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Effect of heat stress on muscle sympathetic nerve activity in humans
Journal of the Autonomic Nervous System 63 Ž1997. 61–67
Effect of heat stress on muscle sympathetic nerve activity in humans Yuki Niimi a
a,b
, Toshiyoshi Matsukawa a , Yoshiki Sugiyama a , A.S.M. Shamsuzzaman a , Hiroki Ito a,b, Gen Sobue b, Tadaaki Mano a,)
Department of Autonomic Neuroscience, DiÕision of Higher NerÕous Control, Research Institute of EnÕironmental Medicine, Nagoya UniÕersity, Nagoya 464-01, Japan b Department of Neurology, Nagoya UniÕersity School of Medicine, Nagoya 466, Japan Received 17 September 1996; revised 15 November 1996; accepted 15 November 1996
Abstract To elucidate the effect of heat stress on the sympathetic nervous system, we evaluated changes in muscle sympathetic nerve activity ŽMSNA., plasma arginine vasopressin ŽAVP., tympanic temperature, skin blood flow, cardiac output, mean blood pressure, and heart rate in 9 subjects in response to acute heat stress induced by raising the ambient temperature from 29 to 348C and then to 408C. With the heat exposure, MSNA was significantly increased with a significant increase in tympanic temperature. Skin blood flow and heart rate were also significantly increased, while mean blood pressure tended to decline and cardiac output tended to increase. The combination of the increased MSNA and skin blood flow may have caused the redistribution of the circulatory blood volume from the muscles to the skin, facilitating convection heat loss. The increases in MSNA counteracted the lowered blood pressure during heat exposure. Thus, the increased MSNA may play an important role both in thermoregulation and in the maintenance of blood pressure against heat stress. Keywords: Heat stress; Muscle sympathetic nerve activity; Skin blood flow; Thermoregulation; Blood pressure
1. Introduction The sympathetic nervous system plays an important role in thermoregulation and blood pressure regulation w2,5,8,13,15,20,22,23 x. When humans are exposed to acute heat stress, skin sympathetic nerve activity, which is composed of vasoconstrictor and sudomotor activities, responds to actively induce heat loss by increasing skin blood flow and sweating w2x. Another vasomotor sympathetic nerve activity leading to the muscles, i.e., muscle sympathetic nerve activity ŽMSNA., is essential for blood pressure regulation by controlling peripheral vascular resistance in the muscles w17,29x. Previous animal studies suggest that heat stress induced decreases in the blood flow to the organs including viscera, kidney and muscle which may be caused by increases in vasoconstrictor sympathetic nerve activity, and that the decreased blood flow in these organs during heat exposure caused the redistribution of blood volume from the body core to the skin, thereby contributing to thermoregulation w5,10,23x. However, in humans, it has not yet been clarified how MSNA responds )
Corresponding author. Tel.: q81 52 7893883; fax: q81 52 7895047.
to heat stress or how MSNA contributes to thermoregulation in relation to blood pressure regulation. The purpose of the present study was to determine the role of MSNA in thermoregulation and blood pressure regulation during acute heat stress.
2. Subjects and methods 2.1. Subjects The subjects were seventeen healthy adults Ž16 men and 1 woman., aged 28 to 37 years. Informed consent was obtained from each subject before the experiment. The study was approved by the Human Research Committee of Research Institute of Environmental Medicine, Nagoya University, and was conducted in accordance with the guidelines of the Japan Microneurography Society. 2.2. Procedure The subjects fasted overnight, from 9.00 p.m. of the previous evening. The experiment was performed in an
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Y. Niimi et al.r Journal of the Autonomic NerÕous System 63 (1997) 61–67
artificial climate chamber. The subject wore only shorts and lay on a bed in the supine position in thermo-neutral conditions with an ambient temperature of 298C and relative humidity of 40%. The right antecubital vein was cannulated for blood sampling. Blood pressure was measured continuously by the tonometry method ŽJENTOW7000, Colin Electronics, Komaki.. The tonometry method is applied to a superficial artery on a bony structure, commonly used the radial artery. An array of 30 piezoresistive pressure transducers with frequency response ) 50 Hz Žflat to 1.0 dB. and hysteresis - 1.0% are embedded in a tonometric sensor. Intra-arterial pressure can be measured by pressure transducers located over the flattened portion of the arterial wall, because circumferential tension in the flattened arterial wall that acts to the transducers is negligible w27x. Heart rate was measured by electrocardiography on the chest, and skin blood flow was recorded on the forearm by laser Doppler flowmetry ŽALF21, Advance, Tokyo.. Cardiac output was measured by impedance plethysmography ŽNCCOM3-R7, BoMed Medical Manufacturing, Irvine, CA.. Tympanic temperature was recorded continuously using thermistor elements with a soft coil spring devised by Masuda and Uchino w18x. Its placement on the tympanic membrane was easy and caused little pain. The external auditory canal was plugged with a piece of absorbent cotton. 2.3. Recording and quantitatiÕe analysis of MSNA MSNA was recorded microneurographically from the tibial nerve at the popliteal fossa. To record the MSNA, a tungsten microelectrode, 100 m m in diameter, with an uninsulated tapered tip of 1–5 m m and an impedance of about 5 M V ŽNo. 26-05-1, Federick Haer, Brunswick, ME. was inserted manually through the skin. Spike potentials were amplified ŽDAM-6A, World Precision Instruments, New Haven, CT. and monitored visually on an oscilloscope Ž5113, Tektronix, Beaverton, OR. and as sounds through a speaker. The amplified neurogram was fed through a bandpass filter ŽE3201A, NF Corporation, Yokohama. with a band width of 500 to 5000 Hz. Next, the filtered neurogram was full-wave rectified and passed through an analogue integrator with a time constant of 0.1 s to obtain the mean voltage neurogram of MSNA w1,17,19,34x. The spikes were identified as corresponding to the MSNA according to the following criteria, defined in previous studies w19,34x: Ž1. tapping or stretching the muscle and tendon supplied by the impaled fascicle of the tibial nerve elicited afferent mechanoreceptor discharge, whereas stroking the skin innervated by the tibial nerve did not; and Ž2. spikes revealed a characteristic pulse-synchronous ‘spontaneous’ discharge during phases II and III of Valsalva’s maneuver. For the quantitative analysis of MSNA, the mean voltage neurogram of MSNA was decoded on a personal
computer. MSNA was quantified as total MSNA by measuring the area of MSNA bursts per min on the mean voltage neurogram, according to the method of our previous study w30x. The maximal amplitude in the mean voltage neurogram during the thermo-neutral condition from each subject was fixed as 1,000 units, and the total MSNA was expressed as units s miny1 at each step. 2.4. Analysis of tympanic temperature, mean blood pressure, heart rate, skin blood flow and cardiac output The tympanic temperature, blood pressure wave, electrocardiogram, skin blood flow and cardiac output were fed into the personal computer, and mean values of the tympanic temperature, mean blood pressure, heart rate, skin blood flow and cardiac output were calculated at each step. 2.5. Determination of plasma leÕels of noradrenaline and arginine Õasopressin, and plasma osmolality To determine the plasma levels of noradrenaline ŽNA., blood samples collected in chilled tubes containing 0.2 mol ascorbic acid and 0.2 mol EDTA–disodium solutions were centrifuged at 6000 rpm for 10 min, and the plasma was separated. The plasma levels of NA were analyzed with a fully automatic catecholamine analyzer ŽHLC-725CA, Toyo Soda, Tokyo., using the diphenylethylenediamine method w21x. This assay was sensitive to 8.5 pg mly1 , with a coefficient of variation of 1.0%. To measure plasma arginine vasopressin ŽAVP., heparinized blood samples were centrifuged at 3000 rpm for 10 min. Samples were extracted on a microcolumn of resin and assayed radioimmunologically, using a highly specific antibody to AVP w11x. This assay was sensitive to 0.15 pg mly1 , with a coefficient of variation of 10%. Plasma osmolality was measured by cryoscopy Ž3Cll Cryomatic TM Multisample Automatic, Advance, Tokyo.. The measurement range of this assay was 0–2000 mosmol kgy1 , and the coefficient of variation was 1%. 2.6. Protocol (Fig. 1) In nine subjects, after more than 60 min of supine rest in the thermo-neutral condition Ž298C, relative humidity 40%., the ambient temperature was set in three steps Ž29, 34, 408C; relative humidity 40% in all steps. and kept for 20 min at each step. We obtained the means of variables at the last 10 min period in each step Žperiod I, period II, period III.. To determine the plasma levels of NA and AVP, and plasma osmolality, blood samples were obtained from the venous cannulae at the last 1 min period in each step. As a control study, the same variables were measured in the thermo-neutral condition for 60 min in the other eight subjects. We also obtained the means of variables at
Y. Niimi et al.r Journal of the Autonomic NerÕous System 63 (1997) 61–67
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Fig. 1. Protocol of studies.
a period of 10–20 min Žperiod IX ., 30–40 min Žperiod IIX ., or 50–60 min Žperiod IIIX ..
2.7. Statistics Data are expressed as means " SE. Differences in means were assessed by ANOVA with Students t-test, and were considered to be significant when P values were less than 0.05.
3. Results Tympanic temperature rose significantly with the ambient temperature elevation to 34 and 408C Ž P - 0.05. ŽFig. 2.. With the ambient temperature increase, MSNA tended to increase at 348C Ž P s 0.14., and increased significantly at 408C Ž P - 0.05. ŽFig. 3.. Fig. 4 shows changes in skin blood flow and heart rate, and Fig. 5 shows cardiac output and mean blood pressure during acute heat exposure. Skin blood flow increased significantly with the elevated ambi-
Fig. 2. Changes in tympanic temperature during acute heat exposure from 29 to 348C and 408C. The tympanic temperature: period I, 36.94 " 0.088C; X X X period II, 37.00 " 0.098C; period III, 37.13 " 0.09, and period I , 36.81 " 0.048C; period II , 36.74 " 0.048C; period III , 36.78 " 0.038C. ) P - 0.05 X X X Ž . versus control group period I versus I , period II versus II , or period III versus III .
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Fig. 3. Changes in MSNA during acute heat exposure from 29 to 348C and 408C. MSNA: period I, 4576 " 978 units s miny1 ; period II, 6704 " 1542 units X X X s miny1 ; period III, 7664 " 1502 units s miny1 , and period I , 3305 " 963 units s miny1 ; period II , 3822 " 1646 units s miny1 ; period III , 3564 " 1458 X X X y1 ) Ž . units s min . P - 0.05 versus control group period I versus I , period II versus II , or period III versus III .
Fig. 4. Changes in skin blood flow and heart rate during acute heat exposure from 29 to 348C and 408C. Skin blood flow: period I, 2.57 " 0.37 ml miny1 X X 100 gy1 ; period II, 3.48 " 0.58 ml miny1 100 gy1 ; period III, 6.76 " 1.28 ml miny1 100 gy1 , and period I , 3.80 " 0.57 ml miny1 100 gy1 ; period II , X y1 y1 y1 y1 y1 3.68 " 0.55 ml min 100 g ; period III , 3.65 " 0.60 ml min 100 g . Heart rate: period I 65.6 " 2.7 beats min ; period II, 65.6 " 3.1 beats X X X miny1 ; period III, 69.4 " 3.6 beats miny1 , and period I , 63.6 " 3.3 beats miny1 ; period II , 67.8 " 3.1 beats min -1 ; period III , 68.3 " 3.4 beats miny1 . X X X ) Ž . P - 0.05 versus control group period I versus I , period II versus II , or period III versus III .
Y. Niimi et al.r Journal of the Autonomic NerÕous System 63 (1997) 61–67
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Fig. 5. Changes in cardiac output and mean blood pressure during acute heat exposure from 29 to 348C and 408C. Cardiac output: period I, 4.99 " 0.59 l X X X miny1 ; period II, 5.33 " 0.67 l miny1 ; period III, 5.45 " 0.66 l miny1 , and period I , 5.30 " 0.39 l miny1 ; period II , 5.34 " 0.41 l miny1 ; period III , 5.34 " 0.42 ml miny1 100 gy1 . Mean blood pressure: period I, 91.8 " 4.9 mmHg; period II, 87.3 " 4.6 mmHg; period III, 86.5 " 5.3 mmHg, and period X X X X X I , 95.4 " 5.8 mmHg; period II , 95.9 " 4.2 mmHg; period III , 96.0 " 4.2 mmHg. ) P - 0.05 versus control group Žperiod I versus I , period II versus II , X or period III versus III ..
ent temperature and was significantly greater at 34 and 408C than at 298C. The heart rate rose with the ambient temperature increase, and at 408C was significantly higher than that at 298C. Cardiac output tended to increase with the ambient temperature at 408C Ž P s 0.12., but not to a significant extent. Mean blood pressure had a tendency to decline at 348 Ž P s 0.18. and at 408C Ž P s 0.09., but not to a significant extent. NA increased significantly with the ambient temperature at 34 and 408C ŽTable 1.. AVP increased significantly at 408C, while plasma osmolality was not change significantly at either 34 or 408C ŽTable 1.. In our previous study, we observed no significant changes in NA and AVP in the thermo-neutral condition for 60 min w31x. During the 60 min control study in the thermoneutral Table 1 Changes of plasma noradrenaline, arginine vasopressin and plasma osmolality at period I, period II and period III Period I Ž298C. Noradrenaline Žpg mly1 .
140
"31
Period II Ž348C. 155
"32
Period III Ž408C. )
161
"32
)
Arginine vasopressin 1.26" 0.17 1.40" 0.29 1.61" 0.19 Žpg mly1 . Plasma osmolality 282 " 1 281 " 1 282 " 1 Žmosmol kgy1 . Data are expressed as mean"SE. ) P - 0.05 versus period I.
condition, no variables changed significantly ŽFigs. 2–5.. There were significant differences between the heat exposure study group and the control study group in tympanic temperature, MSNA and skin blood flow, but not in heart rate, cardiac output and mean blood pressure ŽFigs. 2–5..
4. Discussion In the present study, we directly measured the sympathetic nerve activity in humans and examined the effect of acute heat stress on it. There were several key observations. Acute heat stress induced increases in MSNA with rises in tympanic temperature, and produced increases in skin blood flow and heart rate. The plasma levels of NA and AVP were also increased by acute heat stress without plasma osmolality change. The cardiac output tended to increase and mean blood pressure tended to decline by acute heat stress. Cardiovascular and sympathocirculatory responses to acute heat stress have been described in earlier studies w12,16,23–26x. When animals were exposed to a hot air environment, skin vasoconstrictor activity was decreased, resulting in a marked increase of skin blood flow, while the blood flow to the organs such as viscera, kidney and muscle was reduced w5,10,23x. The increase of skin blood flow facilitates convection heat loss from the skin. The skin circulation modifies the extent of heat transfer from
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the deep tissues to the surface. The increased skin blood flow and the decreased blood flow in viscera and muscle cause the redistribution of blood flow from the body core to the skin. This redistribution favors heat loss from the viewpoint of countercurrent heat exchange w23x. In the present study, we observed increases in skin blood flow with MSNA increasing during acute heat exposure in humans. Thus, the increases in MSNA in response to acute heat stress may reduce muscular blood flow neurally and cause the redistribution of the circulatory blood flow from the muscles to the skin, contributing to heat loss. The present observation that cardiac output showed a tendency to rise with the increase in heart rate during heat exposure is consistent with earlier studies w12,23–25x. The increase in cardiac output during heat exposure may contribute in part to the increase in skin blood flow w3x. It is empirically well known that syncope or fainting is induced in hot environments such as the summer season or a hot bath w9,33x. Excessive vasodilatation in the skin may lead to syncope during heat exposure. The dilatation of the skin blood vessels may cause the reduction of the peripheral vascular resistance, resulting in lowered blood pressure w9,23x. Increased MSNA in response to heat stress may play another important role in the maintenance of the total peripheral resistance, resulting in blood pressure regulation w29x. The mechanisms of increasing MSNA in response to acute heat stress are unknown, but several possible explanations can be offered as follows. One may be a baroreflex mechanism; in the present study, we observed a trend towards a decline in mean blood pressure by heat stress. During the heat exposure, mean blood pressure was reported to decrease mildly because of the reduction of the peripheral vascular resistance due to dilatation of the skin blood vessels w9,23x. During the heat exposure, central venous pressure is reported to decrease with slight or mild decrease in mean blood pressure in humans w2,6,24x. These findings suggest that heat exposure induces an unloading of cardiopulmonary and arterial baroreceptors. We also observed an increase in AVP without plasma osmolality change during heat exposure, in agreement with earlier studies w23,28x. Not only NA but also the secretion of AVP are well known to be enhanced by unloading of the baroreceptors in humans w4,28,32x. Thus, the increases in MSNA with NA and AVP increases observed during the heat exposure may be due in part to the unloading of the baroreceptors. Another possibility for the mechanism of increasing MSNA is a primary response to acute heat stress via the thermoregulatory center. The possibility of elevated sympathetic outflow due primarily to heat stress has been described in earlier animal studies w7,15,20,22x. Alphaadrenergic receptor blockade in hyperthermic baboons eliminated the elevation in mesenteric vascular resistance w22x, and celiac ganglionectomy in the rat abolished the rise in mesenteric resistance, reducing thermal tolerance
w14x. Gisolfi et al. w7x quantitated splanchnic sympathetic nerve activity while monitoring core temperature and mean blood pressure during heat exposure in rats, and found that sympathetic nerve activity rose and core temperature increased significantly, suggesting that the rise in core temperature elevates the sympathetic nerve activity by stimulating deep body thermoreceptors w20x. We found in the present study that in heat-stressed humans, MSNA increased significantly with rising tympanic temperature, which reflects core temperature. These findings suggest that the primary response to acute heat stress via the thermoregulatory center may cause increases in sympathetic outflow to muscle and viscera, resulting in the rise in vascular resistance. In conclusion, MSNA increased with an increase of core temperature in response to acute heat stress, possibly via thermoregulatory and baroreflex mechanisms. MSNA may play an important role in the homeostatic regulation of body temperature and blood pressure against heat stress.
Acknowledgements We thank Dr. Yasuo Koike and Dr. Junichi Sugenoya for their comments on this manuscript, and Ms. Hatsue Suzuki for her technical support.
References w1x Anderson, E.A., Christine, A.S., Lawton, W.J. and Mark, A.L., Elevated sympathetic nerve activity in borderline hypertensive humans, Hypertension, 14 Ž1989. 177–183. w2x Collins, K.J., The autonomic nervous system and the regulation of body temperature. In R. Bannistter ŽEd.., Autonomic Failure. Oxford University Press, London, 1992, pp. 212–230. w3x Detry, J.R., Brengelmann, G.L., Rowell, L.R. and Wyss, G., Skin and muscle components of forearm blood flow in directly heated resting man, J. Appl. Physiol., 32 Ž1972. 506–511. w4x Egan, B., Grekin, R., Ibsen, H. and Osterziel, K., Role of cardiopulmonary mechanoreceptors in ADH release in normal humans, Hypertension, 6 Ž1984. 832–836. w5x Eisman, M.M. and Rowell, L.B., Renal vascular response to heat stress in baboons-role of renin-angiotensin, J. Appl. Physiol., 43 Ž1977. 739–746. w6x Escourrou, P., Freund, P.R., Rowell, L.B. and Johnson, D.G., Splanchnic vasoconstriction in heat-stressed men: Role of reninangiotensin system, J. Appl. Physiol., 52 Ž1982. 1438–1443. w7x Gisolfi, C.V., Matthers, R.D., Kregel, K.C. and Oppliger, R., Splanchnic sympathetic nerve activity and circulating catecholamines in the hyperthermic rat, J. Appl. Physiol., 70 Ž1991. 1821– 1826. w8x Gorman, A.J. and Proppe, D.W., Influence of heat stress on arterial baroreflex control of heart rate in the Baboon, Circ. Res., 51 Ž1982. 73–82. w9x Hainsworth, R., Syncope and fainting. In R. Bannistter ŽEd.., Autonomic Failure. Oxford University Press, London, 1992, pp. 766–767. w10x Hales, J.R.S., Rowell, L.B. and King, R.B., Regional distribution of blood flow in awake heat-stressed baboons, Am. J. Physiol., 237 Ž1979. H705–H712. w11x Kimura, T., Matsui, K., Ota, K. and Yoshinaga, K., Radioim-
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Shepherd, F.M. Abboud and S.R. Geiger ŽEds.., Handbook of Physiology: The Cardiovascular System, Vol. 3. American Physiological Society, Maryland, 1983, pp. 967–1023. Rowell, L.B., Brengelmann, G.L. and Murray, J.A., Cardiovascular responses to sustained high skin temperature in resting man, J. Appl. Physiol., 27 Ž1969. 673–680. Rowell, L.B., Brengelmann, G.L. and Blackmon, J.R., Redistribution of blood flow during sustained high skin temperature in resting man, J. Appl. Physiol., 28 Ž1970. 415–420. Rowell, L.B., Detry, J.R., Profant, G.D. and Wyss, G. Splanchnic vasoconstriction in hyperthermic man – Role of falling blood pressure, J. Appl. Physiol., 31 Ž1971. 864–869. Sato, T., Nishinaga, M., Kawamoto, A., Ozawa, T., and Takatsuji, H., Accuracy of continuous blood pressure monitor based on arterial tonometry, Hypertension, 21 Ž1993. 866–874. Segar, W.E. and Moore, W.W., The regulation of Antidiuretic Hormone Release in Man. I. Effects of change in position and ambient temperature on blood ADH levels, J. Clin. Invest., 47 Ž1968. 2143–2151. Shepherd, R.F.J. and Shepherd J.T., Control of blood pressure and the circulation in man. In R. Bannistter ŽEd.., Autonomic Failure. Oxford University Press, London, 1992, pp. 78–93. Sugiyama, Y., Matsukawa, T., Shamsuzzaman, A.S.M., Okada, H., Watanabe, T. and Mano, T., Delayed and diminished pressor response to muscle sympathetic nerve activity in the elderly, J. Appl. Physiol., 80 Ž1996. 869–875. Takeuchi, Y., Matsukawa, T., Sugiyama, Y., Iwase, S. and Mano, T., Effect of metoclopramide on muscle sympathetic nerve activity in humans, J. Auton. Nerv. Syst., 58 Ž1996. 115–120. Thrasher, T.N., Baroreceptor regulation of vasopressin and renin secretion: Low-pressure versus high-pressure receptors, Frontiers Neuroendocrinol., 15 Ž1994. 157–196. Vuori, I., Sauna bather’s circulation, Ann. Clin. Res., 20 Ž1988. 249–256. Wallin, B.G., Intraneural recording and autonomic function in man. In R. Bannister ŽEd.., Autonomic Failure. Oxford University Press, London, 1983, pp. 36–51.
Effect of heat stress on muscle sympathetic nerve activity in humans Yuki Niimi a
a,b
, Toshiyoshi Matsukawa a , Yoshiki Sugiyama a , A.S.M. Shamsuzzaman a , Hiroki Ito a,b, Gen Sobue b, Tadaaki Mano a,)
Department of Autonomic Neuroscience, DiÕision of Higher NerÕous Control, Research Institute of EnÕironmental Medicine, Nagoya UniÕersity, Nagoya 464-01, Japan b Department of Neurology, Nagoya UniÕersity School of Medicine, Nagoya 466, Japan Received 17 September 1996; revised 15 November 1996; accepted 15 November 1996
Abstract To elucidate the effect of heat stress on the sympathetic nervous system, we evaluated changes in muscle sympathetic nerve activity ŽMSNA., plasma arginine vasopressin ŽAVP., tympanic temperature, skin blood flow, cardiac output, mean blood pressure, and heart rate in 9 subjects in response to acute heat stress induced by raising the ambient temperature from 29 to 348C and then to 408C. With the heat exposure, MSNA was significantly increased with a significant increase in tympanic temperature. Skin blood flow and heart rate were also significantly increased, while mean blood pressure tended to decline and cardiac output tended to increase. The combination of the increased MSNA and skin blood flow may have caused the redistribution of the circulatory blood volume from the muscles to the skin, facilitating convection heat loss. The increases in MSNA counteracted the lowered blood pressure during heat exposure. Thus, the increased MSNA may play an important role both in thermoregulation and in the maintenance of blood pressure against heat stress. Keywords: Heat stress; Muscle sympathetic nerve activity; Skin blood flow; Thermoregulation; Blood pressure
1. Introduction The sympathetic nervous system plays an important role in thermoregulation and blood pressure regulation w2,5,8,13,15,20,22,23 x. When humans are exposed to acute heat stress, skin sympathetic nerve activity, which is composed of vasoconstrictor and sudomotor activities, responds to actively induce heat loss by increasing skin blood flow and sweating w2x. Another vasomotor sympathetic nerve activity leading to the muscles, i.e., muscle sympathetic nerve activity ŽMSNA., is essential for blood pressure regulation by controlling peripheral vascular resistance in the muscles w17,29x. Previous animal studies suggest that heat stress induced decreases in the blood flow to the organs including viscera, kidney and muscle which may be caused by increases in vasoconstrictor sympathetic nerve activity, and that the decreased blood flow in these organs during heat exposure caused the redistribution of blood volume from the body core to the skin, thereby contributing to thermoregulation w5,10,23x. However, in humans, it has not yet been clarified how MSNA responds )
Corresponding author. Tel.: q81 52 7893883; fax: q81 52 7895047.
to heat stress or how MSNA contributes to thermoregulation in relation to blood pressure regulation. The purpose of the present study was to determine the role of MSNA in thermoregulation and blood pressure regulation during acute heat stress.
2. Subjects and methods 2.1. Subjects The subjects were seventeen healthy adults Ž16 men and 1 woman., aged 28 to 37 years. Informed consent was obtained from each subject before the experiment. The study was approved by the Human Research Committee of Research Institute of Environmental Medicine, Nagoya University, and was conducted in accordance with the guidelines of the Japan Microneurography Society. 2.2. Procedure The subjects fasted overnight, from 9.00 p.m. of the previous evening. The experiment was performed in an
0165-1838r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved. PII S 0 1 6 5 - 1 8 3 8 Ž 9 6 . 0 0 1 3 4 - 8
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artificial climate chamber. The subject wore only shorts and lay on a bed in the supine position in thermo-neutral conditions with an ambient temperature of 298C and relative humidity of 40%. The right antecubital vein was cannulated for blood sampling. Blood pressure was measured continuously by the tonometry method ŽJENTOW7000, Colin Electronics, Komaki.. The tonometry method is applied to a superficial artery on a bony structure, commonly used the radial artery. An array of 30 piezoresistive pressure transducers with frequency response ) 50 Hz Žflat to 1.0 dB. and hysteresis - 1.0% are embedded in a tonometric sensor. Intra-arterial pressure can be measured by pressure transducers located over the flattened portion of the arterial wall, because circumferential tension in the flattened arterial wall that acts to the transducers is negligible w27x. Heart rate was measured by electrocardiography on the chest, and skin blood flow was recorded on the forearm by laser Doppler flowmetry ŽALF21, Advance, Tokyo.. Cardiac output was measured by impedance plethysmography ŽNCCOM3-R7, BoMed Medical Manufacturing, Irvine, CA.. Tympanic temperature was recorded continuously using thermistor elements with a soft coil spring devised by Masuda and Uchino w18x. Its placement on the tympanic membrane was easy and caused little pain. The external auditory canal was plugged with a piece of absorbent cotton. 2.3. Recording and quantitatiÕe analysis of MSNA MSNA was recorded microneurographically from the tibial nerve at the popliteal fossa. To record the MSNA, a tungsten microelectrode, 100 m m in diameter, with an uninsulated tapered tip of 1–5 m m and an impedance of about 5 M V ŽNo. 26-05-1, Federick Haer, Brunswick, ME. was inserted manually through the skin. Spike potentials were amplified ŽDAM-6A, World Precision Instruments, New Haven, CT. and monitored visually on an oscilloscope Ž5113, Tektronix, Beaverton, OR. and as sounds through a speaker. The amplified neurogram was fed through a bandpass filter ŽE3201A, NF Corporation, Yokohama. with a band width of 500 to 5000 Hz. Next, the filtered neurogram was full-wave rectified and passed through an analogue integrator with a time constant of 0.1 s to obtain the mean voltage neurogram of MSNA w1,17,19,34x. The spikes were identified as corresponding to the MSNA according to the following criteria, defined in previous studies w19,34x: Ž1. tapping or stretching the muscle and tendon supplied by the impaled fascicle of the tibial nerve elicited afferent mechanoreceptor discharge, whereas stroking the skin innervated by the tibial nerve did not; and Ž2. spikes revealed a characteristic pulse-synchronous ‘spontaneous’ discharge during phases II and III of Valsalva’s maneuver. For the quantitative analysis of MSNA, the mean voltage neurogram of MSNA was decoded on a personal
computer. MSNA was quantified as total MSNA by measuring the area of MSNA bursts per min on the mean voltage neurogram, according to the method of our previous study w30x. The maximal amplitude in the mean voltage neurogram during the thermo-neutral condition from each subject was fixed as 1,000 units, and the total MSNA was expressed as units s miny1 at each step. 2.4. Analysis of tympanic temperature, mean blood pressure, heart rate, skin blood flow and cardiac output The tympanic temperature, blood pressure wave, electrocardiogram, skin blood flow and cardiac output were fed into the personal computer, and mean values of the tympanic temperature, mean blood pressure, heart rate, skin blood flow and cardiac output were calculated at each step. 2.5. Determination of plasma leÕels of noradrenaline and arginine Õasopressin, and plasma osmolality To determine the plasma levels of noradrenaline ŽNA., blood samples collected in chilled tubes containing 0.2 mol ascorbic acid and 0.2 mol EDTA–disodium solutions were centrifuged at 6000 rpm for 10 min, and the plasma was separated. The plasma levels of NA were analyzed with a fully automatic catecholamine analyzer ŽHLC-725CA, Toyo Soda, Tokyo., using the diphenylethylenediamine method w21x. This assay was sensitive to 8.5 pg mly1 , with a coefficient of variation of 1.0%. To measure plasma arginine vasopressin ŽAVP., heparinized blood samples were centrifuged at 3000 rpm for 10 min. Samples were extracted on a microcolumn of resin and assayed radioimmunologically, using a highly specific antibody to AVP w11x. This assay was sensitive to 0.15 pg mly1 , with a coefficient of variation of 10%. Plasma osmolality was measured by cryoscopy Ž3Cll Cryomatic TM Multisample Automatic, Advance, Tokyo.. The measurement range of this assay was 0–2000 mosmol kgy1 , and the coefficient of variation was 1%. 2.6. Protocol (Fig. 1) In nine subjects, after more than 60 min of supine rest in the thermo-neutral condition Ž298C, relative humidity 40%., the ambient temperature was set in three steps Ž29, 34, 408C; relative humidity 40% in all steps. and kept for 20 min at each step. We obtained the means of variables at the last 10 min period in each step Žperiod I, period II, period III.. To determine the plasma levels of NA and AVP, and plasma osmolality, blood samples were obtained from the venous cannulae at the last 1 min period in each step. As a control study, the same variables were measured in the thermo-neutral condition for 60 min in the other eight subjects. We also obtained the means of variables at
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63
Fig. 1. Protocol of studies.
a period of 10–20 min Žperiod IX ., 30–40 min Žperiod IIX ., or 50–60 min Žperiod IIIX ..
2.7. Statistics Data are expressed as means " SE. Differences in means were assessed by ANOVA with Students t-test, and were considered to be significant when P values were less than 0.05.
3. Results Tympanic temperature rose significantly with the ambient temperature elevation to 34 and 408C Ž P - 0.05. ŽFig. 2.. With the ambient temperature increase, MSNA tended to increase at 348C Ž P s 0.14., and increased significantly at 408C Ž P - 0.05. ŽFig. 3.. Fig. 4 shows changes in skin blood flow and heart rate, and Fig. 5 shows cardiac output and mean blood pressure during acute heat exposure. Skin blood flow increased significantly with the elevated ambi-
Fig. 2. Changes in tympanic temperature during acute heat exposure from 29 to 348C and 408C. The tympanic temperature: period I, 36.94 " 0.088C; X X X period II, 37.00 " 0.098C; period III, 37.13 " 0.09, and period I , 36.81 " 0.048C; period II , 36.74 " 0.048C; period III , 36.78 " 0.038C. ) P - 0.05 X X X Ž . versus control group period I versus I , period II versus II , or period III versus III .
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Fig. 3. Changes in MSNA during acute heat exposure from 29 to 348C and 408C. MSNA: period I, 4576 " 978 units s miny1 ; period II, 6704 " 1542 units X X X s miny1 ; period III, 7664 " 1502 units s miny1 , and period I , 3305 " 963 units s miny1 ; period II , 3822 " 1646 units s miny1 ; period III , 3564 " 1458 X X X y1 ) Ž . units s min . P - 0.05 versus control group period I versus I , period II versus II , or period III versus III .
Fig. 4. Changes in skin blood flow and heart rate during acute heat exposure from 29 to 348C and 408C. Skin blood flow: period I, 2.57 " 0.37 ml miny1 X X 100 gy1 ; period II, 3.48 " 0.58 ml miny1 100 gy1 ; period III, 6.76 " 1.28 ml miny1 100 gy1 , and period I , 3.80 " 0.57 ml miny1 100 gy1 ; period II , X y1 y1 y1 y1 y1 3.68 " 0.55 ml min 100 g ; period III , 3.65 " 0.60 ml min 100 g . Heart rate: period I 65.6 " 2.7 beats min ; period II, 65.6 " 3.1 beats X X X miny1 ; period III, 69.4 " 3.6 beats miny1 , and period I , 63.6 " 3.3 beats miny1 ; period II , 67.8 " 3.1 beats min -1 ; period III , 68.3 " 3.4 beats miny1 . X X X ) Ž . P - 0.05 versus control group period I versus I , period II versus II , or period III versus III .
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65
Fig. 5. Changes in cardiac output and mean blood pressure during acute heat exposure from 29 to 348C and 408C. Cardiac output: period I, 4.99 " 0.59 l X X X miny1 ; period II, 5.33 " 0.67 l miny1 ; period III, 5.45 " 0.66 l miny1 , and period I , 5.30 " 0.39 l miny1 ; period II , 5.34 " 0.41 l miny1 ; period III , 5.34 " 0.42 ml miny1 100 gy1 . Mean blood pressure: period I, 91.8 " 4.9 mmHg; period II, 87.3 " 4.6 mmHg; period III, 86.5 " 5.3 mmHg, and period X X X X X I , 95.4 " 5.8 mmHg; period II , 95.9 " 4.2 mmHg; period III , 96.0 " 4.2 mmHg. ) P - 0.05 versus control group Žperiod I versus I , period II versus II , X or period III versus III ..
ent temperature and was significantly greater at 34 and 408C than at 298C. The heart rate rose with the ambient temperature increase, and at 408C was significantly higher than that at 298C. Cardiac output tended to increase with the ambient temperature at 408C Ž P s 0.12., but not to a significant extent. Mean blood pressure had a tendency to decline at 348 Ž P s 0.18. and at 408C Ž P s 0.09., but not to a significant extent. NA increased significantly with the ambient temperature at 34 and 408C ŽTable 1.. AVP increased significantly at 408C, while plasma osmolality was not change significantly at either 34 or 408C ŽTable 1.. In our previous study, we observed no significant changes in NA and AVP in the thermo-neutral condition for 60 min w31x. During the 60 min control study in the thermoneutral Table 1 Changes of plasma noradrenaline, arginine vasopressin and plasma osmolality at period I, period II and period III Period I Ž298C. Noradrenaline Žpg mly1 .
140
"31
Period II Ž348C. 155
"32
Period III Ž408C. )
161
"32
)
Arginine vasopressin 1.26" 0.17 1.40" 0.29 1.61" 0.19 Žpg mly1 . Plasma osmolality 282 " 1 281 " 1 282 " 1 Žmosmol kgy1 . Data are expressed as mean"SE. ) P - 0.05 versus period I.
condition, no variables changed significantly ŽFigs. 2–5.. There were significant differences between the heat exposure study group and the control study group in tympanic temperature, MSNA and skin blood flow, but not in heart rate, cardiac output and mean blood pressure ŽFigs. 2–5..
4. Discussion In the present study, we directly measured the sympathetic nerve activity in humans and examined the effect of acute heat stress on it. There were several key observations. Acute heat stress induced increases in MSNA with rises in tympanic temperature, and produced increases in skin blood flow and heart rate. The plasma levels of NA and AVP were also increased by acute heat stress without plasma osmolality change. The cardiac output tended to increase and mean blood pressure tended to decline by acute heat stress. Cardiovascular and sympathocirculatory responses to acute heat stress have been described in earlier studies w12,16,23–26x. When animals were exposed to a hot air environment, skin vasoconstrictor activity was decreased, resulting in a marked increase of skin blood flow, while the blood flow to the organs such as viscera, kidney and muscle was reduced w5,10,23x. The increase of skin blood flow facilitates convection heat loss from the skin. The skin circulation modifies the extent of heat transfer from
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the deep tissues to the surface. The increased skin blood flow and the decreased blood flow in viscera and muscle cause the redistribution of blood flow from the body core to the skin. This redistribution favors heat loss from the viewpoint of countercurrent heat exchange w23x. In the present study, we observed increases in skin blood flow with MSNA increasing during acute heat exposure in humans. Thus, the increases in MSNA in response to acute heat stress may reduce muscular blood flow neurally and cause the redistribution of the circulatory blood flow from the muscles to the skin, contributing to heat loss. The present observation that cardiac output showed a tendency to rise with the increase in heart rate during heat exposure is consistent with earlier studies w12,23–25x. The increase in cardiac output during heat exposure may contribute in part to the increase in skin blood flow w3x. It is empirically well known that syncope or fainting is induced in hot environments such as the summer season or a hot bath w9,33x. Excessive vasodilatation in the skin may lead to syncope during heat exposure. The dilatation of the skin blood vessels may cause the reduction of the peripheral vascular resistance, resulting in lowered blood pressure w9,23x. Increased MSNA in response to heat stress may play another important role in the maintenance of the total peripheral resistance, resulting in blood pressure regulation w29x. The mechanisms of increasing MSNA in response to acute heat stress are unknown, but several possible explanations can be offered as follows. One may be a baroreflex mechanism; in the present study, we observed a trend towards a decline in mean blood pressure by heat stress. During the heat exposure, mean blood pressure was reported to decrease mildly because of the reduction of the peripheral vascular resistance due to dilatation of the skin blood vessels w9,23x. During the heat exposure, central venous pressure is reported to decrease with slight or mild decrease in mean blood pressure in humans w2,6,24x. These findings suggest that heat exposure induces an unloading of cardiopulmonary and arterial baroreceptors. We also observed an increase in AVP without plasma osmolality change during heat exposure, in agreement with earlier studies w23,28x. Not only NA but also the secretion of AVP are well known to be enhanced by unloading of the baroreceptors in humans w4,28,32x. Thus, the increases in MSNA with NA and AVP increases observed during the heat exposure may be due in part to the unloading of the baroreceptors. Another possibility for the mechanism of increasing MSNA is a primary response to acute heat stress via the thermoregulatory center. The possibility of elevated sympathetic outflow due primarily to heat stress has been described in earlier animal studies w7,15,20,22x. Alphaadrenergic receptor blockade in hyperthermic baboons eliminated the elevation in mesenteric vascular resistance w22x, and celiac ganglionectomy in the rat abolished the rise in mesenteric resistance, reducing thermal tolerance
w14x. Gisolfi et al. w7x quantitated splanchnic sympathetic nerve activity while monitoring core temperature and mean blood pressure during heat exposure in rats, and found that sympathetic nerve activity rose and core temperature increased significantly, suggesting that the rise in core temperature elevates the sympathetic nerve activity by stimulating deep body thermoreceptors w20x. We found in the present study that in heat-stressed humans, MSNA increased significantly with rising tympanic temperature, which reflects core temperature. These findings suggest that the primary response to acute heat stress via the thermoregulatory center may cause increases in sympathetic outflow to muscle and viscera, resulting in the rise in vascular resistance. In conclusion, MSNA increased with an increase of core temperature in response to acute heat stress, possibly via thermoregulatory and baroreflex mechanisms. MSNA may play an important role in the homeostatic regulation of body temperature and blood pressure against heat stress.
Acknowledgements We thank Dr. Yasuo Koike and Dr. Junichi Sugenoya for their comments on this manuscript, and Ms. Hatsue Suzuki for her technical support.
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