullation

Chloraloseanesthetized rats were implanted with Doppler flow probes on the mesenteric, renal, and external caudal arteries and were exposed to an ambient temperature of 40 degrees C. Heart rate, core (Tc) and tail-skin temperatures, and mean arterial blood pressure (MAP) were also monitored. Before heating, the celiac ganglion was removed (ganglionectomy) from one group of animals (n = 11) and a bilateral adrenal demedullation was performed in a second group (n = 14). As Tc progressively increased from 37 degrees C to 43 degrees C, MAP rose to a plateau then fell precipitously as Tc exceeded 41 degrees C. Ganglionectomy eliminated the rise in mesenteric resistance (P less than 0.05) and attenuated the rise in MAP compared with an intact control group (n = 11). Ganglionectomy also increased the heating rate (P less than 0.05) and reduced heat tolerance time (P less than 0.05). Demedullation attenuated the rise in both mesenteric resistance and MAP (P less than 0.05) and increased the rate of heating (P less than 0.05) compared with controls (n = 10). Renal and caudal resistance changes were similar in all groups. These data show the importance of intact adrenal medullas and sympathetic innervation to the splanchnic region in contributing to thermal tolerance in the rat. However, neither factor alone can explain splanchnic vasoconstriction during severe heat stress.     

Peripheral vascular responses to hyperthermia in the rat

To investigate the sequence and nature of the peripheral vascular responses during the prodromal period of heat stroke, rats were implanted with Doppler flow probes on the superior mesenteric (SMA), left iliac (LIA) or left renal (LRA), and external caudal (ECA) arteries. Studies were performed in unanesthetized rats (n = 6) exposed to 46 degrees C and in chloralose-anesthetized animals (n = 11) at 40 degrees C. Core (Tc) and tail-skin temperatures, heart rate, and mean arterial blood pressure (MAP) were also monitored. In both groups, prolonged (70-150 min) exposure progressively elevated Tc from 37.0 to 44.0 degrees C. MAP rose to a plateau then fell precipitously as Tc exceeded 41.5 degrees C. SMA resistance increased throughout the early stages of heating, with a sharp decline from this elevated level 10-15 min before the precipitous fall in MAP. ECA resistance fell initially but increased in the terminal stage of heating. In unanesthetized animals, LIA resistance progressively declined. In chloralose-anesthetized animals LRA resistance rose progressively, then increased markedly as Tc exceeded 41.5 degrees C. These data support the hypothesis that a selective loss of compensatory splanchnic vasoconstriction may trigger the cascade of events that characterize heat stroke. This differential vascular response was similar in both unanesthetized and anesthetized animals.     

Control of total peripheral resistance during hyperthermia in rats

To elucidate the effect of blood volume on the circulatory adjustment to heat stress, we studied alpha-chloralose-anesthetized rats at three levels of blood volume: normovolemia (NBV), hypervolemia (HBV; +32% plasma volume by isotonic albumin solution infusion), and hypovolemia (LBV; -16% plasma volume by furosemide administration). Body surface heating was performed with an infrared lamp to raise arterial blood temperature (Tb) at the rate of approximately 0.1 degree C/min. Before heating, central venous pressure (CVP) was significantly higher in HBV (0.41 +/- 0.25 mmHg) and lower in LBV (-1.44 +/- 0.22 mmHg) than in NBV (-0.41 +/- 0.10 mmHg). The Tb at which CVP started to decrease was approximately 40 degrees C in HBV, approximately 41 degrees C in NBV, and approximately 42 degrees C in LBV, and it decreased by 1.53 +/- 0.14, 1.92 +/- 0.24, and 0.62 +/- 0.14 mmHg from 37 to 43 degrees C of Tb in HBV, NBV, and LBV, respectively. Stroke volume was closely correlated with CVP, and this relationship was not affected by Tb. Heart rate responses to the raised Tb were similar among the three groups. Mean arterial pressure (MAP) was not affected by blood volume modification or CVP and was maintained at preheating (Tb 37 degrees C) level until Tb rose to 40 degrees C. Above this Tb, MAP increased until Tb reached 43 degrees C (+30-40 mmHg) for all three groups. Total peripheral resistance (TPR) was inversely correlated with CVP, and the slope of the linear relationship between TPR and CVP in LBV was three- to fourfold steeper than in NBV or HBV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thermal adjustments to nonexertional heat stress in mature and senescent Fischer 344 rats

The purpose of this study was to test the hypothesis that the rise in colonic temperature (Tc) during nonexertional heat stress is exaggerated in senescent (SEN, 24 mo, n = 12) vs. mature (MAT, 12 mo, n = 15) conscious unrestrained Fischer 344 rats. On 2 separate days (48 h apart) each SEN and MAT animal was exposed to an ambient temperature (Ta) of 42 degrees C (relative humidity 20%) until a Tc of 41 degrees C was attained and then cooled at a Ta of 26 degrees C until Tc returned to the initial control level. Control Tc was similar in the two groups for both trials. The rate of Tc change during heating was 63% greater (0.070 +/- 0.005 vs. 0.043 +/- 0.004 degrees C/min, P less than 0.05) and the time to 41 degrees C reduced by 36% (54 +/- 6 vs. 85 +/- 10 min, P less than 0.05) in MAT vs. SEN animals during the first exposure, although the cooling rate was slower in the MAT (0.048 +/- 0.004 degrees C/min) vs. SEN (0.062 +/- 0.006 degrees C/min) animals (P less than 0.05). The heating rate was unchanged in MAT animals between trials 1 and 2. However, SEN animals had a 95% increase in heating rate in trial 2 compared with trial 1 (P less than 0.05), and the corresponding time to 41 degrees C was decreased by 44% (P less than 0.05). As a result, rate of heating and time to 41 degrees C were similar in the two groups during trial 2. The cooling rate was similar between trials within each group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Circulatory responses to vasoconstrictor agents during passive heating in the rat

The purpose of this study was to determine the actions of several pharmacological agents on the circulatory system, and more specifically on the superior mesenteric vascular bed, in response to environmental heat stress in chloralose-anesthetized rats. Animals were instrumented with Doppler flow probes on the mesenteric and renal arteries and exposed to an ambient temperature of 40 degrees C. Heart rate, mean arterial blood pressure (MAP), and core (Tc) and tail skin temperatures were also monitored. As Tc progressively increased from 37 degrees C during heat exposure, MAP rose to a plateau and then fell precipitously as Tc exceeded 41.5 degrees C. Mesenteric resistance increased throughout the early stages of heating before sharply declining prior to the reduction in MAP. The pressor and mesenteric resistance responses to constant infusions of several adrenergic agonists after MAP began falling (Tc = 41.3 degrees C) were significantly (P less than 0.05) attenuated compared with infusions into normothermic animals. In a second set of experiments, injections of both norepinephrine and angiotensin II were made 30 min before and approximately 10, 30, 50, 70, and 90 min after initiation of heating. These injections increased both MAP and mesenteric resistance; however, at TcS greater than 40 degrees C, the responses to both agonists were progressively and significantly attenuated. In a final group of animals, barium chloride infusions produced similar pressor and regional resistance changes during both normothermia and severe hyperthermia (Tc greater than 42 degrees C). These results indicate that, in the chloralose-anesthetized rat, hyperthermia disrupts adrenoceptor function but does not alter the intrinsic ability of vascular smooth muscle to contract.     

Mechanism for pressor response to nonexertional heating in the conscious rat

The purpose of this study was to determine the systemic hemodynamic mechanism(s) underlying the pressor response to nonexertional heat stress in the unrestrained conscious rat. After a 60-min control period [ambient temperature (Ta) 24 degrees C], male Sprague-Dawley rats (260-340 g) were exposed to a Ta of 42 degrees C until a colonic temperature (Tc) of 41 degrees C was attained. As Tc rose from control levels (38.1 +/- 0.1 degrees C) to 41 degrees C, mean arterial blood pressure (carotid artery catheter, n = 33) increased from 124 +/- 2 to 151 +/- 2 mmHg (P less than 0.05). During this period, heart rate increased (395 +/- 5 to 430 +/- 6 beats/min, P less than 0.05) and stroke volume remained unchanged. As a result, ascending aorta blood flow velocity (Doppler flow probe, n = 8), used as an index of cardiac output, did not change from control levels during heating, but there was a progressive Tc-dependent increase in systemic vascular resistance (+30% at end heating, P less than 0.05). This systemic vasoconstrictor response was associated with decreases in blood flow (-31 +/- 9 and -21 +/- 5%) and increases in vascular resistance (94 +/- 16 and 53 +/- 8%; all P less than 0.05) in the superior mesenteric and renal arteries (n = 8 each) and increases in plasma norepinephrine (303 +/- 37 to 1,237 +/- 262 pg/ml) and epinephrine (148 +/- 28 to 708 +/- 145 pg/ml) concentrations (n = 12, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related thermoregulatory differences during core cooling in humans

The current study assessed sympathetic neuronal and vasomotor responses, total body oxygen consumption, and sensory thermal perception to identify thermoregulatory differences in younger and older human subjects during core cooling. Cold fluid (40 ml/kg, 4 degrees C) was given intravenously over 30 min to decrease core temperature (Tc) in eight younger (age 18-23) and eight older (age 55-71) individuals. Compared with younger subjects, the older subjects had significantly lower Tc thresholds for vasoconstriction (35.5 +/- 0.3 vs. 36.2 +/- 0.2 degrees C, P = 0.03), heat production (35.2 +/- 0.4 vs. 35.9 +/- 0.1 degrees C, P = 0.04), and plasma norepinephrine (NE) responses (35.0 vs. 36.0 degrees C, P < 0.05). Despite a lower Tc nadir during cooling, the maximum intensities of the vasoconstriction (P = 0.03) and heat production (P = 0.006) responses were less in the older compared with the younger subjects, whereas subjective thermal comfort scores were similar. Plasma NE concentrations increased fourfold in the younger but only twofold in the older subjects at maximal Tc cooling. The vasomotor response for a given change in plasma NE concentration was decreased in the older group (P = 0.01). In summary, aging is associated with 1) a decreased Tc threshold and maximum response intensity for vasoconstriction, total body oxygen consumption, and NE release, 2) decreased vasomotor responsiveness to NE, and 3) decreased subjective sensory thermal perception.     

Effect of thermal stress on the vestibulosympathetic reflexes in humans.

Both heat stress and vestibular activation alter autonomic responses; however, the interaction of these two sympathetic activators is unknown. To determine the effect of heat stress on the vestibulosympathetic reflex, eight subjects performed static head-down rotation (HDR) during normothermia and whole body heating. Muscle sympathetic nerve activity (MSNA; peroneal microneurography), mean arterial blood pressure (MAP), heart rate (HR), and internal temperature were measured during the experimental trials. HDR during normothermia caused a significant increase in MSNA (Delta5 +/- 1 bursts/min; Delta53 +/- 14 arbitrary units/min), whereas no change was observed in MAP, HR, or internal temperature. Whole body heating significantly increased internal temperature (Delta0.9 +/- 0.1 degrees C), MSNA (Delta10 +/- 3 bursts/min; Delta152 +/- 44 arbitrary units/min), and HR (Delta25 +/- 6 beats/min), but it did not alter MAP. HDR during whole body heating increased MSNA (Delta16 +/- 4 bursts/min; Delta233 +/- 90 arbitrary units/min from normothermic baseline), which was not significantly different from the algebraic sum of HDR during normothermia and whole body heating (Delta15 +/- 4 bursts/min; Delta205 +/- 55 arbitrary units/min). These data suggest that heat stress does not modify the vestibulosympathetic reflex and that both the vestibulosympathetic and thermal reflexes are robust, independent sympathetic nervous system activators.     

Cardiovascular-sympathetic adjustments to nonexertional heat stress in mature and senescent Fischer 344 rats

The purpose of this study was to test the hypothesis that the cardiovascular-sympathetic nervous system adjustments during nonexertional heat stress are exaggerated in senescent (S, 24 mo) vs. mature (M, 12 mo) conscious unrestrained Fischer 344 rats. During two separate trials (48 h apart), each animal was exposed to an ambient temperature (Ta) of 42 degrees C until a colonic temperature (Tco) of 41 degrees C was attained and then cooled at a Ta of 26 degrees C until Tco returned to the initial control level. Trial 1: heart rate (HR), mean arterial blood pressure (MAP), and arterial plasma concentrations of norepinephrine (NE), epinephrine (E), and lactate (La) were similar between the S and M groups during the baseline (control) period. The absolute increases in HR, MAP, NE, and E from the control period to the end of heating were of similar magnitudes between groups; however, La increased more in the S than M animals (P less than 0.05). During recovery, the declines toward control levels for all variables were similar or even more rapid in the S vs. M animals (P less than 0.05). Trial 2: the changes in HR and MAP during heating were similar to those observed in trial 1 in both groups. Generally, NE and E control levels were elevated in both groups compared with those in trial 1. The absolute increases in NE during heating were similar to trial 1 in both groups, whereas E increased to a greater extent than in trial 1 in the S animals (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Forebrain and brain stem neural circuits contribute to altered sympathetic responses to heating in senescent rats.

Acute heating in young rats increases visceral sympathetic nerve discharge (SND); however, renal and splanchnic SND responses to hyperthermia are attenuated in senescent compared with young Fischer 344 (F344) rats (Kenney MJ and Fels RJ. Am J Physiol Regul Integr Comp Physiol 283: R513-R520, 2002). Central mechanisms by which aging alters visceral SND responses to heating are unknown. We tested the hypothesis that forebrain neural circuits are involved in suppressing sympathoexcitatory responses to heating in chloralose-anesthetized, senescent F344 rats. Renal and splanchnic SND responses to increased (38 degrees C-41 degrees C) internal temperature were determined in midbrain-transected (MT) and sham-MT young (3-mo-old), mature (12-mo-old), and senescent (24-mo-old) F344 rats and in cervical-transected (CT) and sham-CT senescent rats. Renal SND remained unchanged during heating in MT and sham-MT senescent rats but was increased in CT senescent rats. Splanchnic SND responses to heating were higher in MT vs. sham-MT senescent rats and in CT vs. MT senescent rats. SND responses to heating were similar in MT and sham-MT young and mature rats. Mean arterial pressure (MAP) was increased during heating in MT but not in sham-MT senescent rats, whereas heating-induced increases in MAP were higher in sham-MT vs. MT young rats. These data suggest that in senescent rats suppression of splanchnic SND to heating involves forebrain and brain stem neural circuits, whereas renal suppression is mediated solely by brain stem neural circuits. These results support the concept that aging alters the functional organization of pathways regulating SND and arterial blood pressure responses to acute heating.     

Plasma catecholamines in rats during rewarming from induced hypothermia

The present study sought to quantitate the levels of plasma catecholamines [norepinephrine (NE), epinephrine (E), and dopamine (DA)] during induction and rewarming from hypothermia. Male rats (317 +/- 8 g) were made hypothermic by exposure to 0.9% halothane at -10 to -15 degrees C while blood pressure (carotid artery), heart rate, and colonic temperature (Tc) were monitored. Anesthesia was discontinued when Tc reached 28 degrees C. Tc continued to fall but was held at 20-20.5 degrees C for 30 min. Rewarming was then initiated by raising ambient temperature to 22 degrees C. Arterial blood samples were taken 1) before cooling, 2) just before rewarming, 3) when Tc reached 22 degrees C during rewarming, and 4) when Tc reached 27 degrees C during rewarming. Plasma was assayed radioenzymatically for catecholamines using both phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase procedures, and hypothermic induction resulted in significant increases in NE, E, and DA above control levels (P less than 0.01). With rewarming to Tc = 22 degrees C, all catecholamines increased above the level observed during hypothermia (P less than 0.01), and NE and DA increased still further (P less than 0.01) when Tc reached 27 degrees C. The levels of plasma catecholamines observed during hypothermia and during the rewarming phase indicate a role of the sympathoadrenal medullary system in the metabolic adjustments associated with hypothermia and recovery. During rewarming, the levels of E and NE attained exceed those at which both substances may be expected to act as circulating hormones.     

A subsidiary fever center in the medullary raphé?

In fever, as in normal thermoregulation, signals from the preoptic area drive both cutaneous vasoconstriction and thermogenesis by brown adipose tissue (BAT). Both of these responses are mediated by sympathetic nerves whose premotor neurons are located in the medullary raphé. EP3 receptors, key prostaglandin E2 (PGE2) receptors responsible for fever induction, are expressed in this same medullary raphé region. To investigate whether PGE2 in the medullary raphé might contribute to the febrile response, we tested whether direct injections of PGE2 into the medullary raphé could drive sympathetic nerve activity (SNA) to BAT and cutaneous (tail) vessels in anesthetized rats. Microinjections of glutamate (50 mM, 60-180 nl) into the medullary raphé activated both tail and BAT SNA, as did cooling the trunk skin. PGE2 injections (150-500 ng in 300-1,000 nl) into the medullary raphé had no effect on tail SNA, BAT SNA, body temperature, or heart rate. By contrast, 150 ng PGE2 injected into the preoptic area caused large increases in both tail and BAT SNA (+60 +/- 17 spikes/15 s and 1,591 +/- 150% of control, respectively), increased body temperature (+1.8 +/- 0.2 degrees C), blood pressure (+17 +/- 2 mmHg), and heart rate (+124 +/- 19 beats/min). These results suggest that despite expression of EP3 receptors, neurons in the medullary raphé are unable to drive febrile responses of tail and BAT SNA independently of the preoptic area. Rather, they appear merely to transmit signals for heat production and heat conservation originating from the preoptic area.     

Effects of neuronal norepinephrine uptake blockade on baroreflex neural and peripheral arc transfer characteristics

Neuronal uptake is the most important mechanism by which norepinephrine (NE) is removed from the synaptic clefts at sympathetic nerve terminals. We examined the effects of neuronal NE uptake blockade on the dynamic sympathetic regulation of the arterial baroreflex because dynamic characteristics are important for understanding the system behavior in response to exogenous disturbance. We perturbed intracarotid sinus pressure (CSP) according to a binary white noise sequence in anesthetized rabbits, while recording cardiac sympathetic nerve activity (SNA), arterial pressure (AP), and heart rate (HR). Intravenous administration of desipramine (1 mg/kg) decreased the normalized gain of the neural arc transfer function from CSP to SNA relative to untreated control (1.03 +/- 0.09 vs. 0.60 +/- 0.08 AU/mmHg, mean +/- SE, P < 0.01) but did not affect that of the peripheral arc transfer function from SNA to AP (1.10 +/- 0.05 vs. 1.08 +/- 0.10 mmHg/AU). The normalized gain of the transfer function from SNA to HR was unaffected (1.01 +/- 0.04 vs. 1.09 +/- 0.12 beats.min(-1).AU(-1)). Desipramine decreased the natural frequency of the transfer function from SNA to AP by 28.7 +/- 7.0% (0.046 +/- 0.007 vs. 0.031 +/- 0.002 Hz, P < 0.05) and that of the transfer function from SNA to HR by 64.4 +/- 2.2% (0.071 +/- 0.003 vs. 0.025 +/- 0.002 Hz, P < 0.01). In conclusion, neuronal NE uptake blockade by intravenous desipramine administration reduced the total buffering capacity of the arterial baroreflex mainly through its action on the neural arc. The differential effects of neuronal NE uptake blockade on the dynamic AP and HR responses to SNA may provide clues for understanding the complex pathophysiology of cardiovascular diseases associated with neuronal NE uptake deficiency.     

Comparison between two rat sympathetic pathways activated in cold defense

In cold defense and fever, activity increases in sympathetic nerves supplying both tail vessels and interscapular brown adipose tissue (iBAT). These mediate cutaneous vasoconstrictor and thermogenic responses, respectively, and both depend upon neurons in the rostral medullary raphé. To examine the commonality of brain circuits driving these two outflows, sympathetic nerve activity (SNA) was recorded simultaneously from sympathetic fibers in the ventral tail artery (tail SNA) and the nerve to iBAT (iBAT SNA) in urethane-anesthetized rats. From a warm baseline, cold-defense responses were evoked by intermittently circulating cold water through a water jacket around the animal's shaved trunk. Repeated episodes of trunk skin cooling decreased core (rectal) temperature. The threshold skin temperature to activate iBAT SNA was 37.3 +/- 0.5 degrees C (n = 7), significantly lower than that to activate tail SNA (40.1 +/- 0.4 degrees C; P < 0.01, n = 7). A fall in core temperature always strongly activated tail SNA (threshold 38.3 +/- 0.2 degrees C, n = 7), but its effect on iBAT SNA was absent (2 of 7 rats) or weak (threshold 36.9 +/- 0.1 degrees C, n = 5). The relative sensitivity to core vs. skin cooling (K-ratio) was significantly greater for tail SNA than for iBAT SNA. Spectral analysis of paired recordings showed significant coherence between tail SNA and iBAT SNA only at 1.0 +/- 0.1 Hz. The coherence was due entirely to the modulation of both signals by the ventilatory cycle because it disappeared when the coherence spectrum was partialized with respect to airway pressure. These findings indicate that independent central pathways drive cutaneous vasoconstrictor and thermogenic sympathetic pathways during cold defense.     

Sympathetic nerve regulation to heating is altered in senescent rats

Renal and splanchnic sympathetic nerve discharge (SND) responses to increased (38-41 degrees C) internal temperature were determined in anesthetized young (3-6 mo old), mature (12 mo old), and senescent (24 mo old) Fischer 344 (F344) rats. We hypothesized that SND responses would be altered in senescent and mature rats as demonstrated by attenuated sympathoexcitatory responses to heating and by the absence of hyperthermia-induced SND pattern changes. The following observations were made. 1) Renal and splanchnic SND responses were significantly increased during heating in young and mature but not in senescent rats. 2) At 41 degrees C, renal and splanchnic SND responses were higher in young compared with senescent rats, and renal SND was higher in mature than in senescent rats. 3) Heating changed the SND bursting pattern in young, but not in mature or senescent, rats. 4) SND responses to heating did not differ between baroreceptor-innervated (BRI) and sinoaortic-denervated (SAD) senescent rats but were higher in SAD compared with BRI young rats. These results demonstrate an attenuated responsiveness of sympathetic neural circuits to heating in senescent F344 rats.     

Sympathetic activity in early renal posttransplantation hypertension in rats

The contribution of elevated sympathetic activity to the development of renal posttransplantation hypertension was investigated. F1 hybrids (F1H) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were transplanted with either an SHR or an F1H kidney and bilaterally nephrectomized. Three weeks after transplantation, sympathetic activity was assessed by measuring adrenal tyrosine hydroxylase (TH) mRNA content and recording splanchnic nerve activity (SNA) in conscious animals. To investigate the dependence of arterial pressure on sympathetic activity, animals were treated with the alpha(2)-adrenoceptor agonist guanabenz intracerebroventricularly. Mean arterial pressure (MAP) was 143 +/- 4 mmHg in recipients of an SHR kidney (n = 15) versus 110 +/- 3 mmHg in recipients of an F1H kidney (n = 10; P < 0.001). Adrenal TH mRNA content was 1.93 +/- 0.15 fmol/microg total RNA in recipients of an SHR kidney versus 1.96 +/- 0.17 fmol/microg total RNA in recipients of an F1H kidney (not significant). SNA did not differ significantly between recipients of an SHR kidney (n = 8) and recipients of an F1H kidney (n = 7) in terms of frequency and amplitude of synchronized nerve discharges. In response to cumulative intracerebroventricular administration of 10 and 20 microg guanabenz, SNA fell to 51 +/- 5% of control in recipients of an SHR kidney versus 44 +/- 6% of control in recipients of an F1H kidney (not significant) accompanied by a slight fall in MAP in either group. The results suggest that elevated sympathetic activity is not a major contributor to the development of renal posttransplantation hypertension.     

Heat stress reduces cerebral blood velocity and markedly impairs orthostatic tolerance in humans

Orthostatic tolerance is reduced in the heat-stressed human. This study tested the following hypotheses: 1) whole body heat stress reduces cerebral blood velocity (CBV) and increases cerebral vascular resistance (CVR); and 2) reductions in CBV and increases in CVR in response to an orthostatic challenge will be greater while subjects are heat stressed. Fifteen subjects were instrumented for measurements of CBV (transcranial ultrasonography), mean arterial blood pressure (MAP), heart rate, and internal temperature. Whole body heating increased both internal temperature (36.4+/-0.1 to 37.3+/-0.1 degrees C) and heart rate (59+/-3 to 90+/-3 beats/min); P<0.001. Whole body heating also reduced CBV (62+/-3 to 53+/-2 cm/s) primarily via an elevation in CVR (1.35+/-0.06 to 1.63+/-0.07 mmHg.cm-1.s; P<0.001. A subset of subjects (n=8) were exposed to lower-body negative pressure (LBNP 10, 20, 30, 40 mmHg) in both normothermic and heat-stressed conditions. During normothermia, LBNP of 30 mmHg (highest level of LBNP achieved by the majority of subjects in both thermal conditions) did not significantly alter CBV, CVR, or MAP. During whole body heating, this LBNP decreased MAP (81+/-2 to 75+/-3 mmHg), decreased CBV (50+/-4 to 39+/-1 cm/s), and increased CVR (1.67+/-0.17 to 1.92+/-0.12 mmHg.cm-1.s); P<0.05. These data indicate that heat stress decreases CBV, and the reduction in CBV for a given orthostatic challenge is greater during heat stress. These outcomes reduce the reserve to buffer further decreases in cerebral perfusion before presyncope. Increases in CVR during whole body heating, coupled with even greater increases in CVR during orthostasis and heat stress, likely contribute to orthostatic intolerance.     

Interactive effects of mental and physical stress on cardiovascular control.

Physiological responses to mental tasks and physical exercise were studied independently and combined. We hypothesized that combined mental and physical stresses produce a synergistic interaction. We studied cardiovascular responses to 5 min of static handgrip, mental arithmetic, and the combined stimuli in random order in 12 healthy subjects. Muscle sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP) responses to handgrip and the combined stimuli exceeded responses to mental arithmetic, yet no significant difference existed between responses to handgrip and the combined stimuli. Peak changes in SNA (in %) were greatest during handgrip (188 +/- 41), followed by the combined stimuli (166 +/- 31) and mental arithmetic (51 +/- 9). Peak changes in MAP (in mmHg) were also greatest during handgrip (26 +/- 4), followed by the combined stimuli (23 +/- 3) and then mental arithmetic (8 +/- 2). Peak changes in heart rate (in beats/min) followed the same trend: handgrip (15 +/- 2), combined (13 +/- 2), and mental arithmetic (10 +/- 2). Mental stimulation did not synergistically interact with or add to the responses elicited by handgrip exercise; in fact, a trend existed for math during handgrip to reduce responses relative to handgrip alone.     

Phenylephrine-induced elevations in arterial blood pressure are attenuated in heat-stressed humans

To test the hypothesis that phenylephrine-induced elevations in blood pressure are attenuated in heat-stressed humans, blood pressure was elevated via steady-state infusion of three doses of phenylephrine HCl in 10 healthy subjects in both normothermic and heat stress conditions. Whole body heating significantly increased sublingual temperature by ~0.5 degrees C, muscle sympathetic nerve activity (MSNA), heart rate, and cardiac output and decreased total peripheral vascular resistance (TPR; all P < 0.005) but did not change mean arterial blood pressure (MAP; P > 0.05). At the highest dose of phenylephrine, the increase in MAP and TPR from predrug baselines was significantly attenuated during the heat stress [DeltaMAP 8.4 +/- 1.2 mmHg; DeltaTPR 0.96 +/- 0.85 peripheral resistance units (PRU)] compared with normothermia (DeltaMAP 15.4 +/- 1.4 mmHg, DeltaTPR 7.13 +/- 1.18 PRU; all P < 0.001). The sensitivity of baroreflex control of MSNA and heart rate, expressed as the slope of the relationship between MSNA and diastolic blood pressure, as well as the slope of the relationship between heart rate and systolic blood pressure, respectively, was similar between thermal conditions (each P > 0.05). These data suggest that phenylephrine-induced elevations in MAP are attenuated in heat-stressed humans without affecting baroreflex control of MSNA or heart rate.     

Reduction of DNA-polymerase beta activity of CHO cells by single and combined heat treatments

The effect of single and combined heat treatments on the activity of DNA polymerase beta was studied in CHO cells. The activity of polymerase beta was determined by measuring the amount of [3H]TTP incorporated into activated calf thymus DNA in the presence of aphidicolin, a specific inhibitor of DNA polymerase alpha. Biphasic response curves were obtained for all temperatures tested (40-46 degrees C) showing the sensitivity to decrease during heating. A constant activation energy of Ea = 120 +/- 10 kcal/mole was found for the initial heat sensitivity, whereas the Arrhenius plot for the final sensitivity is characterized by an inflection point at 43 degrees C with Ea = 360 +/- 40 kcal/mole or Ea = 130 +/- 20 kcal/mole for temperatures below or above 43 degrees C, respectively. The observed decrease of the polymerase activity is not due to a decrease in the number of active enzyme molecules but to a change in its affinity, since the inhibition is reversible when increasing concentrations of TTP are applied. When acute or chronic thermo-tolerance was induced by a priming heat treatment at 43 degrees C for 45 min followed by a time interval at 37 degrees C for 16 h or by a preincubation at 40 degrees C for 16 h, respectively, the thermal sensitivity of polymerase beta was lowered by a factor of up to 5. By contrast, pretreatment at a higher temperature followed by a lower temperature (step-down heating) did not alter the sensitivity of polymerase beta to the second treatment. The results indicate that heat-induced cell death cannot be the consequence of the reduction of the polymerase beta activity, confirming earlier studies on this subject.