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The Effect of Intermittent Exposure to Cold on the Development of Hypertension in the Rat
Continuous exposure to a cold (5°C) environment has been shown to induce hypertension in rats. The total time required for the first significant elevation of blood pressure is dependent on a number of factors, including the ambient temperature and the weight of the rat at the time of exposure to cold. The present study was also concerned with the minimal time of daily exposure to cold that would result in a significant elevation of blood pressure. To achieve this, we used four groups of rats. One was exposed to cold for 4 h daily (09:00 to 13:00), a second group was exposed to cold for 8 h daily (09:00 to 17:00), and a third was exposed for 24 h daily. The fourth group remained at 25 °C. Systolic blood pressures of the group exposed to continuous cold became elevated significantly above pre-cold exposure level within 2 weeks of cold exposure. Blood pressures of the groups exposed to cold for 4 and 8 h daily became elevated significantly above
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hronic exposure of laboratory rats to cold is accompanied by an increase in metabolic r a t e , an elevated concentration of norepinephrine in plasma, and an increased metabolic responsiveness to administration of ^-adrenergic agonists, including norepinephrine. " These physio1-3
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the level of the warm-adapted control group by day 27 of exposure to cold, but failed to reach the level of the chronically cold-exposed group even after 42 days of exposure to cold. There was a sigmoid-type relationship between the hours per day exposed to cold and systolic blood pressure at the end of the experiment. Thus, graded elevations of systolic blood pressure occur with increasing daily duration of exposure to cold. The groups exposed to cold for either 8 or 24 h daily also had significant increases in the weight of the heart compared with warmadapted controls. This is a further manifestation of the hypertension induced by exposure to cold. Am J Hypertens 1992:5:548-555
KEY WORDS: Cold, cold-induced hypertension, blood pressure, intermittent cold exposure, cardiac hypertrophy.
logic responses to cold can be considered beneficial because they are involved in the maintenance of body temperature. However, chronic exposure to cold is also accompanied by the development of hypertension. " The mechanisms involved are not known with certainty; however, recent studies revealed that changes in the baroreceptor reflexes, as well as the renin-angiotensin-aldosterone (RAA) system, may play a role. Thus, chronic treatment with the angiotensin I converting enzyme inhibitor, captopril, prevented the development of cold-induced hypertension. Several factors have been shown to influence the development of cold-induced hypertension. These include the body weight at time of exposure to cold, the ambient temperature, and the duration of exposure to cold. The 9
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Received September 16, 1991. Accepted April 28, 1992. From the Department of Physiology, College of Medicine, University of Florida, Gainesville, Florida. This study was supported by grant HL-39154-05 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Dr. Melvin J. Fregly, Department of Physiology, P.O. Box 100274, College of Medicine, University of Florida, Gainesville, FL 32610-0274.
© 1992 by the American Journal of Hypertension, Inc.
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Patricia van Bergen, Melvin J. Fregly, Fabian Rossi, and Orit Shechtman
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present study adds information concerning factors that can influence the elevation of blood pressure by assess ing the length of daily exposure to cold that is required to elevate blood pressure. MATERIALS AND M E T H O D S
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Chasson et a l , using the Technicon Autoanalyzer (Tarrytown, NY). Urinary sodium and potassium con centrations were measured by flame photometry (Corn ing 480; Ciba Corning Diagnostics Corp, Medfield, MA) using lithium as the internal standard. The responsiveness to angiotensin II (Ang II), as as sessed by spontaneous water intake, was measured during the sixth week. Each rat was weighed and placed alone into a metabolic cage without food. The chroni cally cold-treated group remained in the cold and the warm-adapted control group remained at 25 °C. The two intermittently cold-exposed groups had been in the cold for 5 0 % of their daily exposure before the adminis tration of Ang II, ie, Ang II was administered at 2 and 4 h after placement in the cold. After each rat was subcutaneously injected with 150 //g/kg Ang II (#A9525; Sigma Chemical Co., St. Louis, MO), a preweighed water bot tle was placed on its cage. The temperature of the water provided to the animals in the cold was 5°C, while that of the water provided to the warm-adapted controls was 25 °C. Water intakes were measured gravimetrically at 2 h after the administration of Ang II. During the sixth week, all animals were decapitated. Trunk blood was collected in chilled beakers containing EDTA, placed immediately on ice, and centrifuged in the cold. Plasma was removed and frozen at — 20° C for later analysis of plasma renin activity (PRA) by means of the New England Nuclear human radioimmunoassay kit (#1485; Baxter Healthcare Co., Cambridge, MA). At death, the heart, kidneys, thyroid, adrenal glands, and interscapular brown fat pad (IBFP) were removed, cleaned of extraneous tissue, and weighed on a torsion balance. We analyzed the data for systolic blood pressures, body weights, food and water intakes, urine outputs, and urinary outputs of sodium, potassium, and norepi nephrine using the repeated measures, one-way analy sis of variance (ANOVA). Organ weights, PRA, and dipsogenic responses to Ang II were analyzed by one way ANOVA. The post hoc Duncan's New Multiple Range test was used to test the significance of the differ ence between two individual means. The level of signifi cance was set at the 9 5 % confidence limit. All data are expressed as the mean ± SEM. 21
RESULTS Systolic blood pressures of the chronically cold-treated group increased significantly (P < .01) above those of the warm-adapted control group by day 13 of exposure to cold, and remained elevated significantly (P < .01) for the remainder of the experiment (Figure 1 A). Expo sure to cold for either 4 or 8 h daily also increased sys tolic blood pressure significantly from day 27 onward (P < .05 and Ρ < .01, respectively). However, blood pressures of the two groups exposed intermittently to cold did not reach that of the group exposed chronically
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We used 25 male rats of the Sprague-Dawley (Blue Spruce Farms, Indianapolis, IN) strain, initially weigh ing from 175 to 200 g. A 2-week control period preceded the experiment, during which systolic blood pressure and body weight of each rat were measured weekly. At the end of this time, we divided the animals ran domly into four groups and housed them individually in temperature-controlled chambers. Seven rats were ex posed to cold (5 ± 2°C) chronically (24 h/day); six rats were exposed to cold for 4 h/day between 09:00 and 13:00; six more rats were exposed to cold for 8 h/day between 09:00 and 17:00; and six control rats were housed at 25 ± 2°C. The chambers were illuminated from 0700 to 1900 h daily. Food (Purina Laboratory Chow #5001; Purina Mills, Inc., St. Louis, MO) and tap water were freely available to all animals. Fluid contain ers consisted of infant nursing bottles with bronze drinking spouts, and food containers were spillresistant. Systolic blood pressures of the rats in all groups were measured weekly without anesthesia, using the method of Fregly adapted for the NarcoBio Instruments Co. polygraph (Houston, TX). The intermittently coldexposed rats always had their systolic blood pressures measured before exposure to cold. All rats were placed in the thermoregulated box (33 to 35 °C) for 15 min before measurement of blood pressure. The rats that were kept continuously in the cold were removed from cold for 1 h each week before measurement of blood pressure. They were then warmed in the same fashion as the rats exposed intermittently to cold. Other details of measurement are described by Fregly, including cuff width, position of the cuff on the tail, and the relation ship of cuff width to blood pressure. In addition, the results of a correlation between the simultaneous mea surements of blood pressure directly and indirectly are presented. There was a direct linear relationship be tween the two, although the indirect measure of systolic blood pressure was slightly, but consistently, higher than the direct measure. Intakes of food and water, as well as urine outputs of each rat were measured for three consecutive days dur ing the control period, and during the first, second, fourth, and sixth weeks of exposure to cold. Urine was collected in 1 mL 6 Ν HC1, frozen at — 20° C and stored for later analysis of norepinephrine, creatinine, sodium, and potassium. We measured urinary norepinephrine concentration by high-pressure liquid chromatography with electrochemical detection, as described earlier. Urinary creatinine was measured by the method of
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also a significant (P < .001) treatment X time interac tion [F(27,189) = 4.23]. The latter suggests that there 8 140 was a significant difference in the rates of increase in LU body weight among the four groups. 130 We measured food intakes during the 2-week control X period and during the first, second, fourth, and sixth ° r- 120 weeks of exposure to cold (Figure 3A). The chronically cold-treated group, and the group exposed to cold for 110 • A WARM ο V 8 h daily, ingested significantly (P < .01) more food Ο Ο 4 HR IN COLD 100 + • · 8 HR IN COLD than the warm-adapted controls. There was no signifi 1 Δ Δ COLD cant difference in food intake between the warm1 90 1 1 μ——ι 1 1 1 CO adapted control group and the group exposed to cold for 4 h daily. Water intakes of chronically cold-treated rats in 425-τ creased significantly (P < .05) above the level of the 400 -warm-adapted group throughout the experiment (Fig 375-ure 3B). The water intakes of the groups exposed to cold 350I— for 4 and 8 h daily did not differ significantly from those 325χ of the warm-adapted controls. Daily urine outputs of ο LJ 300the chronically cold-treated group were increased signif 275icantly (P < .01) above those of the warm-adapted con >Ω 250-trol group throughout the experiment, whereas the out Ο m 225puts of both intermittently cold-exposed groups were 200not different from that of the warm-adapted control 175-group (Figure 3C). Urinary outputs of sodium did not differ significantly among the four groups before exposure to cold (Figure FIGURE 1. The effect of exposure to cold on systolic blood pres 4A). During exposure to cold, the chronically coldsure (A) and body weight (B) of rats. Treatments began when the exposed group excreted significantly (P < .01) more so rats were placed in cold (day 0). The groups are designated in the dium in urine than either the warm-adapted control figure. Means ± SEM are shown. When SE bars are not shown, group or the groups exposed to cold for 4 or 8 h daily. they fall within the symbol. After 2 weeks of exposure, the urinary sodium outputs of the two intermittently cold-exposed groups were less than, but not significantly different from, that of the to cold. During the same time, there was a nonsignifi cant trend toward an increase in the blood pressure of the warm-adapted control group. A one-way repeated measures ANOVA of the data revealed a significant χ (P < .001) effect of treatment [F(3,21) = 18.92]; a signifi Ε cant ( P < . 0 0 1 ) effect of time [F(8,168) = 27.52] and 140a significant (P < .001) treatment X time interaction or [F(24,168) = 3.47]. The latter suggests that the rates of ω in elevation of blood pressure differed among the four LU 1 3 0 C£ groups. Figure 2 shows that the cold-induced increase in Q_ systolic blood pressures in the treated groups is related Q to the amount of time each day that the animals were Ο ο 120· exposed to cold during the 42-day period. m The body weights did not differ significantly among ο the four groups before exposure to cold (Figure IB). LU
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FIGURE 2 . The relationship between the amount of time spent in cold each day and systolic blood pressure after 42 days of expo sure to cold. Means ± SEM are shown.
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After exposure to cold, body weights of the intermit tently cold-exposed groups were higher than the chron ically cold-treated and warm-adapted control groups; however a one-way repeated measures ANOVA re vealed no significant effect of treatment on body weight [F(3,21) = 2.08], although there was a signifi cant (P < .001) effect of time [F(9,189) = 1148.1] and
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week of exposure to cold when the group exposed to cold for 4 h daily excreted significantly (P < .05) less potassium compared with that of the warm-adapted control group. Urinary norepinephrine outputs did not differ signifi cantly among the four groups before exposure to cold (Figure 4C). After exposure to cold, urinary norepineph rine outputs of the chronically cold-exposed group in creased significantly (P < .01) compared with the warm-adapted control group, and then declined with increasing time. The urinary norepinephrine outputs of the group exposed to cold for 8 h/day showed a tend ency to increase during the first 2 weeks of exposure to cold; however these data were not significantly differ-
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WEEK FIGURE 3. The effects of exposure to cold on the mean daily intakes of food (A) and water (B) and the outputs of urine (C). The four groups are designated in the figure. Means ± SEM are shown.
warm-adapted control group. However, during the fourth week, the group exposed to cold for 4 h daily excreted significantly less (P < .05) sodium than did the warm-adapted controls. Urinary potassium outputs of the chronically coldexposed group increased significantly (P < .01) com pared with those of the other three groups (Figure 4B). The potassium outputs of the intermittently coldexposed groups did not differ significantly from those of the warm-adapted controls, except during the second
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FIGURE 4. The effects of exposure to cold on mean daily uri nary outputs of sodium (A) potassium (B) and norepinephrine (C) are shown for the four groups. Means ± SEM are shown.
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A - A WARM G - O 4 HR IN COLD 8 HR IN C O L D &—A C O L D
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FIGURE 5. Weights of heart (A), kidneys (B), thyroid gland (C), and brown fat (D) are shown for the four groups. Means ± SEM are shown. *P < .05, **P < .01 compared with the warm-adapted control group.
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sufficient to induce an increase in the weights of the heart (P < .05), thyroid gland (P < .05), and interscapu lar brown fat (P < .01), but not of the kidneys, com pared with the warm-adapted group. The weights of all organs of the intermittently cold-exposed groups were significantly less than those of the chronically coldtreated group (P < .05 to .01), except for the thyroid gland of the group exposed to cold for 8 h daily. There was a significant (P < .01) and direct relation ship between the weight of the thyroid gland and that of brown fat (Figure 6A). In addition, the relationship between the weight of the thyroid gland and systolic blood pressure was also significant (P < .01) and direct (Figure 6B). Plasma renin activity did not differ significantly among the groups, although there was a trend for the chronically cold-treated group to have a lower PRA. There were also no significant differences among the groups with respect to the dipsogenic responsiveness to
THYROID GLAND (mg/lOOg BW) FIGURE 6. The relationship between weight of the thyroid gland and weight of the IBFP (A) or systolic blood pressure (B) are shown. The equation, r, and Ρ are given in each figure.
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ent from the warm-adapted controls, except for the sec ond week of exposure to cold (P < .05). Urinary norepi nephrine outputs of the group exposed to cold for 4 h daily did not differ significantly from those of the warm-adapted controls. The outputs of urinary norepi nephrine were expressed as nanograms/milligram of creatinine to adjust for any changes that may have oc curred in renal function. On day 45 of exposure to cold, all of the rats in each group were killed. There was no change in the weight of the adrenal glands among all four groups; therefore, the data are not shown. The weights of the heart, kidneys, thyroid glands, and brown adipose tissue of the chroni cally cold-treated groups were significantly (P < .01) increased compared with those of the warm-adapted control group (Figure 5). Exposure to cold for 4 h/day did not induce a change in the weights of these organs compared with those of the warm-adapted control group, except for the weight of interscapular brown fat (P < .05). However, exposure to cold for 8 h/day was
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acute administration of Ang II; therefore, these data are not shown. DISCUSSION
Chronic exposure to cold also induced cardiac hypertrophy (Figure 5). This was observed in previous studies and was mainly associated with hypertrophy of the left ventricle. The present study suggests that cardiac hypertrophy was apparently less sensitive to exposure to cold than elevation of blood pressure, in that the group exposed to cold for 4 h/day had an elevation of blood pressure without cardiac hypertrophy. However, the group exposed to cold for 8 h/day had an increase in both. It is possible that the difference in cardiac hypertrophy between the two groups exposed intermittently to cold may be accounted for by differences in secretory activity of the thyroid gland. Elevation in serum concentrations of thyroxine (T ) and triiodothyronine (T ), alone and in combination with norepinephrine, can increase the weights of the heart and interscapular brown fat. Although the concentrations of these hormones in plasma were not measured in our study, they have been measured in other studies from this laboratory. Our previous studies have shown no effect of chronic exposure to cold on the T concentration in serum, but a significant increase in serum T concentration. This appears to be related to an increased monodeiodination of T by peripheral tissues of cold-treated rats, especially the liver and kidneys. Thus, there is an increased turnover of thyroid hormones. We measured the weight of the thyroid gland for this study. Consistent with the possibility that the cardiac hypertrophy observed in the group exposed to cold for 8 h/day could have been mediated by an increased turnover of thyroid hormones is the fact that the mean weight of the thyroid gland of this group was increased above those of either the group exposed to cold for 4 h/day or the warm-adapted control group. Also consistent is the fact that the food intake, and therefore the metabolic rate, of the group exposed to cold for 8 h/day was increased significantly above that of either the group exposed to cold for 4 h/ day or the warm-adapted control group. In addition, there was a significant (P < .01) linear relationship between thyroid weight and blood pressure, which suggests that this relationship merits further study (Figure 6). 22,24
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Chronic exposure to cold was accompanied by a significant increase in urinary output of norepinephrine (Figure 4C). An increase in the activity of the sympathetic nervous system during exposure to cold induces the increased production, and as a result, the increased excretion of norepinephrine. Exposure to cold for either 4 or 8 h daily did not significantly increase urinary norepinephrine output. Thus, norepinephrine is more likely to be responsible for maintaining heat production and body temperature of the cold-exposed animal ' than for inducing an elevation in blood pressure. Chronic exposure to cold results in dehydration of the cold-exposed animal, characterized by an increase in osmolality of plasma, a reduced ability to concentrate 4
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Chronic exposure to cold induces the syndrome of hypertension in laboratory r a t s . " The minimal time of exposure to cold required to elevate systolic blood pressure of the chronically cold-treated group was about 2 weeks (Figure 1). Other studies from this laboratory have shown that this time is affected by a number of variables, including the initial body weight of the rats at time of exposure to cold, ambient temperature, and number of days the animals are exposed to cold. It is clear from the results of our study that the number of hours per day that the rats were exposed to cold was also important. However, it is not clear from the data shown in Figures 1 and 2 whether the blood pressures of the groups exposed intermittently to cold might have risen to the level of that of the group exposed continuously to cold if the daily exposures had continued for a sufficient period of time. Thus, whether exposure to cold for 12 h/day would require twice as much time to achieve the same elevation of blood pressure as that achieved by continuous exposure to cold remains a possibility; however, this theory will require additional study for verification. The mechanism(s) responsible for mediation of the elevation of blood pressure during exposure to cold is not fully understood. At present, several possibilities have emerged. The first of these is associated with a significant reduction in baroreceptor sensitivity in the cold-treated rats. This would indicate a reduced inhibitory control of central sympathetic discharge to the periphery and would be accompanied by an increased rate of secretion of norepinephrine. The second possibility, which may be a secondary response to the first, may involve the RAA system. Because the secretion of renin can be stimulated by an increase in the circulating concentration of norepinephrine, it is likely that activation of the RAA system is initiated by the reduction in the baroreceptor sensitivity. Recent studies from this laboratory have shown an activation of the RAA system, as assessed by PRA, within the first 2 weeks of exposure to cold, after which PRA declines. By the fourth week of exposure to cold, PRA was reduced below the level of warm-adapted controls and dipsogenic responsiveness to administered Ang II increased. In that study, a negative linear relationship existed between PRA and dipsogenic responsiveness to Ang I I . This finding would be expected, as the amount of circulating Ang II influences the regulation of its receptors. Further evidence that the RAA system plays a role was provided by the facts that chronic treatment with either captopril, an angiotensin I converting enzyme inhibitor, or spironolactone, an aldosterone receptor antagonist, inhibited the development of cold-induced hypertension. 22
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norepinephrine in cold-adapted and exercise-trained rats. Can J Physiol Pharmacol 1982;60:783-787. 9.
Fregly MJ: Effects of extremes of temperature on hyper tensive rats. Am J Physiol 1954;176:275-281.
10.
Gilson SB: Studies on the adaptation to cold air in the rat. Am J Physiol 1950;161:87-91.
11.
Heroux O, Dugal LP: Effect de l'acide ascorbique sur Thypertension experimental. Can J Med Sci 1961; 29:164-175.
12.
Papanek PE, Wood CE, Fregly MJ: Role of the sympa thetic nervous system in cold-induced hypertension in rats. J Appl Physiol 1991;71(l):300-306.
13.
Fregly MJ, Shechtman O, Van Bergen P, et al: Changes in blood pressure and dipsogenic responsiveness to angio tensin II during chronic exposure of rats to cold. Pharma col Biochem Behav 1991;38:837-842.
14.
Shechtman O, Fregly MJ, Van Bergen P, et al: Prevention of cold-induced increase in blood pressure of rats by captopril. Hypertension 1991;17:763-770.
15.
Shechtman O, Fregly MJ, Papanek PE: Factors affecting cold-induced hypertension in rats. Proc Soc Exp Biol Med 1990;195:364-368.
16.
Lazarow A: Methods for quantitative measurement of water intake. Methods Med Res 1954;6:225-229.
17.
Fregly MJ: A simple and accurate feeding device for rats. J Appl Physiol 1960;15:539.
18.
Fregly MJ: Factors affecting indirect determination of sys tolic blood pressure. J Lab Clin Med 1963;62:223-230.
19.
Carlberg KA, Fregly MJ: Catecholamine excretion and beta-adrenergic responsiveness in estrogen-treated rats. Pharmacology 1986;32:147-156.
20.
Henley WM, Fregly MJ, Wilson KM, et al: Physiologic responses to chronic dietary tyrosine supplementation in DOCA-treated rats. Pharmacology 1986;33:334-347.
21.
Chasson AL, Grady HJ, Stanley MA: Determination of creatinine by means of automatic chemical analysis. Am J Clin Pathol 1961;35:83-88.
22.
Fregly MJ, Kikta DC, Threatte RM, et al: Development of hypertension in rats during chronic exposure to cold. J Appl Physiol 1989;66:741-749.
23.
Fregly MJ, Papanek PE: Cold-induced hypertension in rats, in Mercer JB (ed): Thermal Physiology 1989. Am sterdam, Elsevier, 1989, pp 551-557.
24.
Shechtman O, Papanek PE, Fregly MJ: Reversibility of cold-induced hypertension after removal of rats from cold. Can J Physiol Pharmacol 1990;68:830-835.
25.
Baron A, Riesselmann A, Fregly MJ: Effect of chronic treatment with clonidine and spironolactone on coldinduced elevation of blood pressure. Pharmacology 1991;43:173-186.
26.
Fregly MJ: Activity of the hypothalamic-pituitarythyroid axis during exposure to cold, in Schonbaum E, Lomax Ρ (eds): Thermoregulation: Physiology and Bio chemistry. New York, Pergamon Press, 1990, pp 437494.
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Scammell JG, Shiverick KT, Fregly MJ: In vitro hepatic deiodination of L-thyroxine to 3,5,3'-truodothyronine in cold-acclimated rats. J Appl Physiol Resp Environ Exer cise Physiol 1980;49:386-389.
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ACKNOWLEDGEMENTS The authors thank Ms. Patricia Hill, Mrs. Charlotte Edelstein, Mr. Thomas Connor, and Mr. Scott Stetson for technical assist ance. REFERENCES 1.
Adolph EF: Oxygen consumption of hypothermic rats and acclimation to cold. Am J Physiol 1950;161:359373.
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Ring GC: Thyroid stimulation by cold, including the ef fect of changes in body temperature upon basal metabo lism. Am J Physiol 1939;125:244-250.
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Schwabe DL, Emery FE, Griffith FR: The effect of pro longed exposure to low temperature on the basal metbolism of the rat. J Nutr 1938;15:199-210.
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Leduc J: Catecholamine production and release in expo sure and acclimation to cold. Acta Physiol Scand 1961;53(suppl 183):1-101.
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Barney CC, Katovich MJ, Fregly MJ, et al: Changes in ^-adrenergic responsiveness of rats during chronic cold exposure. J Appl Physiol 1980;49:923-929.
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Fregly MJ, Kaplan BJ, Tyler PE: Increased responsive ness of heart rate to ^-adrenergic stimulation in coldadapted rats. Aviat Space Environ Med 1977;48:413417.
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Fregly MJ, Field FP, Nelson EL, et al: Effect of chronic exposure to cold on some responses to catecholamines. J Appl Physiol 1977;42:349-354.
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urine during a 24-h dehydration in cold, and a striking drinking response that occurs immediately after re moval from cold. Relative dehydration is also sug gested by the fact that the group exposed continuously to cold had a reduced water intake for a given food intake, compared with warm-acclimated controls (Fig ure 3). The groups exposed intermittently to cold did not show this effect. Voluntary dehydration may be an im portant aspect of acclimation and survival in the cold. This will require additional study for verification. An increase in the weight of the IBFP is characteristic of rats exposed to cold and is associated with nonshivering thermogenesis. The fact that all three groups exposed to cold had a significant increase in IBFP sug gests that all three groups were using nonshivering thermogenesis to maintain body temperature. Cold-induced elevation of blood pressure may not be restricted to r a t s . " Elevations of blood pressure have been reported in men living for 42 weeks in Antarctica, as well as seasonally for patients visiting clinics throughout the y e a r . ' Additional studies are needed to determine whether individuals whose occu pations require them to be exposed daily, but intermit tently, to cold are more prone to develop elevations in their blood pressure.
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Fregly MJ: Effect of exposure to cold on fluid and electrolyte exchange, in Claybaugh JR, Wade CE (eds): Hormonal Regulation of Fluid and Electrolytes. New York, Plenum, 1989, pp 87-116.
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Brennan PJ, Greenberg G, Miall WE, et al: Seasonal variation in arterial blood pressure. Br Med J 1982;285:919923.
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Reed HL, Bryce D, Shakir KM, et al: Human thyroidal and cardiovascular responses to prolonged Antarctic residence (abst). Fed Proc 1987,46:332.
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Bull GM, Morton J: Environment, temperature and death rates. Age Ageing 1978;7:210-214.
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Hata T, Ogihara T, Maruyama A, et al: The seasonal variation in blood pressure in patients with essential hy-
Tanaka S, Konno A, Hashimoto A, et al: The influence of cold temperatures on the progression of hypertension: an epidemiological study. J Hypertens 1989;7(suppl 1):S49-S51.
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1992;
5:548-555
The Effect of Intermittent Exposure to Cold on the Development of Hypertension in the Rat
Continuous exposure to a cold (5°C) environment has been shown to induce hypertension in rats. The total time required for the first significant elevation of blood pressure is dependent on a number of factors, including the ambient temperature and the weight of the rat at the time of exposure to cold. The present study was also concerned with the minimal time of daily exposure to cold that would result in a significant elevation of blood pressure. To achieve this, we used four groups of rats. One was exposed to cold for 4 h daily (09:00 to 13:00), a second group was exposed to cold for 8 h daily (09:00 to 17:00), and a third was exposed for 24 h daily. The fourth group remained at 25 °C. Systolic blood pressures of the group exposed to continuous cold became elevated significantly above pre-cold exposure level within 2 weeks of cold exposure. Blood pressures of the groups exposed to cold for 4 and 8 h daily became elevated significantly above
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hronic exposure of laboratory rats to cold is accompanied by an increase in metabolic r a t e , an elevated concentration of norepinephrine in plasma, and an increased metabolic responsiveness to administration of ^-adrenergic agonists, including norepinephrine. " These physio1-3
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the level of the warm-adapted control group by day 27 of exposure to cold, but failed to reach the level of the chronically cold-exposed group even after 42 days of exposure to cold. There was a sigmoid-type relationship between the hours per day exposed to cold and systolic blood pressure at the end of the experiment. Thus, graded elevations of systolic blood pressure occur with increasing daily duration of exposure to cold. The groups exposed to cold for either 8 or 24 h daily also had significant increases in the weight of the heart compared with warmadapted controls. This is a further manifestation of the hypertension induced by exposure to cold. Am J Hypertens 1992:5:548-555
KEY WORDS: Cold, cold-induced hypertension, blood pressure, intermittent cold exposure, cardiac hypertrophy.
logic responses to cold can be considered beneficial because they are involved in the maintenance of body temperature. However, chronic exposure to cold is also accompanied by the development of hypertension. " The mechanisms involved are not known with certainty; however, recent studies revealed that changes in the baroreceptor reflexes, as well as the renin-angiotensin-aldosterone (RAA) system, may play a role. Thus, chronic treatment with the angiotensin I converting enzyme inhibitor, captopril, prevented the development of cold-induced hypertension. Several factors have been shown to influence the development of cold-induced hypertension. These include the body weight at time of exposure to cold, the ambient temperature, and the duration of exposure to cold. The 9
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Received September 16, 1991. Accepted April 28, 1992. From the Department of Physiology, College of Medicine, University of Florida, Gainesville, Florida. This study was supported by grant HL-39154-05 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Address correspondence and reprint requests to Dr. Melvin J. Fregly, Department of Physiology, P.O. Box 100274, College of Medicine, University of Florida, Gainesville, FL 32610-0274.
© 1992 by the American Journal of Hypertension, Inc.
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Patricia van Bergen, Melvin J. Fregly, Fabian Rossi, and Orit Shechtman
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present study adds information concerning factors that can influence the elevation of blood pressure by assess ing the length of daily exposure to cold that is required to elevate blood pressure. MATERIALS AND M E T H O D S
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Chasson et a l , using the Technicon Autoanalyzer (Tarrytown, NY). Urinary sodium and potassium con centrations were measured by flame photometry (Corn ing 480; Ciba Corning Diagnostics Corp, Medfield, MA) using lithium as the internal standard. The responsiveness to angiotensin II (Ang II), as as sessed by spontaneous water intake, was measured during the sixth week. Each rat was weighed and placed alone into a metabolic cage without food. The chroni cally cold-treated group remained in the cold and the warm-adapted control group remained at 25 °C. The two intermittently cold-exposed groups had been in the cold for 5 0 % of their daily exposure before the adminis tration of Ang II, ie, Ang II was administered at 2 and 4 h after placement in the cold. After each rat was subcutaneously injected with 150 //g/kg Ang II (#A9525; Sigma Chemical Co., St. Louis, MO), a preweighed water bot tle was placed on its cage. The temperature of the water provided to the animals in the cold was 5°C, while that of the water provided to the warm-adapted controls was 25 °C. Water intakes were measured gravimetrically at 2 h after the administration of Ang II. During the sixth week, all animals were decapitated. Trunk blood was collected in chilled beakers containing EDTA, placed immediately on ice, and centrifuged in the cold. Plasma was removed and frozen at — 20° C for later analysis of plasma renin activity (PRA) by means of the New England Nuclear human radioimmunoassay kit (#1485; Baxter Healthcare Co., Cambridge, MA). At death, the heart, kidneys, thyroid, adrenal glands, and interscapular brown fat pad (IBFP) were removed, cleaned of extraneous tissue, and weighed on a torsion balance. We analyzed the data for systolic blood pressures, body weights, food and water intakes, urine outputs, and urinary outputs of sodium, potassium, and norepi nephrine using the repeated measures, one-way analy sis of variance (ANOVA). Organ weights, PRA, and dipsogenic responses to Ang II were analyzed by one way ANOVA. The post hoc Duncan's New Multiple Range test was used to test the significance of the differ ence between two individual means. The level of signifi cance was set at the 9 5 % confidence limit. All data are expressed as the mean ± SEM. 21
RESULTS Systolic blood pressures of the chronically cold-treated group increased significantly (P < .01) above those of the warm-adapted control group by day 13 of exposure to cold, and remained elevated significantly (P < .01) for the remainder of the experiment (Figure 1 A). Expo sure to cold for either 4 or 8 h daily also increased sys tolic blood pressure significantly from day 27 onward (P < .05 and Ρ < .01, respectively). However, blood pressures of the two groups exposed intermittently to cold did not reach that of the group exposed chronically
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We used 25 male rats of the Sprague-Dawley (Blue Spruce Farms, Indianapolis, IN) strain, initially weigh ing from 175 to 200 g. A 2-week control period preceded the experiment, during which systolic blood pressure and body weight of each rat were measured weekly. At the end of this time, we divided the animals ran domly into four groups and housed them individually in temperature-controlled chambers. Seven rats were ex posed to cold (5 ± 2°C) chronically (24 h/day); six rats were exposed to cold for 4 h/day between 09:00 and 13:00; six more rats were exposed to cold for 8 h/day between 09:00 and 17:00; and six control rats were housed at 25 ± 2°C. The chambers were illuminated from 0700 to 1900 h daily. Food (Purina Laboratory Chow #5001; Purina Mills, Inc., St. Louis, MO) and tap water were freely available to all animals. Fluid contain ers consisted of infant nursing bottles with bronze drinking spouts, and food containers were spillresistant. Systolic blood pressures of the rats in all groups were measured weekly without anesthesia, using the method of Fregly adapted for the NarcoBio Instruments Co. polygraph (Houston, TX). The intermittently coldexposed rats always had their systolic blood pressures measured before exposure to cold. All rats were placed in the thermoregulated box (33 to 35 °C) for 15 min before measurement of blood pressure. The rats that were kept continuously in the cold were removed from cold for 1 h each week before measurement of blood pressure. They were then warmed in the same fashion as the rats exposed intermittently to cold. Other details of measurement are described by Fregly, including cuff width, position of the cuff on the tail, and the relation ship of cuff width to blood pressure. In addition, the results of a correlation between the simultaneous mea surements of blood pressure directly and indirectly are presented. There was a direct linear relationship be tween the two, although the indirect measure of systolic blood pressure was slightly, but consistently, higher than the direct measure. Intakes of food and water, as well as urine outputs of each rat were measured for three consecutive days dur ing the control period, and during the first, second, fourth, and sixth weeks of exposure to cold. Urine was collected in 1 mL 6 Ν HC1, frozen at — 20° C and stored for later analysis of norepinephrine, creatinine, sodium, and potassium. We measured urinary norepinephrine concentration by high-pressure liquid chromatography with electrochemical detection, as described earlier. Urinary creatinine was measured by the method of
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also a significant (P < .001) treatment X time interac tion [F(27,189) = 4.23]. The latter suggests that there 8 140 was a significant difference in the rates of increase in LU body weight among the four groups. 130 We measured food intakes during the 2-week control X period and during the first, second, fourth, and sixth ° r- 120 weeks of exposure to cold (Figure 3A). The chronically cold-treated group, and the group exposed to cold for 110 • A WARM ο V 8 h daily, ingested significantly (P < .01) more food Ο Ο 4 HR IN COLD 100 + • · 8 HR IN COLD than the warm-adapted controls. There was no signifi 1 Δ Δ COLD cant difference in food intake between the warm1 90 1 1 μ——ι 1 1 1 CO adapted control group and the group exposed to cold for 4 h daily. Water intakes of chronically cold-treated rats in 425-τ creased significantly (P < .05) above the level of the 400 -warm-adapted group throughout the experiment (Fig 375-ure 3B). The water intakes of the groups exposed to cold 350I— for 4 and 8 h daily did not differ significantly from those 325χ of the warm-adapted controls. Daily urine outputs of ο LJ 300the chronically cold-treated group were increased signif 275icantly (P < .01) above those of the warm-adapted con >Ω 250-trol group throughout the experiment, whereas the out Ο m 225puts of both intermittently cold-exposed groups were 200not different from that of the warm-adapted control 175-group (Figure 3C). Urinary outputs of sodium did not differ significantly among the four groups before exposure to cold (Figure FIGURE 1. The effect of exposure to cold on systolic blood pres 4A). During exposure to cold, the chronically coldsure (A) and body weight (B) of rats. Treatments began when the exposed group excreted significantly (P < .01) more so rats were placed in cold (day 0). The groups are designated in the dium in urine than either the warm-adapted control figure. Means ± SEM are shown. When SE bars are not shown, group or the groups exposed to cold for 4 or 8 h daily. they fall within the symbol. After 2 weeks of exposure, the urinary sodium outputs of the two intermittently cold-exposed groups were less than, but not significantly different from, that of the to cold. During the same time, there was a nonsignifi cant trend toward an increase in the blood pressure of the warm-adapted control group. A one-way repeated measures ANOVA of the data revealed a significant χ (P < .001) effect of treatment [F(3,21) = 18.92]; a signifi Ε cant ( P < . 0 0 1 ) effect of time [F(8,168) = 27.52] and 140a significant (P < .001) treatment X time interaction or [F(24,168) = 3.47]. The latter suggests that the rates of ω in elevation of blood pressure differed among the four LU 1 3 0 C£ groups. Figure 2 shows that the cold-induced increase in Q_ systolic blood pressures in the treated groups is related Q to the amount of time each day that the animals were Ο ο 120· exposed to cold during the 42-day period. m The body weights did not differ significantly among ο the four groups before exposure to cold (Figure IB). LU
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FIGURE 2 . The relationship between the amount of time spent in cold each day and systolic blood pressure after 42 days of expo sure to cold. Means ± SEM are shown.
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After exposure to cold, body weights of the intermit tently cold-exposed groups were higher than the chron ically cold-treated and warm-adapted control groups; however a one-way repeated measures ANOVA re vealed no significant effect of treatment on body weight [F(3,21) = 2.08], although there was a signifi cant (P < .001) effect of time [F(9,189) = 1148.1] and
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week of exposure to cold when the group exposed to cold for 4 h daily excreted significantly (P < .05) less potassium compared with that of the warm-adapted control group. Urinary norepinephrine outputs did not differ signifi cantly among the four groups before exposure to cold (Figure 4C). After exposure to cold, urinary norepineph rine outputs of the chronically cold-exposed group in creased significantly (P < .01) compared with the warm-adapted control group, and then declined with increasing time. The urinary norepinephrine outputs of the group exposed to cold for 8 h/day showed a tend ency to increase during the first 2 weeks of exposure to cold; however these data were not significantly differ-
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WEEK FIGURE 3. The effects of exposure to cold on the mean daily intakes of food (A) and water (B) and the outputs of urine (C). The four groups are designated in the figure. Means ± SEM are shown.
warm-adapted control group. However, during the fourth week, the group exposed to cold for 4 h daily excreted significantly less (P < .05) sodium than did the warm-adapted controls. Urinary potassium outputs of the chronically coldexposed group increased significantly (P < .01) com pared with those of the other three groups (Figure 4B). The potassium outputs of the intermittently coldexposed groups did not differ significantly from those of the warm-adapted controls, except during the second
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FIGURE 4. The effects of exposure to cold on mean daily uri nary outputs of sodium (A) potassium (B) and norepinephrine (C) are shown for the four groups. Means ± SEM are shown.
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A - A WARM G - O 4 HR IN COLD 8 HR IN C O L D &—A C O L D
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FIGURE 5. Weights of heart (A), kidneys (B), thyroid gland (C), and brown fat (D) are shown for the four groups. Means ± SEM are shown. *P < .05, **P < .01 compared with the warm-adapted control group.
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sufficient to induce an increase in the weights of the heart (P < .05), thyroid gland (P < .05), and interscapu lar brown fat (P < .01), but not of the kidneys, com pared with the warm-adapted group. The weights of all organs of the intermittently cold-exposed groups were significantly less than those of the chronically coldtreated group (P < .05 to .01), except for the thyroid gland of the group exposed to cold for 8 h daily. There was a significant (P < .01) and direct relation ship between the weight of the thyroid gland and that of brown fat (Figure 6A). In addition, the relationship between the weight of the thyroid gland and systolic blood pressure was also significant (P < .01) and direct (Figure 6B). Plasma renin activity did not differ significantly among the groups, although there was a trend for the chronically cold-treated group to have a lower PRA. There were also no significant differences among the groups with respect to the dipsogenic responsiveness to
THYROID GLAND (mg/lOOg BW) FIGURE 6. The relationship between weight of the thyroid gland and weight of the IBFP (A) or systolic blood pressure (B) are shown. The equation, r, and Ρ are given in each figure.
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ent from the warm-adapted controls, except for the sec ond week of exposure to cold (P < .05). Urinary norepi nephrine outputs of the group exposed to cold for 4 h daily did not differ significantly from those of the warm-adapted controls. The outputs of urinary norepi nephrine were expressed as nanograms/milligram of creatinine to adjust for any changes that may have oc curred in renal function. On day 45 of exposure to cold, all of the rats in each group were killed. There was no change in the weight of the adrenal glands among all four groups; therefore, the data are not shown. The weights of the heart, kidneys, thyroid glands, and brown adipose tissue of the chroni cally cold-treated groups were significantly (P < .01) increased compared with those of the warm-adapted control group (Figure 5). Exposure to cold for 4 h/day did not induce a change in the weights of these organs compared with those of the warm-adapted control group, except for the weight of interscapular brown fat (P < .05). However, exposure to cold for 8 h/day was
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acute administration of Ang II; therefore, these data are not shown. DISCUSSION
Chronic exposure to cold also induced cardiac hypertrophy (Figure 5). This was observed in previous studies and was mainly associated with hypertrophy of the left ventricle. The present study suggests that cardiac hypertrophy was apparently less sensitive to exposure to cold than elevation of blood pressure, in that the group exposed to cold for 4 h/day had an elevation of blood pressure without cardiac hypertrophy. However, the group exposed to cold for 8 h/day had an increase in both. It is possible that the difference in cardiac hypertrophy between the two groups exposed intermittently to cold may be accounted for by differences in secretory activity of the thyroid gland. Elevation in serum concentrations of thyroxine (T ) and triiodothyronine (T ), alone and in combination with norepinephrine, can increase the weights of the heart and interscapular brown fat. Although the concentrations of these hormones in plasma were not measured in our study, they have been measured in other studies from this laboratory. Our previous studies have shown no effect of chronic exposure to cold on the T concentration in serum, but a significant increase in serum T concentration. This appears to be related to an increased monodeiodination of T by peripheral tissues of cold-treated rats, especially the liver and kidneys. Thus, there is an increased turnover of thyroid hormones. We measured the weight of the thyroid gland for this study. Consistent with the possibility that the cardiac hypertrophy observed in the group exposed to cold for 8 h/day could have been mediated by an increased turnover of thyroid hormones is the fact that the mean weight of the thyroid gland of this group was increased above those of either the group exposed to cold for 4 h/day or the warm-adapted control group. Also consistent is the fact that the food intake, and therefore the metabolic rate, of the group exposed to cold for 8 h/day was increased significantly above that of either the group exposed to cold for 4 h/ day or the warm-adapted control group. In addition, there was a significant (P < .01) linear relationship between thyroid weight and blood pressure, which suggests that this relationship merits further study (Figure 6). 22,24
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Chronic exposure to cold was accompanied by a significant increase in urinary output of norepinephrine (Figure 4C). An increase in the activity of the sympathetic nervous system during exposure to cold induces the increased production, and as a result, the increased excretion of norepinephrine. Exposure to cold for either 4 or 8 h daily did not significantly increase urinary norepinephrine output. Thus, norepinephrine is more likely to be responsible for maintaining heat production and body temperature of the cold-exposed animal ' than for inducing an elevation in blood pressure. Chronic exposure to cold results in dehydration of the cold-exposed animal, characterized by an increase in osmolality of plasma, a reduced ability to concentrate 4
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Chronic exposure to cold induces the syndrome of hypertension in laboratory r a t s . " The minimal time of exposure to cold required to elevate systolic blood pressure of the chronically cold-treated group was about 2 weeks (Figure 1). Other studies from this laboratory have shown that this time is affected by a number of variables, including the initial body weight of the rats at time of exposure to cold, ambient temperature, and number of days the animals are exposed to cold. It is clear from the results of our study that the number of hours per day that the rats were exposed to cold was also important. However, it is not clear from the data shown in Figures 1 and 2 whether the blood pressures of the groups exposed intermittently to cold might have risen to the level of that of the group exposed continuously to cold if the daily exposures had continued for a sufficient period of time. Thus, whether exposure to cold for 12 h/day would require twice as much time to achieve the same elevation of blood pressure as that achieved by continuous exposure to cold remains a possibility; however, this theory will require additional study for verification. The mechanism(s) responsible for mediation of the elevation of blood pressure during exposure to cold is not fully understood. At present, several possibilities have emerged. The first of these is associated with a significant reduction in baroreceptor sensitivity in the cold-treated rats. This would indicate a reduced inhibitory control of central sympathetic discharge to the periphery and would be accompanied by an increased rate of secretion of norepinephrine. The second possibility, which may be a secondary response to the first, may involve the RAA system. Because the secretion of renin can be stimulated by an increase in the circulating concentration of norepinephrine, it is likely that activation of the RAA system is initiated by the reduction in the baroreceptor sensitivity. Recent studies from this laboratory have shown an activation of the RAA system, as assessed by PRA, within the first 2 weeks of exposure to cold, after which PRA declines. By the fourth week of exposure to cold, PRA was reduced below the level of warm-adapted controls and dipsogenic responsiveness to administered Ang II increased. In that study, a negative linear relationship existed between PRA and dipsogenic responsiveness to Ang I I . This finding would be expected, as the amount of circulating Ang II influences the regulation of its receptors. Further evidence that the RAA system plays a role was provided by the facts that chronic treatment with either captopril, an angiotensin I converting enzyme inhibitor, or spironolactone, an aldosterone receptor antagonist, inhibited the development of cold-induced hypertension. 22
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norepinephrine in cold-adapted and exercise-trained rats. Can J Physiol Pharmacol 1982;60:783-787. 9.
Fregly MJ: Effects of extremes of temperature on hyper tensive rats. Am J Physiol 1954;176:275-281.
10.
Gilson SB: Studies on the adaptation to cold air in the rat. Am J Physiol 1950;161:87-91.
11.
Heroux O, Dugal LP: Effect de l'acide ascorbique sur Thypertension experimental. Can J Med Sci 1961; 29:164-175.
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Papanek PE, Wood CE, Fregly MJ: Role of the sympa thetic nervous system in cold-induced hypertension in rats. J Appl Physiol 1991;71(l):300-306.
13.
Fregly MJ, Shechtman O, Van Bergen P, et al: Changes in blood pressure and dipsogenic responsiveness to angio tensin II during chronic exposure of rats to cold. Pharma col Biochem Behav 1991;38:837-842.
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Shechtman O, Fregly MJ, Van Bergen P, et al: Prevention of cold-induced increase in blood pressure of rats by captopril. Hypertension 1991;17:763-770.
15.
Shechtman O, Fregly MJ, Papanek PE: Factors affecting cold-induced hypertension in rats. Proc Soc Exp Biol Med 1990;195:364-368.
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Lazarow A: Methods for quantitative measurement of water intake. Methods Med Res 1954;6:225-229.
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Fregly MJ: A simple and accurate feeding device for rats. J Appl Physiol 1960;15:539.
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Fregly MJ: Factors affecting indirect determination of sys tolic blood pressure. J Lab Clin Med 1963;62:223-230.
19.
Carlberg KA, Fregly MJ: Catecholamine excretion and beta-adrenergic responsiveness in estrogen-treated rats. Pharmacology 1986;32:147-156.
20.
Henley WM, Fregly MJ, Wilson KM, et al: Physiologic responses to chronic dietary tyrosine supplementation in DOCA-treated rats. Pharmacology 1986;33:334-347.
21.
Chasson AL, Grady HJ, Stanley MA: Determination of creatinine by means of automatic chemical analysis. Am J Clin Pathol 1961;35:83-88.
22.
Fregly MJ, Kikta DC, Threatte RM, et al: Development of hypertension in rats during chronic exposure to cold. J Appl Physiol 1989;66:741-749.
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Fregly MJ, Papanek PE: Cold-induced hypertension in rats, in Mercer JB (ed): Thermal Physiology 1989. Am sterdam, Elsevier, 1989, pp 551-557.
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Shechtman O, Papanek PE, Fregly MJ: Reversibility of cold-induced hypertension after removal of rats from cold. Can J Physiol Pharmacol 1990;68:830-835.
25.
Baron A, Riesselmann A, Fregly MJ: Effect of chronic treatment with clonidine and spironolactone on coldinduced elevation of blood pressure. Pharmacology 1991;43:173-186.
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Fregly MJ: Activity of the hypothalamic-pituitarythyroid axis during exposure to cold, in Schonbaum E, Lomax Ρ (eds): Thermoregulation: Physiology and Bio chemistry. New York, Pergamon Press, 1990, pp 437494.
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Scammell JG, Shiverick KT, Fregly MJ: In vitro hepatic deiodination of L-thyroxine to 3,5,3'-truodothyronine in cold-acclimated rats. J Appl Physiol Resp Environ Exer cise Physiol 1980;49:386-389.
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ACKNOWLEDGEMENTS The authors thank Ms. Patricia Hill, Mrs. Charlotte Edelstein, Mr. Thomas Connor, and Mr. Scott Stetson for technical assist ance. REFERENCES 1.
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Fregly MJ, Kaplan BJ, Tyler PE: Increased responsive ness of heart rate to ^-adrenergic stimulation in coldadapted rats. Aviat Space Environ Med 1977;48:413417.
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urine during a 24-h dehydration in cold, and a striking drinking response that occurs immediately after re moval from cold. Relative dehydration is also sug gested by the fact that the group exposed continuously to cold had a reduced water intake for a given food intake, compared with warm-acclimated controls (Fig ure 3). The groups exposed intermittently to cold did not show this effect. Voluntary dehydration may be an im portant aspect of acclimation and survival in the cold. This will require additional study for verification. An increase in the weight of the IBFP is characteristic of rats exposed to cold and is associated with nonshivering thermogenesis. The fact that all three groups exposed to cold had a significant increase in IBFP sug gests that all three groups were using nonshivering thermogenesis to maintain body temperature. Cold-induced elevation of blood pressure may not be restricted to r a t s . " Elevations of blood pressure have been reported in men living for 42 weeks in Antarctica, as well as seasonally for patients visiting clinics throughout the y e a r . ' Additional studies are needed to determine whether individuals whose occu pations require them to be exposed daily, but intermit tently, to cold are more prone to develop elevations in their blood pressure.
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