00s1-9;2x/92/i503-0~5050D.00/0 Journal of Cbnical Endocrinology and Metabolism Copyright C 1992 by The Endocrine Society
Vol. 75, No. :3 Prmted I” USA
Vasopressin, Corticotrophin-Releasing Pituitary Adrenal Responses to Acute Normal Humans* G. A. WITTERT, H. K. OR, J. H. LIVESEY, AND E. A. ESPINER Department
of Endocrinology,
The Princess
Margaret
A. M. RICHARDS, Hospital,
Christchurch,
Factor, and Cold Stress in
R. A. DONALD, New Zealand
level (P = O.OOOl), but no change in plasma epinephrine or in plasma ANF. Plasma AVP levels fell significantly (P < 0.01) to reach a nadir at 5-10 min after cold exposure before returning to baseline levels. A significant fall in plasma cortisol levels occurred during the first 15 min of the baseline period and remained stable thereafter. No significant changes in plasma corticotrophin-releasing factor or ACTH occurred. These results suggest that cold inhibition of AVP release, presumably via afferent baroreceptor pathways, may act to reduce the response of the corticotrophs to a potentially noxious stimulus. Inhibition of AVP and/or ACTH during acute cold exposure are not dependent upon an increase in plasma ANF. (J Clin Endocrinol Metub 75: 750-755, 1992)
ABSTRACT Acute cold stress is a consistent stimulus to ACTH secretion in rats yet inhibits arginine vasopressin (AVP) in both rats and humans. We have studied the interrelationships of AVP, corticotrophin-releasing factor, and atria1 natriuretic factor (ANF) in the hypothalamo-pituitary-adrenal response to acute cold stress in normal humans. Six healthy male volunteers deprived of food and fluid for 6 h, and minimally clothed, were studied in the early afternoon. After a 30.min period at 22 C, subjects were exposed to cold stress (4 C for 30 min), followed by a 30-min equilibration period at 22 C. By the end of the period of cold exposure there was a fall in plasma volume of 7.8 f 1.4% (mean + SEM), a significant increase in both systolic blood pressure (P = 0.0001) and in plasma norepinephrine
I
T IS generally accepted that both corticotrophin-releasing factor (CRF) (1) and arginine vasopressin (AVP) (2) are physiologically important factors regulating stress induced ACTH secretion. However, the relative importance of these ACTH secretagogues in the stress response varies in different species as well as with the type of stressor employed (3-8). Whereas acute cold exposure in conscious rats is a reproducible stimulus to the hypothalamo-pituitary adrenal (HPA) axis (9-ll), the HPA response of humans to cold exposure is less consistent (12-18). However, acute cold exposure in man and animals inhibits AVP secretion (19-22). Since increases in peripheral blood AVP appear to be a consistent finding during acute stress-induced ACTH secretion in humans (6-&J), it is possible that the pattern or degree of HPA response to cold stress in humans differs from that observed with other stressors. Further, cold exposure in humans increases blood pressure and sympathetic nervous activity (12, 14-17, 23) and in rats is reported to increase peripheral levels of atria1 natriuretic factor (ANF) (24). There is evidence that ANF may inhibit AVP (25) and/or ACTH (26) secretion. Accordingly, we have studied the interrelationships of AVP, HPA activation, and ANF in response to acute cold stress in healthy volunteers.
Subjects
and Methods
Subjects Six healthy males aged between 20 and 23 yr volunteered for the study. The mean body mass index of the group was 24 f 1 kg/m’ (range 21-27 kg/m’). All were nonsmokers, on no medication, and had abstained from alcohol and exercise for 24 h before the study. Informed consent was obtained and the study was approved by the Canterbury Area Health Board Ethics Committee.
Protocol The studies were all conducted through August and September (Southern hemisphere spring). Subjects arrived at the metabolic study room at 1300 h, having been deprived of food and fluid for 6 h. Subjects were clad in teeshirts and shorts and were barefoot for the entire experimental period. A 24-h urine collection for sodium excretion (mean 162 + 24 mmo1/24 h) was completed just before the study with a double voided specimen for the measurement of osmolality (mean 731 + 63 mosm/L). A 14.gauge 20.3-cm long cannula (Bardicath), in which two side holes were made, was inserted via a vein in the antecubital fossa. A rectal temperature probe (Hi-Lo Temp, Mallinckrodt, Glens Falls, NY) was inserted 10 cm into the rectum for the measurement of rectal temperature, which together with environmental temperature was continuously recorded (Supermon 7210, Kontron Instruments Ltd, Watford, England). Subjects then adopted a seated posture in a wheel chair which was maintained throughout the study. After a 30.min resting period at ambient temperature (21-22 C) blood was sampled at 0, 15, and 30 min to obtain baseline hormone levels. Subjects were then wheeled into a cold room (4-5 C), for a period of 30 min, and then returned to ambient temperature for a further 30 min. Blood samples were drawn at 2, 5, 10, 15, and 30 min after each change in room temperature. Blood was collected into prechilled ethylenediamine tetraacetate tubes and separated immediately and the plasma stored at -20 C (-80 C for catecholamines) until assayed. Previously
Received September 3, 1991. Address all correspondence and requests for reprints to: Professor E. A. Espiner, Department of Endocrinology, The Princess Margaret Hospital, Cashmere Road, Christchurch, New Zealand. *Support was provided by the Medical Research Council of New Zealand and the Canterbury Area Health Board.
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HPA RESPONSE reported methods were used to assay ANF (27), PRA (28), epinephrine, norepinephrine (29), and AVP (30) (all time intervals), CRF (6), ACTH (31), cortisol (enzyme-linked radiosorbant assay), aldosterone (32), and prolactin (Microparticle enzyme immunoassay, IMx, Abbott Laboratories, Abbott Park, IL) (15 and 30 min intervals). Plasma sodium and potassium were measured by flame photometry (model IL 443), and osmolality by freezing point depression (Digimatic Osmometer, model 3D2m, Advanced Instruments, inc., Needham Heights, MA). All samples from any one subject were analyzed in the same assay. The intraassay coefficients of variation for individual hormones ranged from 4.5% (CRF), to 10.1% (epinephrine). Detection limits of the assays (at the 95% confidence level) were: ACTH 3.0 pmol/L in 0.5-mL plasma extracts, AVP 0.05 pmol/L, CRF 0.1 pmol/L, ANF 5.0 pmol/L in 2.0 mL plasma extracts, PRA 0.02 nmol/l. h, prolactin 14 mu/L, epinephrine 150 pmol/ L, norepinephrine 0.3 nmol/L, and cortisol 55 nmol/L. Haemoglobin (Coulter counter, model STKS) and haematocrit (by centrifugation) were measured at the beginning and end of the cold period in order to calculate change in plasma volume (33). Blood pressure and pulse measurements were always made just before blood sampling (semiautomatic Rose Box).
Statistical
TO ACUTE
COLD
751
A 1200 ‘ac 1000 g .2 g
000 600 400
‘g b z
200 0
6 I
I
analysis
Results are expressed as means & SE. Hormone concentrations were transformed to logarithms before analysis. Data were analyzed by analysis of variance with repeated measures, using time as a within subject factor. Calculations were performed with program P2V of the BMDP package (34). Hunyh-Feldt probabilities were used where required to adjust for violations of sphericity assumptions with repeated measures, The polynomial orthogonal components of the time factor were individually tested for significance. After analysis of variance, Tukeys procedure was used to assess the significance of differences between time points. The graphs of the data contain the plot of the untransformed arithmetic means.
OJI -30
Results
The study was completed without incident and data collection was complete. No changes were observed in rectal temperature during cold exposure. After 30 min cold exposure the mean fall in plasma volume was 7.8 + 1.4% (range, 3-13.3s). Systolic blood pressure increased significantly with time during cold exposure (P = 0.001). The increase was apparent by 2 min, peaked at the end of the cold period and returned to baseline within 15 min of reexposure to an ambient temperature of 21 C (Fig. 1). No significant changes in diastolic blood pressure or pulse rate occurred (Table 1). Similarly, plasma norepinephrine levels increased significantly during cold exposure (P = O.OOOl),the increasebeing apparent after 2 min and reaching a peak at 15 min (Fig. 1). Plasma norepinephrine levels fell after completion of cold exposure, but levels were still higher than baseline at the completion of the study. No significant changes occurred in plasma epinephrine levels (Table 1). Prior to cold exposure plasma AVP levels were variable, but commensuratewith fluid deprivation and urine osmolalities. Levels decreasedfrom baseline values during exposure to cold (Fig. 1). Analysis of variance revealed a significant effect for time (quadratic orthogonal component, P < 0.01). The fall from baseline values was significant at the 5- and IO-min intervals after leaving the cold room with prompt return to baseline levels by 15 min.
-15
0
5 10 15 Time
30 35 40 45
60
(Minutes)
FIG. 1. Mean (+ SEM) systolic blood pressure, plasma norepinephrine, AVP, and ANF levels in 6 healthy, seated male volunteers during 3 consecutive 30-min exposures to an ambient temperature of 22 C, 4 C (cold stress), and 22 C, respectively. Increases in systolic blood pressure and in plasma norepinephrine during cold stress were both highly significant (P = 0.0001). The fall in plasma AVP during and after cold stress was also significant (P < 0.01).
Plasma ANF levels remained unchanged throughout the study (Fig. 1). There was no evidence of HPA activation during or after cold exposure (Fig. 2). Analysis of variance for plasma cortisol level revealed a significant effect of time (P < 0.01); however, this was confined to a fall in the cortisol level at 15 min after the initial baseline value and there were no significant differences after this time. No significant changes occurred in plasma ACTH or CRF during the course of the study. Although plasma sodium levels tended to increase during the 30-min period of cold exposure (Fig. 3), analysis of variance revealed no significant change over time. Similarly, there was no significant change in plasma osmolality (Table 1). Plasma potassium concentrations on the other hand showed a significant increase with time (P < 0.001). This was significant by 2 min after cold exposure and reached a peak after 30 min before returning to baseline (Fig. 3). Whereas no significant change in PRA occurred at any time during cold exposure, levels increased progressively to
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752
WITTERT
ET AL.
60 -1 P I
JCE & M. 1992 Vol75.No3
.
50 40. 30. 20
.
-30
-15
0
5
10
Time
15
30
35 40 45
60
(Minutes)
FIG. 2. Mean (+ SEM) plasma cortisol, ACTH, and CRF healthy, seated male volunteers during 3 consecutive 30-min to an ambient temperature of 22 C, 4 C (cold stress), respectively. No significant change in hormones occurred after cold stress.
levels in 6 exposures and 22 C, during or
peak at 30 min after leaving the cold room (P < 0.01, Fig. 3). Despite increasein plasma potassiumand PRA no significant changes in plasma aldosterone levels occurred during the course of the study (Fig. 3). Plasma prolactin levels fell during the period of cold exposure and levels were significantly lower than baseline values after 30 min (P < 0.001). No significant further change occurred in the 30-min period after leaving the cold room (Table 1). Discussion
Our findings of increased systolic blood pressure, increased sympathetic nervous system activation (as indicated by increased plasma norepinephrine levels), fall in plasma volume, and inhibition of prolactin secretion are in keeping with previous findings on the effect of acute cold stressin humans (12-17, 23). In the present study we did not observe the increase in diastolic blood pressureor decreasein pulse rate which are reported to occur after longer periods of cold exposure (14, 17). Our finding that plasma epinephrine levels did not increaseis consistent with the findings of most other investigators (14, 16, 17, 23), although a small increase has been reported (15). Plasma AVP fell on exposure to the cold environment and was significantly decreased by 5-10 min after leaving the cold room. This fall occurred despite a drop in plasmavolume and trend for plasma sodium concentration and osmolality to increase. The lowest levels of AVP followed shortly after
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HPA RESPONSE
142 g
141
g
140
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139
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-?
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-15
0
5
10 Time
15
30 35
40 45
60
(Minutes)
FIG. 3. Mean
(k SEM) PRA, aldosterone, sodium, and potassium levels in 6 healthy, seated male volunteers during 3 consecutive 30-min exposures td an ambient temperature of 22 C, 4 C (cold stress), and 22 C, respectively. Increases in plasma potassium (P < O.OOl), and in PRA after cold stress (P < 0.01) were significant.
the peaks in systolic blood pressure and plasmanorepinephrine, findings compatible with a baroreceptor mediated feed back suppression of AVP release (21, 35). Interestingly, inhibition of osmotic-induced AVP secretion by ice chips placed in the oropharynx has been reported in humans and is presumably mediated by vagal afferents from cold-sensitive oropharyngeal receptors (20). Nonosmotic suppression of AVP in responseto cold exposure has been noted in both animals (21) and in man (19), and may be the basis of the cold diuresis (19). It has been suggestedthat the inhibition of AVP releaseis the result of increased central blood volume consequentto peripheral vasoconstriction (19). However, this is made lesslikely by our failure to observe any increase in plasma ANF during cold exposure. In rats a 2-fold rise in plasma ANF was observed at 15 min after exposure to 13 C (24). However, our subjects were all mildly fluid deprived and were seated throughout the study-factors which may attenuate atria1hormone responsiveness(36), and which may also reduce any diuresis (37). In any event it seemsunlikely that systemic ANF levels contribute to the fall in plasma AVP in the circumstancesof our study. Taken together these findings suggestthat cold-induced inhibition of AVP secretion is mediated by baroreceptor afferents projecting to cen-
TO ACUTE
COLD
753
tral a-adrenergic pathways. Although regarded as a noxious stimulus, cold exposure for 30 min did not activate the HPA axis in our subjects. Despite this it is not possibleto exclude a small rise in plasma ACTH or cortisol, since a time-controlled study was not done in these same subjects. However, we chose to study the subjects at a time of day when the diurnal change (decrease) in ACTH and cortisol levels would be minimal. Previous studies of cold exposure in normal humans have given equivocal findings, with evidence of increase in plasma ACTH (16), or cortisol(12, 14, 15), in somebut not all studies (13, 17, 18). Differences in experimental protocols, particularly the severity of the cold stressemployed, may account for these inconsistencies. Whereas mild cold exposure (14, 18) is clearly not a stimulus in humans, more severe (12) and prolonged (12, 14) cold exposure (e.g. 4 C or lower in lightly or unclad subjects) is reported to increase plasma cortisol levels when compared to control day observations. Taken together with the present findings, it would appear that the human is less responsive than the rat where acute cold exposure is a reproducible and strong stimulus to HPA activity (9-11). The basis for the different responsepattern in the two speciesis unclear but the neuronal regulation of ACTH secretion in the rat, which retains the intermediate lobe, is likely to be different from that of humans. Alternatively, it may be that placing the conscious rat in the cold results in ACTH secretion due to a neurogenic or emotional responseto a novel and unpleasant environment rather than a response to the cold itself. Our human subjects were in a relaxed and emotionally unstressed state. Furthermore, it is of interest that hypothermia in anaesthetized rats results in inhibition of ACTH secretion which has been attributed to decreasedhypothalamic AVP secretion and thus diminished pituitary responsivenessto CRF (22). In the current study we observed no change in plasma CRF levels but whether peripheral plasma levels of CRF reflect hypothalamic secretion of CRF is controversial. In some (38), but not other (39) studies, plasma CRF is reported to vary with perturbations of the HPA axis. We have previously shown that during acute hypoglycaemia both CRF and AVP levels increase(6), whereas during vigorous exercisethere is an increaseonly in plasma AVP (7). To our knowledge the ACTH responseto exogenous CRF during cold stress has not been studied in humans but it is possible that the failure of cold stressto activate the HPA, is, in part, related to a concomitant lack (or inhibition) of AVP and/or associatedwith reduced sensitivity to CRF. Our finding of an increase in plasma renin activity seen 30 min after the period of cold exposure is in contrast to the findings of Hiramatsu et al. (14). However, it is consistent with the known effect of increased sympathetic tone on renin releasefrom the kidney (40) and the documented fall in plasma volume. Renal blood flow has been reported to decreasein response to acute cold exposure (41), and this may be an additional mechanism for increased renin secretion. Despite the increase in PRA there was no increase in aldosterone secretion. It is to be noted, however, that changes in PRA were small and occurred just prior to the studies
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WITTERT
754
conclusion. In humans, plasma aldosterone is reported to increase in response to acute cold exposure, possibly as a result of stress-induced ACTH secretion in some studies (14). No significant increase in plasma ACTH was seen in the current study. However, a small but significant increase in plasma potassium [which may be a stimulus to aldosterone secretion (42)] was observed. Increases in plasma potassium during acute cold exposure have not previously been documented. In the current study blood was drawn through a wide bore cannula with side holes, and immediately centrifuged and separated and none of the samples were hemolyzed. Since plasma norepinephrine levels rose, a fall (rather than a rise) in plasma potassium might have been expected (43). One possible explanation for the increase in plasma potassium may come from a recent in vitro observation (44) in which cold-induced vasoconstriction in cutaneous veins was associated with inhibition of Na’,K+-adenosine triphosphatase. Inhibition of this enzyme would be expected to raise intracellular sodium concentration and induce potassium efflux. In addition, the hemoconcentration seen in the present study (a well recognized effect of acute cold exposure) might be the consequence of water moving into cells as a result of the cold inhibition of the Na+,K+-adenosine triphosphatase. A cold diuresis (which we did not observe) is unlikely to be responsible and, although ANF may cause hemoconcentration (45), plasma ANF levels did not increase in the current study. We conclude that acute cold exposure is a very weak stimulus to the HPA axis in humans. We suggest that cold inhibition of AVP release, via afferent baroreceptor pathways, may be acting to reduce the response of the corticotrophs to a potentially noxious stimulus. Without an increase in AVP, or CRF release, no increase in ACTH secretion occurs. Inhibition of AVP and/or ACTH secretion during cold exposure are not dependent upon an increase in systemic ANF. Acknowledgments We wish to thank the Special Tests nursing staff for their assistance; the Department of Respiratory Medicine for use of the Kontron; and the staff of the Endocrine, Steroid and Biochemistry laboratories for performing the assays.
References 1. Orth DH, Jackson RV, De Cherney CR, et al. 1983 Effect of synthetic ovine corticotrophin-releasing factor: dose response of plasma adrenocorticotrophin and cortisol. J Clin Invest 71:587-95. SR, Conaglen JV, Donald RA, Espiner EA, Nicholls MG, 2. Milsom Livesey JH. 1985 Augmentation of the response to CRF in man: relative contributions of endogenous angiotensin and vasopressin. Clin Endocrinol (Oxf). 22:623-8. D, Pham T, Fullerton M, Ooi G, Funder JW, Clarke IJ. 3. Engler 1989 Studies on the secretion of corticotrophin releasing factor and arginine vasopressin into the hypophysial portal secretion of the conscious sheep. Neuroendocrinolgv. 49:367-81. 4. Plotsky PM, Bruhn TO, Vale W. 1785 Hypophysiotropic regulation of adrenocorticotrophin secretion in response to insulin induced hypoglycaemia. Endocrinology. 117:323-9. 5. Alexander SL, Irvine CHG, Ellis MJ, Donald RA. 1991 The effect of acute exercise on the secretion of AVP, CRF and ACTH in pituitary venous blood from the horse. Endocrinology. 128:65-72.
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6. Ellis MJ, Schmidli RS, Donald RA, Livesey JH, Espiner EA. 1990 Plasma corticotrophin releasing factor and vasopressin responses to hypoglycaemia in normal man. Clin Endocrinol (Oxf). 32:93-100. 7. Wittert GA, Stewart DE, Graves MP, et al. 1991 Plasma corticotrophin releasing factor and vasopressin responses to exercise in normal man. Clin Endocrinol (Oxf). 35:31 l-7. 8. Wittert GA, Perry E, Ward M, Donald RA, Espiner EA, 1991 Plasma corticotrophin, vasopressin and corticotrophin releasing factor responses to abdominal surgery in humans. Programme of the Annual Meeting of the Endocrine Society of Australia, 34 (Abstract 59). 9. Usategai R, Gillioz P, Oliver C. 1977 Effect of cold exposure on alpha MSH and ACTH release in the rat. Horm Metab Res. 9:519. 10. Giagnoni G, Santgostino R, Senini R, Fumagilli, P, Gori E. 1983 Cold stress in the rat induces parallel changes in plasma and pituitary levels of endorphin and ACTH. Pharrnacol Res Comm. 15:15-21. 11. Donnerer J, Lembeck F. 1990 Different control of the adrenocorticotrophin-corticosterone response and of prolactin secretion during cold stress, anaesthesia, surgery and nicotine injection in the rat: involvement of capsicain-sensitive neurones. Endocrinology. 126: 921-6. 12. Wilson 0, Hedner P, Laurel1 S, Nosslin B, Rerup C, Rosegren E. 1970 Thyroid and adrenal responses to acute cold exposure in man. J Appl I’hysiol. 28:543-8. 13. Wilkerson JE, Raven PB, Bolduan NW, Hovarth SM. 1974 Adaptations in man’s adrenal function in response to acute cold stress. J Appl Physiol. 35:183-9. 14. Hiramatsu K, Yamada T, Katakura M. 1984 Acute effects of cold on blood pressure, renin-angiotensin-aldosterone system, catecholamine and adrenal steroids in man. Clin Exp Pharmacol Physiol. 11:171-9. 15. Wagner JA, Hovarth SM, Kitagawa K, Bolduan NW. 1987 Comparisons of blood and urinary responses to cold exposures in young and older men and women. J Gerontol. 41:173-9. K, Kuroshima A. 1987 Effect of 16. Ohno H, Yahata T, Yamashita acute cold exposure on ACTH and zinc concentrations in human plasma. Jpn J Physiology. 37:749-55. 17. Leppaluoto J, Korhonen I, Huttunen P, Hassi J. 1988 Serum levels of thyroid and adrenal hormones, testosterone, TSH, LH, GH and prl in men after a two hour stay in a cold room. Acta Physiol Stand. 132:543-8. 18. Goldstein-Golaire J, Vanhaelst L, Bruno OD, Leclercq R, Copinschi, G. 1970 Acute effects of cold on blood levels of growth hormone, cortisol, and thyrotropin in man. J Appl Physiol. 29:6226. 19. Segar WE, Moore WW. 1968 The regulation of antidiuretic hormone release in man: effects of change in postition and ambient temperature on blood ADH levels. J Clin Invest. 47:2143-8. 20. Salata RA, Verbalis JG, Robinson AG. 1987 Cold water stimulation of oropharyngeal receptors in man inhibits release of vasopressin. J Clin Endocrinol Metab. 65:561-7. 21. Morgan ML, Anderson RJ, Ellis MA, Berl T. 1983 Mechanism of cold diuresis in the rat. Am J Physiol. 244:F210-6. 22. Gibbs DM. 1985 Inhibition of corticotrophin release during hypothermia: the role of corticotrophin releasing factor, vasooressin, and oxytocin. Endocrinology. 1161723-7. 23 O’Mallev BP, Cook N. Richardson A, Barnett DB. Rosenthal FD. 1984 Cir&lating catecholamine, thyrotropin, thyroid hormone and prolactin responses of normal subjects to acute cold exposure. Clin Endocrinol (Oxf). 21:285-91. 24 Reddix-Cheri R, Martin BJ. 1990 Cold dimesis: a possible role for atria1 natriuretic peptide. FASEB J. 74th Annual Meeting (Abstract 4780). 25 Allen MJ, Ang VTY, Bennett ED, Jenkins JS. 1988 Atria1 natriuretic peptide inhibits osmolality-induced arginine vasopressin release in man. Clin Sci. 75:35-9. 26 Makino S, Kozo H, Ota Z. 1989 Atria1 natriuretic polypeptide attenuates central angiotensin II-induced catecholamine and ACTH secretion. Brain Res. 501:84-9. TG, Espiner EA, Nicholls MG, Duff H. 1986 Radio27. Yandle immunoassay and characterisation of atrial natriuretic peptide in
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human plasma. J Clin Endocrinol Metab. 63:72-9. 28. Dunn PJ, Espiner EA. 1976 Outpatient screening test for primary aldosteronism. Aust N Z J Med. 6:131-5. 29. Peuler JD, Johnson GA. 1977 Simultaneous single isotope radioenzymatic assays of plasma norepinephrine, epinephrine and dopamine. Life Sci. 21:625-633. 30. Sadler WA, Lynskey C, Gilchrist N, Espiner EA, Nicholls MG. 1983 A sensitive radioimmunoassay for measuring plasma antidiuretic hormone in man. N Z Medical J. 96:959-63. 31. Donald RA. 1977 Radioimmunoassay of corticotrophin (ACTH). In: Abrahams G, ed. Handbook of endocrinology. New York: Marcel Dekker; 319. 32. Lun S, Espiner EA, Nicholls MG, Yandle TG. 1983 A direct radioimmunoassay for aldosterone in plasma. Clin Chem. 29:26871. 33. Dill DB, Costill DL. 1974 Calculation of the percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol. 37:247-8. 34. Dixon WJ. 1985 BMDP statistical software. Berkeley, California: University of California Press. 35. Berl T, Cadnapaphornchai P, Harbottle JA, Schrier RW. 1973 Mechanism of suppression of vasopressin during alpha-adrenergic stimulation with norepinephrine. J Clin Invest, 53:219-27. 36. Burrell LM, Baylis PH. 1990 Release of atria1 natriuretic peptide during hypertonic saline infusion: the importance of posture. Clin Endocrinol (Oxf). 32:491-6.
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37. Knight DR, Horvath SM. 1982 The relative contributions of gravity, buoyancy, and cold to the changes of human plasma volume during simulated weightlessness. Physiologist. 25:S81-2. 38. Sasaki A, Sato S, Murakami 0, et al. 1987 Immunoreactive corticotrophin releasing factor present in human plasma may be derived from both hypothalamic and extrahypothalamic sources. J Clin Endocrinol Metab. 65:176-82. 39. Cunnah D, Jessop D, Besser GM, Rees LH. 1987 Measurement of circulating CRF in man. J Endocrinol. 113:123-31. 40. Gordon RD, Kuchel 0, Liddle GW, Island DP. 1967 Role of the sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest. 46:599-605. 41. Wallenberg LR, Granberg PO. 1975 Tubular sodium handling in cold exposed man during inhibition of distal tubular reabsorption of sodium. Stand J Clin Lab Invest. 35:319-22. 42. Himathongham T, Dluhy RG, Williams GH. 1975 Potassium aldosterone and renin interaction. J Clin Endocrinol Metab. 41:1539. 43. Williams ME, Gervino EV, Rosa RM, et al. 1985 Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med. 312:823-7. 44. Thulesius 0, Yousif MH. 1991 Na+K+-ATPase inhibition, a new mechanism for cold induced vasoconstriction in cutaneous veins. Acta Physiol Stand. 141:127-8. 45. Tonolo G, McMilan M, Polonia J, et al. 1988 Plasma clearance and effects of alpha-hANP infused in patients with end-stage renal failure. Am J Physiol. 23:F895-9.
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Vol. 75, No. :3 Prmted I” USA
Vasopressin, Corticotrophin-Releasing Pituitary Adrenal Responses to Acute Normal Humans* G. A. WITTERT, H. K. OR, J. H. LIVESEY, AND E. A. ESPINER Department
of Endocrinology,
The Princess
Margaret
A. M. RICHARDS, Hospital,
Christchurch,
Factor, and Cold Stress in
R. A. DONALD, New Zealand
level (P = O.OOOl), but no change in plasma epinephrine or in plasma ANF. Plasma AVP levels fell significantly (P < 0.01) to reach a nadir at 5-10 min after cold exposure before returning to baseline levels. A significant fall in plasma cortisol levels occurred during the first 15 min of the baseline period and remained stable thereafter. No significant changes in plasma corticotrophin-releasing factor or ACTH occurred. These results suggest that cold inhibition of AVP release, presumably via afferent baroreceptor pathways, may act to reduce the response of the corticotrophs to a potentially noxious stimulus. Inhibition of AVP and/or ACTH during acute cold exposure are not dependent upon an increase in plasma ANF. (J Clin Endocrinol Metub 75: 750-755, 1992)
ABSTRACT Acute cold stress is a consistent stimulus to ACTH secretion in rats yet inhibits arginine vasopressin (AVP) in both rats and humans. We have studied the interrelationships of AVP, corticotrophin-releasing factor, and atria1 natriuretic factor (ANF) in the hypothalamo-pituitary-adrenal response to acute cold stress in normal humans. Six healthy male volunteers deprived of food and fluid for 6 h, and minimally clothed, were studied in the early afternoon. After a 30.min period at 22 C, subjects were exposed to cold stress (4 C for 30 min), followed by a 30-min equilibration period at 22 C. By the end of the period of cold exposure there was a fall in plasma volume of 7.8 f 1.4% (mean + SEM), a significant increase in both systolic blood pressure (P = 0.0001) and in plasma norepinephrine
I
T IS generally accepted that both corticotrophin-releasing factor (CRF) (1) and arginine vasopressin (AVP) (2) are physiologically important factors regulating stress induced ACTH secretion. However, the relative importance of these ACTH secretagogues in the stress response varies in different species as well as with the type of stressor employed (3-8). Whereas acute cold exposure in conscious rats is a reproducible stimulus to the hypothalamo-pituitary adrenal (HPA) axis (9-ll), the HPA response of humans to cold exposure is less consistent (12-18). However, acute cold exposure in man and animals inhibits AVP secretion (19-22). Since increases in peripheral blood AVP appear to be a consistent finding during acute stress-induced ACTH secretion in humans (6-&J), it is possible that the pattern or degree of HPA response to cold stress in humans differs from that observed with other stressors. Further, cold exposure in humans increases blood pressure and sympathetic nervous activity (12, 14-17, 23) and in rats is reported to increase peripheral levels of atria1 natriuretic factor (ANF) (24). There is evidence that ANF may inhibit AVP (25) and/or ACTH (26) secretion. Accordingly, we have studied the interrelationships of AVP, HPA activation, and ANF in response to acute cold stress in healthy volunteers.
Subjects
and Methods
Subjects Six healthy males aged between 20 and 23 yr volunteered for the study. The mean body mass index of the group was 24 f 1 kg/m’ (range 21-27 kg/m’). All were nonsmokers, on no medication, and had abstained from alcohol and exercise for 24 h before the study. Informed consent was obtained and the study was approved by the Canterbury Area Health Board Ethics Committee.
Protocol The studies were all conducted through August and September (Southern hemisphere spring). Subjects arrived at the metabolic study room at 1300 h, having been deprived of food and fluid for 6 h. Subjects were clad in teeshirts and shorts and were barefoot for the entire experimental period. A 24-h urine collection for sodium excretion (mean 162 + 24 mmo1/24 h) was completed just before the study with a double voided specimen for the measurement of osmolality (mean 731 + 63 mosm/L). A 14.gauge 20.3-cm long cannula (Bardicath), in which two side holes were made, was inserted via a vein in the antecubital fossa. A rectal temperature probe (Hi-Lo Temp, Mallinckrodt, Glens Falls, NY) was inserted 10 cm into the rectum for the measurement of rectal temperature, which together with environmental temperature was continuously recorded (Supermon 7210, Kontron Instruments Ltd, Watford, England). Subjects then adopted a seated posture in a wheel chair which was maintained throughout the study. After a 30.min resting period at ambient temperature (21-22 C) blood was sampled at 0, 15, and 30 min to obtain baseline hormone levels. Subjects were then wheeled into a cold room (4-5 C), for a period of 30 min, and then returned to ambient temperature for a further 30 min. Blood samples were drawn at 2, 5, 10, 15, and 30 min after each change in room temperature. Blood was collected into prechilled ethylenediamine tetraacetate tubes and separated immediately and the plasma stored at -20 C (-80 C for catecholamines) until assayed. Previously
Received September 3, 1991. Address all correspondence and requests for reprints to: Professor E. A. Espiner, Department of Endocrinology, The Princess Margaret Hospital, Cashmere Road, Christchurch, New Zealand. *Support was provided by the Medical Research Council of New Zealand and the Canterbury Area Health Board.
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HPA RESPONSE reported methods were used to assay ANF (27), PRA (28), epinephrine, norepinephrine (29), and AVP (30) (all time intervals), CRF (6), ACTH (31), cortisol (enzyme-linked radiosorbant assay), aldosterone (32), and prolactin (Microparticle enzyme immunoassay, IMx, Abbott Laboratories, Abbott Park, IL) (15 and 30 min intervals). Plasma sodium and potassium were measured by flame photometry (model IL 443), and osmolality by freezing point depression (Digimatic Osmometer, model 3D2m, Advanced Instruments, inc., Needham Heights, MA). All samples from any one subject were analyzed in the same assay. The intraassay coefficients of variation for individual hormones ranged from 4.5% (CRF), to 10.1% (epinephrine). Detection limits of the assays (at the 95% confidence level) were: ACTH 3.0 pmol/L in 0.5-mL plasma extracts, AVP 0.05 pmol/L, CRF 0.1 pmol/L, ANF 5.0 pmol/L in 2.0 mL plasma extracts, PRA 0.02 nmol/l. h, prolactin 14 mu/L, epinephrine 150 pmol/ L, norepinephrine 0.3 nmol/L, and cortisol 55 nmol/L. Haemoglobin (Coulter counter, model STKS) and haematocrit (by centrifugation) were measured at the beginning and end of the cold period in order to calculate change in plasma volume (33). Blood pressure and pulse measurements were always made just before blood sampling (semiautomatic Rose Box).
Statistical
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A 1200 ‘ac 1000 g .2 g
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analysis
Results are expressed as means & SE. Hormone concentrations were transformed to logarithms before analysis. Data were analyzed by analysis of variance with repeated measures, using time as a within subject factor. Calculations were performed with program P2V of the BMDP package (34). Hunyh-Feldt probabilities were used where required to adjust for violations of sphericity assumptions with repeated measures, The polynomial orthogonal components of the time factor were individually tested for significance. After analysis of variance, Tukeys procedure was used to assess the significance of differences between time points. The graphs of the data contain the plot of the untransformed arithmetic means.
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Results
The study was completed without incident and data collection was complete. No changes were observed in rectal temperature during cold exposure. After 30 min cold exposure the mean fall in plasma volume was 7.8 + 1.4% (range, 3-13.3s). Systolic blood pressure increased significantly with time during cold exposure (P = 0.001). The increase was apparent by 2 min, peaked at the end of the cold period and returned to baseline within 15 min of reexposure to an ambient temperature of 21 C (Fig. 1). No significant changes in diastolic blood pressure or pulse rate occurred (Table 1). Similarly, plasma norepinephrine levels increased significantly during cold exposure (P = O.OOOl),the increasebeing apparent after 2 min and reaching a peak at 15 min (Fig. 1). Plasma norepinephrine levels fell after completion of cold exposure, but levels were still higher than baseline at the completion of the study. No significant changes occurred in plasma epinephrine levels (Table 1). Prior to cold exposure plasma AVP levels were variable, but commensuratewith fluid deprivation and urine osmolalities. Levels decreasedfrom baseline values during exposure to cold (Fig. 1). Analysis of variance revealed a significant effect for time (quadratic orthogonal component, P < 0.01). The fall from baseline values was significant at the 5- and IO-min intervals after leaving the cold room with prompt return to baseline levels by 15 min.
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30 35 40 45
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FIG. 1. Mean (+ SEM) systolic blood pressure, plasma norepinephrine, AVP, and ANF levels in 6 healthy, seated male volunteers during 3 consecutive 30-min exposures to an ambient temperature of 22 C, 4 C (cold stress), and 22 C, respectively. Increases in systolic blood pressure and in plasma norepinephrine during cold stress were both highly significant (P = 0.0001). The fall in plasma AVP during and after cold stress was also significant (P < 0.01).
Plasma ANF levels remained unchanged throughout the study (Fig. 1). There was no evidence of HPA activation during or after cold exposure (Fig. 2). Analysis of variance for plasma cortisol level revealed a significant effect of time (P < 0.01); however, this was confined to a fall in the cortisol level at 15 min after the initial baseline value and there were no significant differences after this time. No significant changes occurred in plasma ACTH or CRF during the course of the study. Although plasma sodium levels tended to increase during the 30-min period of cold exposure (Fig. 3), analysis of variance revealed no significant change over time. Similarly, there was no significant change in plasma osmolality (Table 1). Plasma potassium concentrations on the other hand showed a significant increase with time (P < 0.001). This was significant by 2 min after cold exposure and reached a peak after 30 min before returning to baseline (Fig. 3). Whereas no significant change in PRA occurred at any time during cold exposure, levels increased progressively to
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50 40. 30. 20
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FIG. 2. Mean (+ SEM) plasma cortisol, ACTH, and CRF healthy, seated male volunteers during 3 consecutive 30-min to an ambient temperature of 22 C, 4 C (cold stress), respectively. No significant change in hormones occurred after cold stress.
levels in 6 exposures and 22 C, during or
peak at 30 min after leaving the cold room (P < 0.01, Fig. 3). Despite increasein plasma potassiumand PRA no significant changes in plasma aldosterone levels occurred during the course of the study (Fig. 3). Plasma prolactin levels fell during the period of cold exposure and levels were significantly lower than baseline values after 30 min (P < 0.001). No significant further change occurred in the 30-min period after leaving the cold room (Table 1). Discussion
Our findings of increased systolic blood pressure, increased sympathetic nervous system activation (as indicated by increased plasma norepinephrine levels), fall in plasma volume, and inhibition of prolactin secretion are in keeping with previous findings on the effect of acute cold stressin humans (12-17, 23). In the present study we did not observe the increase in diastolic blood pressureor decreasein pulse rate which are reported to occur after longer periods of cold exposure (14, 17). Our finding that plasma epinephrine levels did not increaseis consistent with the findings of most other investigators (14, 16, 17, 23), although a small increase has been reported (15). Plasma AVP fell on exposure to the cold environment and was significantly decreased by 5-10 min after leaving the cold room. This fall occurred despite a drop in plasmavolume and trend for plasma sodium concentration and osmolality to increase. The lowest levels of AVP followed shortly after
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HPA RESPONSE
142 g
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FIG. 3. Mean
(k SEM) PRA, aldosterone, sodium, and potassium levels in 6 healthy, seated male volunteers during 3 consecutive 30-min exposures td an ambient temperature of 22 C, 4 C (cold stress), and 22 C, respectively. Increases in plasma potassium (P < O.OOl), and in PRA after cold stress (P < 0.01) were significant.
the peaks in systolic blood pressure and plasmanorepinephrine, findings compatible with a baroreceptor mediated feed back suppression of AVP release (21, 35). Interestingly, inhibition of osmotic-induced AVP secretion by ice chips placed in the oropharynx has been reported in humans and is presumably mediated by vagal afferents from cold-sensitive oropharyngeal receptors (20). Nonosmotic suppression of AVP in responseto cold exposure has been noted in both animals (21) and in man (19), and may be the basis of the cold diuresis (19). It has been suggestedthat the inhibition of AVP releaseis the result of increased central blood volume consequentto peripheral vasoconstriction (19). However, this is made lesslikely by our failure to observe any increase in plasma ANF during cold exposure. In rats a 2-fold rise in plasma ANF was observed at 15 min after exposure to 13 C (24). However, our subjects were all mildly fluid deprived and were seated throughout the study-factors which may attenuate atria1hormone responsiveness(36), and which may also reduce any diuresis (37). In any event it seemsunlikely that systemic ANF levels contribute to the fall in plasma AVP in the circumstancesof our study. Taken together these findings suggestthat cold-induced inhibition of AVP secretion is mediated by baroreceptor afferents projecting to cen-
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tral a-adrenergic pathways. Although regarded as a noxious stimulus, cold exposure for 30 min did not activate the HPA axis in our subjects. Despite this it is not possibleto exclude a small rise in plasma ACTH or cortisol, since a time-controlled study was not done in these same subjects. However, we chose to study the subjects at a time of day when the diurnal change (decrease) in ACTH and cortisol levels would be minimal. Previous studies of cold exposure in normal humans have given equivocal findings, with evidence of increase in plasma ACTH (16), or cortisol(12, 14, 15), in somebut not all studies (13, 17, 18). Differences in experimental protocols, particularly the severity of the cold stressemployed, may account for these inconsistencies. Whereas mild cold exposure (14, 18) is clearly not a stimulus in humans, more severe (12) and prolonged (12, 14) cold exposure (e.g. 4 C or lower in lightly or unclad subjects) is reported to increase plasma cortisol levels when compared to control day observations. Taken together with the present findings, it would appear that the human is less responsive than the rat where acute cold exposure is a reproducible and strong stimulus to HPA activity (9-11). The basis for the different responsepattern in the two speciesis unclear but the neuronal regulation of ACTH secretion in the rat, which retains the intermediate lobe, is likely to be different from that of humans. Alternatively, it may be that placing the conscious rat in the cold results in ACTH secretion due to a neurogenic or emotional responseto a novel and unpleasant environment rather than a response to the cold itself. Our human subjects were in a relaxed and emotionally unstressed state. Furthermore, it is of interest that hypothermia in anaesthetized rats results in inhibition of ACTH secretion which has been attributed to decreasedhypothalamic AVP secretion and thus diminished pituitary responsivenessto CRF (22). In the current study we observed no change in plasma CRF levels but whether peripheral plasma levels of CRF reflect hypothalamic secretion of CRF is controversial. In some (38), but not other (39) studies, plasma CRF is reported to vary with perturbations of the HPA axis. We have previously shown that during acute hypoglycaemia both CRF and AVP levels increase(6), whereas during vigorous exercisethere is an increaseonly in plasma AVP (7). To our knowledge the ACTH responseto exogenous CRF during cold stress has not been studied in humans but it is possible that the failure of cold stressto activate the HPA, is, in part, related to a concomitant lack (or inhibition) of AVP and/or associatedwith reduced sensitivity to CRF. Our finding of an increase in plasma renin activity seen 30 min after the period of cold exposure is in contrast to the findings of Hiramatsu et al. (14). However, it is consistent with the known effect of increased sympathetic tone on renin releasefrom the kidney (40) and the documented fall in plasma volume. Renal blood flow has been reported to decreasein response to acute cold exposure (41), and this may be an additional mechanism for increased renin secretion. Despite the increase in PRA there was no increase in aldosterone secretion. It is to be noted, however, that changes in PRA were small and occurred just prior to the studies
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conclusion. In humans, plasma aldosterone is reported to increase in response to acute cold exposure, possibly as a result of stress-induced ACTH secretion in some studies (14). No significant increase in plasma ACTH was seen in the current study. However, a small but significant increase in plasma potassium [which may be a stimulus to aldosterone secretion (42)] was observed. Increases in plasma potassium during acute cold exposure have not previously been documented. In the current study blood was drawn through a wide bore cannula with side holes, and immediately centrifuged and separated and none of the samples were hemolyzed. Since plasma norepinephrine levels rose, a fall (rather than a rise) in plasma potassium might have been expected (43). One possible explanation for the increase in plasma potassium may come from a recent in vitro observation (44) in which cold-induced vasoconstriction in cutaneous veins was associated with inhibition of Na’,K+-adenosine triphosphatase. Inhibition of this enzyme would be expected to raise intracellular sodium concentration and induce potassium efflux. In addition, the hemoconcentration seen in the present study (a well recognized effect of acute cold exposure) might be the consequence of water moving into cells as a result of the cold inhibition of the Na+,K+-adenosine triphosphatase. A cold diuresis (which we did not observe) is unlikely to be responsible and, although ANF may cause hemoconcentration (45), plasma ANF levels did not increase in the current study. We conclude that acute cold exposure is a very weak stimulus to the HPA axis in humans. We suggest that cold inhibition of AVP release, via afferent baroreceptor pathways, may be acting to reduce the response of the corticotrophs to a potentially noxious stimulus. Without an increase in AVP, or CRF release, no increase in ACTH secretion occurs. Inhibition of AVP and/or ACTH secretion during cold exposure are not dependent upon an increase in systemic ANF. Acknowledgments We wish to thank the Special Tests nursing staff for their assistance; the Department of Respiratory Medicine for use of the Kontron; and the staff of the Endocrine, Steroid and Biochemistry laboratories for performing the assays.
References 1. Orth DH, Jackson RV, De Cherney CR, et al. 1983 Effect of synthetic ovine corticotrophin-releasing factor: dose response of plasma adrenocorticotrophin and cortisol. J Clin Invest 71:587-95. SR, Conaglen JV, Donald RA, Espiner EA, Nicholls MG, 2. Milsom Livesey JH. 1985 Augmentation of the response to CRF in man: relative contributions of endogenous angiotensin and vasopressin. Clin Endocrinol (Oxf). 22:623-8. D, Pham T, Fullerton M, Ooi G, Funder JW, Clarke IJ. 3. Engler 1989 Studies on the secretion of corticotrophin releasing factor and arginine vasopressin into the hypophysial portal secretion of the conscious sheep. Neuroendocrinolgv. 49:367-81. 4. Plotsky PM, Bruhn TO, Vale W. 1785 Hypophysiotropic regulation of adrenocorticotrophin secretion in response to insulin induced hypoglycaemia. Endocrinology. 117:323-9. 5. Alexander SL, Irvine CHG, Ellis MJ, Donald RA. 1991 The effect of acute exercise on the secretion of AVP, CRF and ACTH in pituitary venous blood from the horse. Endocrinology. 128:65-72.
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6. Ellis MJ, Schmidli RS, Donald RA, Livesey JH, Espiner EA. 1990 Plasma corticotrophin releasing factor and vasopressin responses to hypoglycaemia in normal man. Clin Endocrinol (Oxf). 32:93-100. 7. Wittert GA, Stewart DE, Graves MP, et al. 1991 Plasma corticotrophin releasing factor and vasopressin responses to exercise in normal man. Clin Endocrinol (Oxf). 35:31 l-7. 8. Wittert GA, Perry E, Ward M, Donald RA, Espiner EA, 1991 Plasma corticotrophin, vasopressin and corticotrophin releasing factor responses to abdominal surgery in humans. Programme of the Annual Meeting of the Endocrine Society of Australia, 34 (Abstract 59). 9. Usategai R, Gillioz P, Oliver C. 1977 Effect of cold exposure on alpha MSH and ACTH release in the rat. Horm Metab Res. 9:519. 10. Giagnoni G, Santgostino R, Senini R, Fumagilli, P, Gori E. 1983 Cold stress in the rat induces parallel changes in plasma and pituitary levels of endorphin and ACTH. Pharrnacol Res Comm. 15:15-21. 11. Donnerer J, Lembeck F. 1990 Different control of the adrenocorticotrophin-corticosterone response and of prolactin secretion during cold stress, anaesthesia, surgery and nicotine injection in the rat: involvement of capsicain-sensitive neurones. Endocrinology. 126: 921-6. 12. Wilson 0, Hedner P, Laurel1 S, Nosslin B, Rerup C, Rosegren E. 1970 Thyroid and adrenal responses to acute cold exposure in man. J Appl I’hysiol. 28:543-8. 13. Wilkerson JE, Raven PB, Bolduan NW, Hovarth SM. 1974 Adaptations in man’s adrenal function in response to acute cold stress. J Appl Physiol. 35:183-9. 14. Hiramatsu K, Yamada T, Katakura M. 1984 Acute effects of cold on blood pressure, renin-angiotensin-aldosterone system, catecholamine and adrenal steroids in man. Clin Exp Pharmacol Physiol. 11:171-9. 15. Wagner JA, Hovarth SM, Kitagawa K, Bolduan NW. 1987 Comparisons of blood and urinary responses to cold exposures in young and older men and women. J Gerontol. 41:173-9. K, Kuroshima A. 1987 Effect of 16. Ohno H, Yahata T, Yamashita acute cold exposure on ACTH and zinc concentrations in human plasma. Jpn J Physiology. 37:749-55. 17. Leppaluoto J, Korhonen I, Huttunen P, Hassi J. 1988 Serum levels of thyroid and adrenal hormones, testosterone, TSH, LH, GH and prl in men after a two hour stay in a cold room. Acta Physiol Stand. 132:543-8. 18. Goldstein-Golaire J, Vanhaelst L, Bruno OD, Leclercq R, Copinschi, G. 1970 Acute effects of cold on blood levels of growth hormone, cortisol, and thyrotropin in man. J Appl Physiol. 29:6226. 19. Segar WE, Moore WW. 1968 The regulation of antidiuretic hormone release in man: effects of change in postition and ambient temperature on blood ADH levels. J Clin Invest. 47:2143-8. 20. Salata RA, Verbalis JG, Robinson AG. 1987 Cold water stimulation of oropharyngeal receptors in man inhibits release of vasopressin. J Clin Endocrinol Metab. 65:561-7. 21. Morgan ML, Anderson RJ, Ellis MA, Berl T. 1983 Mechanism of cold diuresis in the rat. Am J Physiol. 244:F210-6. 22. Gibbs DM. 1985 Inhibition of corticotrophin release during hypothermia: the role of corticotrophin releasing factor, vasooressin, and oxytocin. Endocrinology. 1161723-7. 23 O’Mallev BP, Cook N. Richardson A, Barnett DB. Rosenthal FD. 1984 Cir&lating catecholamine, thyrotropin, thyroid hormone and prolactin responses of normal subjects to acute cold exposure. Clin Endocrinol (Oxf). 21:285-91. 24 Reddix-Cheri R, Martin BJ. 1990 Cold dimesis: a possible role for atria1 natriuretic peptide. FASEB J. 74th Annual Meeting (Abstract 4780). 25 Allen MJ, Ang VTY, Bennett ED, Jenkins JS. 1988 Atria1 natriuretic peptide inhibits osmolality-induced arginine vasopressin release in man. Clin Sci. 75:35-9. 26 Makino S, Kozo H, Ota Z. 1989 Atria1 natriuretic polypeptide attenuates central angiotensin II-induced catecholamine and ACTH secretion. Brain Res. 501:84-9. TG, Espiner EA, Nicholls MG, Duff H. 1986 Radio27. Yandle immunoassay and characterisation of atrial natriuretic peptide in
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human plasma. J Clin Endocrinol Metab. 63:72-9. 28. Dunn PJ, Espiner EA. 1976 Outpatient screening test for primary aldosteronism. Aust N Z J Med. 6:131-5. 29. Peuler JD, Johnson GA. 1977 Simultaneous single isotope radioenzymatic assays of plasma norepinephrine, epinephrine and dopamine. Life Sci. 21:625-633. 30. Sadler WA, Lynskey C, Gilchrist N, Espiner EA, Nicholls MG. 1983 A sensitive radioimmunoassay for measuring plasma antidiuretic hormone in man. N Z Medical J. 96:959-63. 31. Donald RA. 1977 Radioimmunoassay of corticotrophin (ACTH). In: Abrahams G, ed. Handbook of endocrinology. New York: Marcel Dekker; 319. 32. Lun S, Espiner EA, Nicholls MG, Yandle TG. 1983 A direct radioimmunoassay for aldosterone in plasma. Clin Chem. 29:26871. 33. Dill DB, Costill DL. 1974 Calculation of the percentage changes in volumes of blood, plasma, and red cells in dehydration. J Appl Physiol. 37:247-8. 34. Dixon WJ. 1985 BMDP statistical software. Berkeley, California: University of California Press. 35. Berl T, Cadnapaphornchai P, Harbottle JA, Schrier RW. 1973 Mechanism of suppression of vasopressin during alpha-adrenergic stimulation with norepinephrine. J Clin Invest, 53:219-27. 36. Burrell LM, Baylis PH. 1990 Release of atria1 natriuretic peptide during hypertonic saline infusion: the importance of posture. Clin Endocrinol (Oxf). 32:491-6.
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37. Knight DR, Horvath SM. 1982 The relative contributions of gravity, buoyancy, and cold to the changes of human plasma volume during simulated weightlessness. Physiologist. 25:S81-2. 38. Sasaki A, Sato S, Murakami 0, et al. 1987 Immunoreactive corticotrophin releasing factor present in human plasma may be derived from both hypothalamic and extrahypothalamic sources. J Clin Endocrinol Metab. 65:176-82. 39. Cunnah D, Jessop D, Besser GM, Rees LH. 1987 Measurement of circulating CRF in man. J Endocrinol. 113:123-31. 40. Gordon RD, Kuchel 0, Liddle GW, Island DP. 1967 Role of the sympathetic nervous system in regulating renin and aldosterone production in man. J Clin Invest. 46:599-605. 41. Wallenberg LR, Granberg PO. 1975 Tubular sodium handling in cold exposed man during inhibition of distal tubular reabsorption of sodium. Stand J Clin Lab Invest. 35:319-22. 42. Himathongham T, Dluhy RG, Williams GH. 1975 Potassium aldosterone and renin interaction. J Clin Endocrinol Metab. 41:1539. 43. Williams ME, Gervino EV, Rosa RM, et al. 1985 Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med. 312:823-7. 44. Thulesius 0, Yousif MH. 1991 Na+K+-ATPase inhibition, a new mechanism for cold induced vasoconstriction in cutaneous veins. Acta Physiol Stand. 141:127-8. 45. Tonolo G, McMilan M, Polonia J, et al. 1988 Plasma clearance and effects of alpha-hANP infused in patients with end-stage renal failure. Am J Physiol. 23:F895-9.
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