Selected contribution: Hyperthermia-induced intestinal permeability and the role of oxidative and nitrosative stress.

The purpose of this study was to characterize intestinal permeability changes over a range of physiologically relevant body temperatures in vivo and in vitro. Initially, FITC-dextran (4,000 Da), a large fluorescent molecule, was loaded into the small intestine of anesthetized rats. The rats were then maintained at approximately 37 degrees C or heated over 90 min to a core body temperature of approximately 41, approximately 41.5, or approximately 42.5 degrees C. Permeability was greater in the 42.5 degrees C group compared with the 37, 41, or 41.5 degrees C groups. Histological analysis revealed intestinal epithelial damage in heated groups. Everted intestinal sacs were then used to further characterize hyperthermia-induced intestinal permeability and to study the potential role of oxidative and nitrosative stress. Increased permeability to 4,000-Da FITC-dextran in both small intestinal and colonic sacs was observed at a temperature of 41.5-42 degrees C compared with 37 degrees C, along with widespread intestinal epithelial damage. Administration of antioxidant enzyme mimics or a nitric oxide synthase inhibitor did not reduce permeability due to heat stress, and tissue concentrations of a lipid peroxidation product were not altered by heat stress, suggesting that oxidative and nitrosative stress were not likely mediators of this phenomenon in vitro. In conclusion, hyperthermia produced increased permeability and marked intestinal epithelial damage both in vivo and in vitro, suggesting that thermal disruption of epithelial membranes contributes to the intestinal barrier dysfunction manifested with heat stress.

Nitric oxide synthase inhibitors decrease coronary sinus-free radical concentration and ameliorate myocardial stunning in an ischemia-reperfusion model.

OBJECTIVES: Our objective was to determine the effect of a nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NNA) on free radical generation and myocardial contractility after ischemia-reperfusion. BACKGROUND: Cardiotoxic free radicals are generated by ischemia-reperfusion sequences. Nitric oxide reacts with superoxide radical to form peroxynitrite, which generates additional free radicals. Our hypothesis was that by inhibiting NO production, free radical formation will be diminished, which should be cardioprotective. METHODS: We studied 32 dogs. Coronary occlusion-reperfusion (20 min each) sequences were created by intracoronary balloon angioplasty inflation-deflation. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc*-), a measure of total oxidative flux. The L-NNA (4.8 mg/kg total) was infused intravenously during occlusion-reperfusion; control dogs received saline. Immunohistochemical staining demonstrated the peroxynitration product nitrotyrosine. RESULTS: In the control dogs Asc*- rose from 3.2 +/- SD 0.5 nmol/l to 4.8 +/- 1.1 nmol/l with reperfusion, a 50% rise. With L-NNA the Asc*- rose from 3.2 +/- 0.9 nmol/l to 4.0 +/- 1.2 nmol/l, a 25% rise (p < 0.01, L-NNA vs. control). Echocardiographic left ventricular fractional area shortening (FAS) in the control dogs declined from 38 +/- 19% (baseline) to 26 +/- 14% (ischemia), and to 22 +/- 11% with reperfusion (p < 0.01 vs. baseline). With L-NNA, FAS declined from 36 +/- 13% (baseline) to 27 +/- 12% (ischemia) but then rose to 33 +/- 14 with reperfusion (p = NS vs. baseline). Nitrotyrosine was present in the myocardium subjected to ischemia-reperfusion, but almost absent in dogs receiving L-NNA. Myocardial perfusion was not altered by L-NNA. CONCLUSIONS: The NO synthase inhibitors decrease coronary sinus free radical concentration and ameliorate myocardial stunning after ischemia-reperfusion.

Aging lowers steady-state antioxidant enzyme and stress protein expression in primary hepatocytes.

It has been reported that the isolation and culture of primary hepatocytes can compromise cellular ability to constituitively express antioxidant enzyme (AE) genes, making it difficult to study their regulation ex vivo. In the present study, the steady-state expression of manganese-containing superoxide dismutase, copper- and zinc-containing superoxide dismutase, catalase, and glutathione peroxidase was assessed in primary hepatocytes isolated from young and senescent rats and cultured in MATRIGEL: There was no change in steady-state superoxide dismutase protein or activity levels in cells collected from young animals and cultured for 7 days. Catalase expression was initially increased, and then it declined 30%. In contrast, superoxide dismutase expression declined 60% and catalase expression declined 50% in cells from senescent animals. Constitutive and inducible 70-kDa heat shock protein expression increased coincident with declining AE levels in the young cells but not senescent cells. For both age groups, electron micrographs showed rounded hepatocytes with abundant rough endoplasmic reticulum, mitochondria, and peroxisomes. Hepatocytes were organized into clusters of 6-12 cells surrounding a large central lumen devoid of microvilli. Each cluster also contained smaller microvilli-lined lumens between adjacent hepatocytes that resembled canniculi. The plasma membranes of these lumens were sealed from the extracellular space by junctional complexes. Gap junctions in the plasma membrane suggest that hepatocytes were capable of intercellular communication. We conclude that the Matrigel system can be used to study AE regulation in primary hepatocytes from young and senescent animals, provided that experiments can be conducted within a time frame of 5-7 days in culture. These data also support the hypothesis that aging compromises hepatocellular ability to maintain AE status and upregulate stress protein expression.

Vascular reactivity and baroreflex function during hyperthermia in conscious rats.

The hemodynamic responses to vasoconstrictor agents are blunted during heating in anesthetized rats. It is unknown whether reflex neural responses to these agents are also altered during hyperthermia. Therefore, the purpose of this study was to determine the effect of hyperthermia on the hemodynamic and baroreflex-mediated sympathetic neural responses to vasoactive agents in conscious, unrestrained rats. The splanchnic sympathetic nerve activity (SpNA) and systemic and regional hemodynamic responses to injections of phenylephrine and sodium nitroprusside were measured during normothermia (37 degrees C) and hyperthermia (41.5 degrees C). The hemodynamic responses to phenylephrine and sodium nitroprusside were blunted with heating, whereas the SpNA responses to both agents were augmented or unchanged. At 41.5 degrees C, the baroreflex curves relating heart rate (HR) and SpNA to mean arterial blood pressure were shifted to the right. The operating range and gain of the blood pressure (BP)-HR reflex were significantly reduced during heating, whereas the operating range of the BP-SpNA reflex was augmented at 41.5 degrees C. These results indicate that heating alters the cardiovascular and sympathetic neural responses to vasoactive agents in vivo. Furthermore, the data suggest that heating differentially affects arterial baroreflex control of HR and SpNA, shifting both curves toward higher BP values but selectively attenuating baroreflex control of HR.

Aging reduces adaptive capacity and stress protein expression in the liver after heat stress.

A decline in an organism's ability to cope with stress through acute response protein expression may contribute to stress intolerance with aging. We investigated the influence of aging on stress tolerance and the capacity to synthesize the 70-kDa heat shock protein (HSP70) in young and old rats exposed to an environmental heating protocol. Livers were assessed for injury and HSP70 expression after heat stress by use of immunohistochemical and immunoblotting techniques. The inducible HSP70 response in the cytoplasm and nucleus was markedly reduced with age at several time points over a 48-h recovery period, although senescent rats were able to strongly express HSP70 early in recovery. Older animals had extensive zone-specific liver injury, which corresponded to the diminished HSP70 response observed in these regions, and a significant reduction in thermotolerance compared with their young counterparts. These data highlight the regional nature of stress-induced injury and HSP70 expression in the liver and the impact of aging on these responses. Furthermore, the results suggest a functional link between the age-related decrements in the expression of inducible HSP70 and the pathophysiological responses to heat stress.

Caloric restriction improves thermotolerance and reduces hyperthermia-induced cellular damage in old rats.

Adult-onset, long-term caloric restriction (CR) prolongs maximum life span in laboratory rodents. However, the effect of this intervention on an organism's ability to cope with a physical challenge has not been explored. We investigated the influence of CR and aging on stress tolerance in old rats exposed to an environmental heating protocol on two consecutive days. We hypothesized that CR would increase heat tolerance by reducing cellular stress and subsequent accrual of oxidative injury. All calorically restricted rats survived both heat exposures compared with only 50% of their control-fed counterparts. CR also decreased heat-induced radical generation, stress protein accumulation, and cellular injury in the liver. In addition, heat stress stimulated marked induction of the antioxidant enzymes manganese-containing superoxide dismutase and catalase, along with strong nuclear catalase expression in liver samples from rats subjected to CR. In contrast, stress-related induction of antioxidant enzymes was blunted, and nuclear catalase expression was unchanged from euthermic conditions in the control-fed group. These data suggest that CR reduces cellular injury and improves heat tolerance of old animals by lowering radical production and preserving cellular ability to adapt to stress through antioxidant enzyme induction and translocation of these proteins to the nucleus.

Modulation of temperature-induced tone by vasoconstrictor agents.

One of the primary cardiovascular adjustments to hyperthermia is a sympathetically mediated increase in vascular resistance in the viscera. Nonneural factors such as a change in vascular tone or reactivity may also contribute to this response. Therefore, the aim of this study was to determine whether vascular smooth muscle tone is altered during heating to physiologically relevant temperatures >37 degrees C. Gradually increasing bath temperature from 37 degrees C (normothermia) to 43 degrees C (severe hyperthermia) produced graded contractions in vascular ring segments from rat mesenteric arteries and thoracic aortae. In untreated rings these contractions were relatively small, whereas hyperthermia elicited near-maximal increases in tension when rings were constricted with phenylephrine or KCl before heating. In phenylephrine-treated mesenteric arterial rings, the contractile responses to heating were markedly attenuated by the Ca2+ channel antagonists nifedipine and diltiazem. Diltiazem also blocked the contractile responses to heating in thoracic aortic rings. These results demonstrate that hyperthermia has a limited effect on tension generation in rat vascular smooth muscle in the absence of vascular tone. However, in the presence of agonist-induced tone, tension generation during heating is markedly enhanced and dependent on extracellular Ca2+. In conclusion, these data suggest that local regulation of vascular tone can contribute to the hemodynamic adjustments to hyperthermia.

Correlation integral of blood pressure as a marker for exercise intensities.

The purpose of this study was to test the hypothesis that the correlation integral technique detects altered regulation of cardiovascular function during graded treadmill exercise. Arterial blood pressure (BP) was measured via telemetry before and during graded treadmill exercise in Sprague-Dawley rats. During treadmill running at mild, moderate, and heavy exercise intensities, the slope of the correlation integrals (SCI) continuously increased from 5.45 +/- 0.17 to 7.12 +/- 0.18, 7.92 +/- 0.23, and 8.40 +/- 0.23, respectively. However, corresponding changes in pulse interval, blood pressure, and systolic blood pressure with increasing workload were not consistently observed. Low-frequency, midfrequency, and high-frequency powers of BP were not different between adjacent exercise grades; only the low-frequency component of pulse interval was different between resting state and mild exercise, and BP variance was significantly different between mild and moderate grades. Comparison of the SCI values with those obtained from surrogate data sets suggests that these differences originate mainly from nonlinear components in the cardiovascular control system. These findings support the hypothesis that SCI detects alterations in cardiovascular regulation associated with graded exercise. Furthermore, SCI may be superior to linear techniques in detecting altered regulation with changing exercise intensities.

Effect of heating on the hemodynamic responses to vasoactive agents.

During hyperthermia, vasoconstrictor tone in the viscera is lost despite high levels of sympathetic neural outflow and plasma catecholamines, suggesting that vascular responsiveness to adrenergic receptor stimulation is reduced. The purpose of this study was to determine whether adrenoceptor-mediated control of vascular resistance is altered at high body core temperatures. The hemodynamic responses to adrenoceptor agonists were examined in chloralose-anesthetized rats heated to colonic temperatures (Tco) of 37, 39, and 41.5 degrees C. Elevating Tco to 39 degrees C did not alter the hemodynamic responses to any of these agents. Further heating to 41.5 degrees C markedly attenuated the hemodynamic responses to alpha- and beta-adrenoceptor agonists. Similarly, the regional and systemic hemodynamic responses to ANG II and endothelin were also reduced at 41.5 degrees C. In contrast, the hemodynamic responses to endothelium-dependent and -independent vasodilator agents were unchanged or slightly reduced at 41.5 degrees C. The blunted hemodynamic responses observed at 41.5 degrees C indicate that vascular reactivity to vasoconstrictor agents is reduced with hyperthermia and suggest that this nonspecific change in vascular responsiveness may contribute the circulatory collapse associated with high body temperatures.

Effect of heating on vascular reactivity in rat mesenteric arteries.

Vasoconstriction in the viscera is one of the primary cardiovascular adjustments to heating. Local temperature can influence vascular responsiveness to catecholamines and sympathetic nerve activity. Therefore, we hypothesized that heating would alter vascular reactivity in rat mesenteric arteries. Concentration-response curves to norepinephrine, phenylephrine, potassium chloride (KCl), calcium, acetylcholine, and sodium nitroprusside were obtained in vascular ring segments from rat mesenteric arteries at 37 and 41 degrees C. In some rings, basal tension increased slightly during heating. Heating to 41 degrees C did not alter the contractile responses to norepinephrine in endothelium-intact or -denuded rings but augmented the responses to KCl and calcium in endothelium-intact rings. The potentiating effect of heating on the responses to KCl and calcium was eliminated after endothelium removal. In contrast, the relaxant responses to acetylcholine and sodium nitroprusside were significantly attenuated at 41 degrees C. Collectively, these results demonstrate that heating alters vascular reactivity in rat mesenteric arteries. Furthermore, these data imply that heating reduces the ability of vascular smooth muscle to relax, possibly due to a decrease in sensitivity to nitric oxide.

Frequency response characteristics of sympathetically mediated vasomotor waves in humans.

In a recent study, we demonstrated that transmission from peripheral sympathetic nerves to vascular smooth muscles is strongest in the frequency band from 0.2 to 0.5 Hz in conscious rats. In contrast, sympathetic modulation of vasomotor tone in humans is suggested to be reflected in the power spectrum of arterial blood pressure in a frequency range centered around approximately 0.1 Hz. Therefore, we addressed whether frequency response characteristics of sympathetic transmission from peripheral sympathetic nerves to vascular smooth muscles in humans differ from those in rats. In 12 male subjects, skin-sympathetic fibers of the left median nerve were electrically stimulated via microneurography needles with stimulation frequencies ranging from 0.01 to 0.5 Hz. Simultaneously, blood flow in the innervated skin area at the palm of the ipsilateral hand was recorded by a laser-Doppler device. The skin blood flow in the same area of the contralateral hand was recorded as a control. Median nerve stimulation produced transient decreases in skin blood flow in the ipsilateral hand. At frequencies ranging from 0.025 to 0.10 Hz, median nerve stimulation evoked high-power peaks at the same frequencies in the skin blood flow power spectra of the ipsilateral but not of the contralateral hand. The greatest responses were found in the frequency range from 0.075 to 0.10 Hz. Therefore, these data indicate that the transmission from peripheral sympathetic nerves to cutaneous vascular smooth muscles in humans is slower than in rats. In addition, the frequency range believed to be most important in sympathetic modulation of vasomotor activity in humans corresponds to the frequency band of the greatest response of cutaneous vascular smooth muscle contraction to sympathetic nerve stimulation.

Role of nitrosyl factors in the hemodynamic adjustments to heat stress in the rat.

The present study examined the mechanisms responsible for the hindlimb vasodilation produced by elevating core body (colonic) temperature (Tco) of alpha-chloralose-anesthetized rats from 37 to 39 degrees C. Elevating Tco to 39 degrees C produced equivalent decreases in hindlimb vascular resistance in sham-operated (-48 +/- 2%) and sinoaortic baroreceptor-denervated rats (-44 +/- 3%) rats. There were no changes in mean arterial blood pressure, heart rate, or lumbar sympathetic nerve activity in either group. The prior administration of the alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg i.v.) did not prevent the heat-induced decrease in hindlimb resistance in sham-operated rats (-52 +/- 7% vs. baseline). In contrast, the fall in hindlimb resistance was markedly attenuated (-20 +/- 5% vs. baseline) in sham-operated rats that had received a prior injection of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (100 mumol/kg i.v.). Dexamethasone (1 mg/kg i.v.), administered to prevent the possible induction of inducible NOS, did not modify the heat-induced hindlimb vasodilation in sham-operated rats (-41 +/- 5%). These results demonstrate that the elevation of Tco to 39 degrees C in alpha-chloralose-anesthetized rats produces a relative vasodilation in the hindlimb that is not obviously linked to an alteration in lumbar sympathetic nerve activity. Because the vasodilation occurred in the presence of prazosin, it is unlikely that the decline in resistance is due to the loss of the vasoconstrictor potency of neurally derived catecholamines. The findings that NG-nitro-L-arginine methyl ester, but not dexamethasone, diminished the heat-induced hindlimb vasodilation suggests that the fall in resistance is due in part to constitutive NOS and supports a role for NOS as a mediator of thermoregulatory active vasodilation.

Frequency-response characteristics of autonomic nervous system function in conscious rats.

To characterize the efferent pathway from the hypothalamic paraventricular nucleus (PVN) to peripheral autonomic neurons and finally to selected effector organs, we stimulated the PVN in 10 conscious rats at frequencies ranging from 0.05 to 2.0 Hz. Simultaneously, blood pressure, heart rate, splanchnic sympathetic nerve activity, and mesenteric artery blood flow were measured. The sinus node of the heart responded to PVN stimulation via the parasympathetic pathway (during beta 1-adrenergic blockade) up to a stimulation frequency of 2.0 Hz, whereas the sympathetically mediated response (during muscarinic blockade) was limited to stimulation frequencies < 0.5 Hz. The splanchnic nerve responded to PVN stimulation with synchronous discharges up to stimulation frequencies of 2.0 Hz, whereas the oscillatory component of the vasoconstrictor response of the mesenteric artery was negligible beyond stimulation frequencies of 1.0 Hz. We conclude that sympathetic transmission to the heart is at least four times slower than parasympathetic transmission. In addition, the time-limiting step in sympathetic transmission from the hypothalamus to vascular smooth muscle contraction and pacemaker activity of the sinus node may be located at the site of synaptic transmission to the adrenergic receptors.

Modulation of baroreflex sensitivity and spectral power of blood pressure by heat stress and aging.

To investigate the effects of hyperthermia and aging on baroreceptor-heart rate reflex sensitivity (BRS), cardiovascular parameters were recorded during a progressive rise in core temperature in conscious mature and senescent Fischer 344 rats. BRS was calculated from spontaneous changes in blood pressure and interbeat interval. Low- (LF, 0.01-0.20 Hz) and mid- (MF, 0.2-0.5 Hz) frequency blood pressure power were also determined. In both age groups, hyperthermia caused an increase in blood pressure, renal resistance, and LF but no changes in renal nerve activity, whereas a tachycardia was only observed in the older rats. Increases in BRS (0.80 +/- 0.14 vs. 1.72 +/- 0.34 ms/mmHg, P < 0.05) and MF (3.10 +/- 0.55 vs. 7.81 +/- 1.89 mmHg2, P < 0.05) and a positive correlation between BRS and MF (r = 0.50, P < 0.01) were observed with heating in mature but not senescent rats. These results indicate that LF, which increased with elevated core temperature, may be modulated by thermal stimuli. The augmented BRS in the mature group may contribute to the hemodynamic adjustments that occur with hyperthermia, whereas the lack of an increase in BRS during heat stress in the senescent group suggests that baroreceptor reflex modulation is impaired with aging. The positive correlation between BRS and MF in mature rats, together with the lack of an increase in renal sympathetic nerve activity, indicates that MF may reflect the modulating influence of the efferent sympathetic portion of the baroreceptor reflex loop on arterial blood pressure rather than merely the activity of the peripheral sympathetic nervous system.

Influence of simulated microgravity on the sympathetic response to exercise.

Rats exposed to simulated conditions of microgravity exhibit reductions in aerobic exercise capacity that may be due to an impaired ability of the sympathetic nervous system (SNS) to mediate an increase in cardiac output and to redistribute blood flow. The purpose of this study was to quantify the sympathetic response to exercise in rats after exposure to 14 days of simulated microgravity or control conditions. To achieve this aim, rats were exposed to 14 days of head-down suspension (HDS) or cage control (CC) conditions. On day 14, norepinephrine (NE) synthesis was blocked with alpha-methyl-p-tyrosine, and the rate of NE depletion after synthesis blockade was used to estimate SNS activity in the left ventricle, spleen, and soleus muscle during treadmill exercise at 75% of maximal oxygen uptake. When compared with CC rats, the sympathetic response to exercise in HDS rats was characterized by a lower rate of NE depletion in the left ventricle (-82%) and spleen (-42%). The rate of NE depletion in the soleus muscle was 47% higher. These differences could contribute to the decrement in aerobic capacity of HDS rats by impairing their ability to augment cardiac output and to redirect blood flow to actively contracting skeletal muscle during exercise.

Frequency response characteristic of sympathetic-mediated vasomotor waves in conscious rats.

Power spectrum analysis of arterial blood pressure (BP) and heart rate (HR) has been used to investigate autonomic nervous system activity. Sympathetic-mediated vasomotor tone has been attributed to the BP power at frequencies between 0.05 and 0.15 Hz in humans and dogs and between 0.2 and 0.8 Hz in rats. In contrast, it has been suggested that the sympathetic nervous system is too sluggish to transmit frequencies higher than 0.017 Hz in dogs. Thus we investigated the frequency-response characteristics of the transmission of peripheral sympathetic nerve discharge to peripheral vascular resistance and arterial blood pressure in conscious rats. Eleven rats were instrumented with arterial catheters, nerve electrodes on the sympathetic splanchnic nerve, and flow probes on the superior mesenteric artery. The splanchnic nerve was cut proximal to the electrode to avoid afferent nerve stimulation. The next day the nerve was stimulated at frequencies of 0.05, 0.1, 0.2, 0.5, 1.0, and 2.0 Hz while mesenteric blood flow, BP, and HR were recorded in conscious rats. Mesenteric resistance (MR) was calculated off-line. Nerve stimulation at 0.05, 0.1, 0.2, 0.5, and 1.0 Hz significantly increased the power in MR at these respective frequencies. The greatest response was found between 0.2 and 0.5 Hz. These oscillations in MR were translated to oscillations in BP, but not in HR. Nerve stimulation on the second day, when the nerve was degenerated, did not elicit oscillations in MR or BP. We conclude that the peripheral sympathetic nervous system in rats can transmit signals at frequencies higher than those traditionally assigned to sympathetic vasomotor activity in several species, including humans, and may even overlap with the respiration-related high-frequency range.

Aging is not accompanied by sympathetic hyperresponsiveness to air-jet stress.

It has been postulated that sympathetic nervous system reactivity to acutely applied stress is increased with age. We investigated the autonomic and hemodynamic adjustments to air-jet stress in 9 mature (12-mo-old) and 11 senescent (24-mo-old) Fischer 344 rats. Rats were instrumented with arterial and venous catheters, flow probes around the renal artery, and nerve electrodes on the ipsilateral renal nerve. After the rats recovered from surgery, blood pressure, heart rate, renal blood flow, and renal sympathetic nerve activity were recorded during control conditions and during an 8-min continuous air-jet application. Renal resistance and the low (0.01-0.20 Hz)- and mid-frequency (0.20-0.50 Hz) power of blood pressure were computed off-line. The air jet induced an increase in blood pressure, heart rate, renal resistance, renal nerve activity, and blood pressure power in the low- and mid-frequency ranges in both groups. Blood pressure and low-frequency blood pressure power increased less, and the elevations in renal resistance and renal nerve activity were of shorter duration in senescent compared with mature rats. These data suggest that sympathetic responsiveness to air-jet stress is not enhanced with increasing age.

Cardiovascular and sympathoadrenal responses to heat stress following water deprivation in rats.

This study was designed to characterize the regional and systemic hemodynamic and sympathoadrenal responses to heating after 24 and 48 h of water deprivation in chloralose-anesthetized, male Sprague-Dawley rats (n = 7 per group). Water deprivation produced significant decreases in body weight of 8.1 and 13.7% in the 24- and 48-h groups (P < 0.05), respectively. After water deprivation, rats were exposed to an ambient temperature of 43 degrees C. After correction for body weight differences, heating rates were faster in the 48-h group compared with both euhydrated and 24-h groups. Mean arterial blood pressure (MAP), heart rate, and colonic (Tco) and tail (Ttail) temperatures increased above baseline in all groups during heating. Renal and mesenteric artery blood flow velocities decreased, and vascular resistances increased in response to heating. Compared with euhydrated controls, 48-h water-deprived rats exhibited attenuated pressor (delta MAP = 36 +/- 3 vs. 18 +/- 3 mmHg) and visceral vasoconstrictor (% delta in mesenteric resistance = 122.6 +/- 27.3 vs. 54.9 +/- 6.9%) responses during heating. Tail-skin blood flow estimated from Ttail was also lower at baseline and the onset of heating in water-deprived rats. However, peak Ttail and Tco values were similar across groups. Plasma catecholamines measured in separate groups of rats (n = 6 per group) were significantly higher at baseline and the end of heating in the 48-h group compared with euhydrated and 24-h groups. Despite this exaggerated sympathoadrenal response, the 48-h group exhibited attenuated hemodynamic responses to nonexertional heating compared with euhydrated and 24-h water-deprived rats. These data suggest that cardiovascular and thermoregulatory adjustments can compensate for small changes in hydration state (i.e., 24 h), but more severe levels of hypohydration significantly alter blood pressure and body temperature regulation during heat stress.

Alterations in autonomic adjustments to acute hypoxia in conscious rats with aging.

The experimental objective was to determine whether sympathetic nervous system activity and cardiovascular adjustments to hypoxia are altered with advancing age. Norepinephrine (NE) synthesis was blocked with alpha-methyl-DL-p-tyrosine, and NE turnover rates were determined in the left ventricle of the heart, kidney, liver, and adrenal gland in groups of conscious unrestrained mature (12-mo-old) and senescent (24-mo-old) Fischer 344 rats in conditions of normoxia and acute hypocapnic hypoxia (10% O2-90% N2). Calculated NE turnover rates were similar in all four tissues sampled for both age groups in the normoxic condition. Thirty minutes of hypoxia produced elevations in NE turnover rates in the kidney, liver, and adrenal gland, but not in the heart, for both the mature and senescent groups. However, NE turnover rates were attenuated in the kidney (92 vs. 195%) and liver (119 vs. 190%) of senescent compared with mature rats. Hypoxia produced no change in mean arterial pressure from normoxic levels in the mature rats, whereas older rats had a progressive decline in mean arterial pressure (-24 +/- 3 mmHg from baseline) over the course of the hypoxic exposure. In contrast, heart rate responses were similar in the normoxic and hypoxic conditions for both age groups. These findings indicate that sympathetic nerve activity, as estimated from NE turnover rates, increases in a tissue-specific manner with moderate hypoxia, but this increase is markedly attenuated in the kidney and liver with advancing age. In addition, the ability to maintain MAP during a hypoxic challenge is impaired with aging, perhaps due, in part, to a reduced sympathetic vasoconstriction to selected internal organs.

Differential effects of exercise and heat stress on liver HSP70 accumulation with aging.

Previous reports have suggested that the heat shock response to passive heating may be blunted by aging. However, during exertional heating, factors in addition to elevated temperature may amplify the degree of stress compared with hyperthermia alone. The purpose of this study was to compare the pattern of accumulation of the highly inducible 72-kDa heat shock protein (HSP72) in liver tissue of mature (12-mo-old) and senescent (24-mo-old) male Fischer 344 rats after either passive or exertional heat stress. A euthermic control group was exposed to an ambient temperature (Ta) of 25 degrees C for 4.5 h. A passive heating (heat) group was exposed to an Ta of 42 degrees C until colonic temperature (Tco) reached 41 degrees C. An exertional heating (exercise) group performed intermittent moderate-intensity treadmill exercise (similar absolute intensities for the two age groups) at an Ta of 32 degrees C until Tco reached 41 degrees C. Heating rates were similar in the heat and exercise groups (approximately 0.08 degrees C/min). Rats in both the heat and exercise groups were maintained at a Tco of 41 degrees C for an additional 30 min and subsequently returned to an Ta of 25 degrees C for 3 h. Liver HSP72 accumulation was increased in mature rats after both the heat (+192% vs. control) and exercise (+292%) protocols. In contrast, the senescent rats demonstrated no significant increase in inducible HSP70 with heating but a large increase with exercise (+232%; P < 0.01 compared with control and heat groups). These data suggest that the blunted heat shock protein response to heating observed with aging is not a result of the inability to produce inducible HSP72 because older rats had an robust response to exertional hyperthermia.