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J Appl Physiol 100: 1719-1726, 2006. First published December 29, 2005; doi:10.1152/japplphysiol.01407.2005
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HIGHLIGHTED TOPICS
A Physiological Systems Approach to Human and Mammalian Thermoregulation

Effects of chronic cold exposure on the endothelin system

Gin-Fu Chen and Zhongjie Sun

Departments of Medicine and Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, Florida

Submitted 7 November 2005 ; accepted in final form 22 December 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Cold temperatures have adverse effects on the human cardiovascular system. Endothelin (ET)-1 is a potent vasoconstrictor. We hypothesized that cold exposure increases ET-1 production and upregulates ET type A (ETA) receptors. The aim of this study was to determine the effect of cold exposure on regulation of the ET system. Four groups of rats (6–7 rats/group) were used: three groups were exposed to moderate cold (6.7 ± 2°C) for 1, 3, and 5 wk, respectively, and the remaining group was maintained at room temperature (25°C) and served as control. Cold exposure significantly increased ET-1 levels in the heart, mesenteric arteries, renal cortex, and renal medulla. Cold exposure increased ETA receptor protein expression in the heart and renal cortex. ET type B (ETB) receptor expression, however, was decreased significantly in the heart and renal medulla of cold-exposed rats. Cold exposure significantly increased the ratio of ETA to ETB receptors in the heart. An additional four groups of rats (3 rats/group) were used to localize changes in ETA and ETB receptors at 1, 3, and 5 wk of cold exposure. Immunohistochemical analysis showed an increase in ETA, but a decrease in ETB, receptor immunoreactivity in cardiomyocytes of cold-exposed rats. Increased ETA receptor immunoreactivity was also found in vascular smooth muscle cells of cold-exposed rats. Cold exposure increased ETA receptor immunoreactivity in tubule epithelial cells in the renal cortex but decreased ETB receptor immunoreactivity in tubule epithelial cells in the renal medulla. Therefore, cold exposure increased ET-1 production, upregulated ETA receptors, and downregulated ETB receptors.

endothelin type A receptors; endothelin type B receptors; cold-induced hypertension; cardiac hypertrophy

IT IS WELL DOCUMENTED that cold temperatures have adverse effects on the human cardiovascular system (5, 12, 14, 21, 30, 35, 37). Hypertension and related cardiovascular diseases are more prevalent in people who live in cold climates. Mortality and morbidity of cardiovascular diseases are highest in the cold winter season in the United States (5, 36, 37). Cold temperatures exacerbate hypertension in hypertensive patients (12, 14, 21, 30, 37). Chronic cold exposure induces hypertension and cardiac hypertrophy, namely, cold-induced hypertension (CIH), in rats within 1–3 wk (39, 45). CIH provides a noninvasive and natural method for inducing a consistent form of hypertension and cardiac hypertrophy. However, the mechanisms mediating CIH and other cold-related cardiovascular complications are not fully understood, although the involvement of the renin-angiotensin system (RAS) has been studied (43, 44, 46).

The endothelin (ET) system plays an important role in regulation of blood pressure (BP), vascular tone, myocardial contractility, fluid balance, and hemodynamics (1, 15). The ETs are a group of vasoconstrictor peptides derived from vascular endothelial cells (9, 25, 51). Three ETs, ET-1, -2, and -3, all consisting of 21 amino acids, have been identified. ET-1, the predominant representative of the ET family, is the most potent natural mammalian vasoconstrictor agent yet discovered (31–41 times stronger than ANG II) (25) and is essential for cardiovascular regulation (1, 15, 35). The vasoconstrictive effect of ET-1 is mainly mediated by the endothelin type A (ETA) receptor, which increases intracellular Ca2+ concentration (28). ET-1 also has a vasodilatory effect (8), an action mediated by an ET type B (ETB) receptor in endothelial cells (ETB1). ETB2 receptors have been found in vascular smooth muscle cells (VSMC) and can mediate vasoconstriction in multiple blood vessels, primarily veins. Although the discrete function and location of ETB receptors were proposed in humans, these two subtypes of ETB receptors have not been cloned in rats. Thus ETB receptors are quantified as a whole in rats.

An increase in the production of ET-1, but not ET-2 or ET-3, has been reported to contribute to the development of hypertension (1, 3, 15, 31, 49, 52). The ET system may be involved in human hypertension (35, 49). For example, ET-1 plays a role in salt-sensitive hypertension (1, 27, 29, 31). Mice with cardiomyocyte-specific ET-1 disruption did not develop hyperthyroid cardiac hypertrophy (38). Blockade of ET receptors attenuated cardiac hypertrophy and end-organ damage in hypertensive rats (11). It seems that ETA receptors contribute to the pathogenesis of hypertension, whereas ETB receptors protect against vascular and renal injury (29). Therefore, ET-1 knockout in the renal collecting duct, a region of high ETB receptor expression, results in hypertension (3).

Although ET-1 is produced predominantly by endothelial cells, it also is generated in cardiomyocytes, VSMC, and renal tubule epithelial cells (15, 23, 25). The ET system exerts a broad range of actions on these tissues that modulate BP and control extracellular fluid volume. ET-1 is a local hormone, and its distribution and function may vary with tissues in response to environmental stimuli. It is not known, however, whether changes in the activity of the ET system and in the regulation of ET receptors occur during chronic cold exposure. This information is critical for understanding the contribution of the ET system to cold-induced cardiovascular complications. We hypothesized that cold exposure increases ET-1 production and upregulates ETA receptors in cardiovascular and renal tissues. Thus the purpose of this experiment was to determine whether and to what extent cold exposure alters the ET system by assessing the production of ET-1 and the regulation of ET receptors at 1, 3, and 5 wk of cold exposure.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Experiment 1

Animals and experimental protocols.   The study was carried out according to the guidelines of the National Institutes of Health on the care and use of laboratory animals. The project, of which this study was a part, was approved by the Institutional Animal Care and Use Committee.

Twenty-five male Harlan Sprague Dawley rats [180–200 g body wt (BW)] were divided into four groups (6 or 7 rats/group). All animals were housed individually, and standard rat chow and tap water were provided. BP and BW were measured twice during a 1-wk control period at room temperature (RT, 25°C, warm control). Systolic BP was measured from the tail of each unanesthetized rat by the tail-cuff method, with slight warming (28°C), but not heating, of the tail. All rats were handled frequently (2 twice per day) to minimize handling stress. Animals did not appear stressed during BP measurement. The tail-cuff method has been commonly used by us (43–45) and others (33, 55) to delineate cold-induced elevation of BP. Intra-arterial cannulation has confirmed that the noninvasive tail-cuff method is effective and reliable in monitoring systolic BP in rats exposed to cold (11, 40).

After the control period, three groups (6 rats/group) were moved into a cold climate-controlled walk-in chamber (6.7 ± 2°C), and the remaining group (7 rats/group) was maintained in an identical warm chamber (RT, 25 ± 2°C) and served as a control. Relative humidity was controlled automatically and maintained at 45 ± 5% in both thermal environments. Our previous studies showed that rats are able to maintain their core temperatures during exposure to moderate cold (48). BP and BW were measured weekly during exposure to cold. At 1 and 3 wk of exposure to cold, one cold-exposed group and two rats from the warm control (RT, 25°C) group were killed by decapitation. At 5 wk of exposure to cold, the last group from the cold environment and three rats from the warm control (RT, 25°C) group were killed. Although the control rats were killed at different times, they were considered one control (warm control) group (7 rats) for the purpose of statistical analysis, because there were no significant changes in biochemical measurements (e.g., ET-1, prepro-ET-1 mRNA, and ET receptor expression) among the three time points. Blood was collected in vials containing 200 µl of 0.1 M EDTA and centrifuged at 4°C (1,000 g) for 15 min. Plasma was collected for measurement of plasma ET-1. The heart and kidneys were removed, cleaned, and weighed. The heart, kidneys, and third-order and smaller branches of superior and inferior mesenteric arteries were removed for measurement of tissue ET-1 and ET receptor protein expression. Third-order and smaller branches of mesenteric arteries are regarded as resistance vessels (18, 50).

ET-1 measurements.   Tissue samples were weighed and homogenized in 1.0 M acetic acid with 0.000015 M pepstatin for 1 min. The homogenate was centrifuged at 4°C (20,000 g) for 30 min. The supernatant was stored at –80°C. ET-1 levels in the heart, kidneys, mesenteric arteries, and plasma were measured using the ET-1 (human) TiterZyme immunoassay kit (Assay Design) according to the manufacturer's instruction.

Western blot.   Western blot analysis was performed as described previously (46, 52). Briefly, the membrane was blocked with 5% fat-free milk for 30 min and then incubated in rabbit anti-ETA antibody (1:200 dilution) or rabbit anti-ETB antibody (1:200 dilution; Alomone Labs, Jerusalem, Israel) for 12–18 h. These antibodies have been confirmed, by the manufacturer and other investigators, to be specific for rat ETA and ETB receptors, respectively (19). The membrane was then incubated for 1 h (ETB) or 2 h (ETA) with a secondary antibody, goat anti-rabbit antibody labeled with horseradish peroxidase (1:1,000 dilution). GAPDH protein expression was measured and served as an internal control. Protein band density was measured using the Gel Doc system (Bio-Rad).

Experiment 2

Immunohistochemistry.   For experiment 2, an additional four groups of rats (3 rats/group) were treated as described for experiment 1. Briefly, at 1, 3, and 5 wk of exposure to cold, one group of cold-exposed rats and one rat from the RT group were perfused transcardially with heparinized saline and then with 4% paraformaldehyde as described in our previous studies (46, 53). The three rats from the RT group were considered one control group (warm control), because there was no difference in ET receptor immunostaining across the three time points. The heart and left kidney were removed and fixed in 4% paraformaldehyde overnight at 4°C. The tissues were embedded in paraffin, cut at 4 µm, and mounted onto poly-L-lysine-coated slides. The slices were blocked with 10% goat serum albumin for 1 h and incubated with rabbit anti-ETA or rabbit anti-ETB (1:200 dilution) antibody for 1 h. Staining was visualized with a horseradish peroxidase system (DakoCytomation). Digital photographs were taken using a Zeiss microscope and imaging software (SPOT).

Statistical Analysis

BP and BW data were analyzed by one-way ANOVA for repeated measurements (in time). The data for ET-1 concentration, organ weights, and ratio of ETA to ETB receptor protein expression were analyzed by one-way ANOVA. Newman-Keuls procedure was used to assess the significance of differences between means. Significance was set at the 95% confidence limit.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Effects of Cold Exposure on BP and Heart Weight

BP did not differ significantly among the four groups during the control period at RT (Fig. 1). BP of rats exposed to 6.7°C increased significantly as early as 1 wk of exposure to cold. BP reached 162.89 ± 3.6 mmHg at 5 wk of exposure to cold. The warm control group maintained a steady BP, averaging 112.3 ± 4.2 mmHg, over the 5-wk period at RT (Fig. 1).


Figure 1
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  		Fig. 1. Systolic blood pressure of cold-exposed (6.7°C) rats and rats maintained at room temperature (warm control). Values are means ± SE (n = 6–7).

 
All cold-exposed rats appeared healthy, with a normal rate of weight gain (data not shown). Chronic cold exposure significantly increased heart weight (Fig. 2A) and kidney weight (Fig. 2B). Heart and kidney weights did not differ significantly between 1 and 5 wk of exposure to cold, indicating that cardiac and renal hypertrophy were not further exacerbated with increased duration of cold exposure.


Figure 2
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  		Fig. 2. Heart weight (A) and kidney weight (B) of rats exposed to cold for 1, 3, and 5 wk. Values are means ± SE (n = 6–7). **P < 0.01; ***P < 0.001 vs. warm control. ++P < 0.01; +++P < 0.001 vs. cold 1 week.

 
Effects of Cold Exposure on ET-1 Production

The immunoreactive ET-1 level in mesenteric resistance arteries increased significantly at 1 wk of exposure to cold (Fig. 3B). ET-1 in the cold-exposed rats increased approximately fourfold compared with the rats maintained at RT (warm control). However, the ET-1 level in mesenteric arteries began to decrease at 3 wk of exposure to cold and returned to the control level by 5 wk of cold exposure. The ET-1 level in mesenteric arteries remained elevated at 3 wk of cold exposure (P < 0.001 vs. warm control), although it was decreased significantly compared with 1 wk of cold exposure (Fig. 3B). In contrast, ET-1 levels in the heart did not increase significantly until 5 wk of exposure to cold (Fig. 3A). Total kidney ET-1 content increased significantly as early as 1 wk of exposure to cold and continued to increase throughout cold exposure (Fig. 3C). The ET-1 level in the renal cortex increased significantly during the first 3 wk and reached to the highest level by 5 wk of cold exposure (Fig. 3D). However, the ET-1 level in the renal medulla did not change significantly during the first 3 wk of exposure to cold but increased significantly by 5 wk of cold exposure (Fig. 3E). Plasma ET-1 did not change significantly throughout cold exposure (Fig. 3F).


Figure 3
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  		Fig. 3. Effects of cold exposure on endothelin (ET)-1 concentration in heart (A), mesenteric arteries (B), kidneys (C), renal cortex (D), renal medulla (E), and plasma (F). Values are means ± SE (n = 6–7). *P < 0.05; **P < 0.01; ***P < 0.001 vs. warm control. +P < 0.05; ++P < 0.01; +++P < 0.001 vs. cold 1 week.

 
Effects of Cold Exposure on ET Receptor Protein Expression

Western blot analysis indicated that ETA receptor protein expression in the heart was increased significantly at 3 wk of exposure to cold (P < 0.01) and was further increased (P < 0.001) by 5 wk of cold exposure (Fig. 4, A and B). In contrast, ETB receptor protein expression in the heart was decreased significantly (P < 0.001) as early as 1 wk of exposure to cold and remained at a low level throughout cold exposure (Fig. 4, A and C). Cold exposure decreased ETB receptor expression ~10-fold. The ratio of ETA to ETB receptor expression was <1 at RT (warm control; Fig. 4D). Chronic cold exposure significantly increased the ratio of ETA to ETB receptor expression. The ratio of ETA to ETB receptor expression was about 4:1 at 1 wk of exposure to cold and increased to 6:1 by 5 wk of cold exposure (Fig. 4D).


Figure 4
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  		Fig. 4. A: Western blot analysis of ET type A and B (ETA and ETB) receptor expression in left ventricle (50 µg/lane of total protein) of rats maintained at room temperature (warm control) and rats exposed to cold for 1, 3, and 5 wk. B and C: optical density of ETA and ETB receptor expression in heart. D: ratio of ETA to ETB receptor density in heart. ODu, optical density unit. Values are means ± SE (n = 6–7). **P < 0.01; ***P < 0.001 vs. warm control. ++P < 0.01; +++P < 0.001 vs. cold 1 week.

 
ETA receptor expression in the renal cortex increased significantly at 3 wk of exposure to cold and further increased at 5 wk of cold exposure (P < 0.001) compared with control rats maintained at RT (warm control; Fig. 5A). ETB receptor protein expression was not detectable in the renal cortex. However, ETB receptor expression in the renal medulla was abundant in rats maintained at RT (warm control). ETB receptor expression was decreased significantly by 1–5 wk of cold exposure (Fig. 5B). ETA receptor expression was not detectable in the renal medulla.


Figure 5
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  		Fig. 5. Western blot analysis of ETA receptor expression in renal cortex (50 µg/lane of total protein; A) and ETB receptor expression in renal medulla (50 µg/lane of total protein; B) in rats maintained at room temperature (warm control) and rats exposed to cold for 1, 3, and 5 wk. Values are means ± SE (n = 6–7). **P < 0.01; ***P < 0.001 vs. warm control. ++P < 0.01; +++P < 0.001 vs. cold 1 week.

 
Immunohistochemical Analysis of ET Receptor Expression

ETA receptor immunostaining was barely detectable in the left ventricle of rats maintained at RT (warm control; Fig. 6A). ETA receptor immunoreactivity was increased by 1 wk of exposure to cold and further increased with the duration of cold exposure. The strongest ETA receptor immunoreactivity in the left ventricle was found at 5 wk of cold exposure (Fig. 6A). The increased ETA receptor immunoreactivity was localized in cardiomyocytes and VSMC. In contrast, strong ETB receptor immunostaining was found in cardiomyocytes of rats maintained at RT (warm control; Fig. 6B). However, ETB receptor immunoreactivity was decreased by 1 wk of exposure to cold and remained at a low expression level throughout cold exposure (Fig. 6B). ETB receptor immunoreactivity was weaker in VSMC and endothelial cells than in myocytes.


Figure 6
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  		Fig. 6. A: immunohistochemical analysis of ETA receptor expression in left ventricle of rats maintained at room temperature (warm control) and rats exposed to cold for 5 wk. Arrows, regions of anti-ETA antibody staining (brown). Cold-induced increase in ETA receptor immunostaining was localized in cardiomyocytes and vascular smooth muscle cells. B: immunohistochemical analysis of ETB receptor expression in left ventricle of rats maintained at room temperature (warm control) and rats exposed to cold for 5 wk. Arrows, regions of intense anti-ETB antibody staining (brown). ETB receptor immunostaining was localized in cardiomyocytes and was decreased by cold exposure. Magnification x40.

 
ETA receptor immunostaining was barely detectable in the renal cortex of rats maintained at RT (warm control; Fig. 7A). ETA receptor immunoreactivity was increased in the renal cortex at 3–5 wk of cold exposure (Fig. 7A). The increased ETA receptor expression was found in glomerular VSMC and tubule epithelial cells of cold-exposed rats. In contrast, ETB receptors were mainly localized in renal tubule epithelial cells, with strong expression in rats maintained at RT (warm control; Fig. 7B). ETB receptor immunoreactivity was decreased greatly by 1–5 wk of cold exposure.


Figure 7
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  		Fig. 7. A: immunohistochemical analysis of ETA receptor expression in renal cortex of rats maintained at room temperature (warm control) and rats exposed to cold for 5 wk. Arrows, regions of anti-ETA antibody staining (brown). Cold-induced increase in ETA receptor immunostaining was localized in glomerular vascular smooth muscle cells and tubule epithelial cells. B: immunohistochemical analysis of ETB receptor expression in renal medulla of rats maintained at room temperature (warm control) and rats exposed to cold for 5 wk. Arrows, regions of intense anti-ETB receptor antibody staining (brown). ETB receptor immunostaining was mainly localized in tubule epithelial cells and was increased by cold exposure. Magnification x40.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The present data clearly showed that chronic cold exposure increased ET-1 levels in cardiovascular tissues. The most dramatic increase in ET-1 occurred in mesenteric resistance arteries as early as 1 wk of exposure to cold, when BP began to rise. These results suggest, but do not prove, that ET-1 contributes to the initiation of CIH. However, chronic cold exposure did not change plasma levels of ET-1. On the other hand, acute (minutes or hours) cold exposure increases plasma ET-1 levels (24, 26). Thus plasma ET-1 responds differently to acute and chronic cold exposure. It should be emphasized that ET-1 is produced in endothelial cells and is predominantly secreted toward the adjacent VSMC, supporting the notion that ET-1 is an autocrine/paracrine agent, rather than a circulating hormone. Thus tissue levels of ET-1 are more important than plasma levels of ET-1 in assessing the contribution of the ET system to CIH. Physiologically, an increase in BP inhibits vascular ET formation. Therefore, the cold-induced increase in ET-1 production, at least during the early stage of cold exposure, is not due to hypertension-associated endothelial damage, because CIH is not fully established until 5 wk after exposure to cold (39). Thus the cold-induced increase in ET-1 production may be due to endocrine changes associated with cold exposure. It has been reported that ANG II is an important stimulus for the production of ET (4, 6, 13, 49). Our previous studies indicated that cold exposure activates the RAS (42, 45, 46). Therefore, the hypothesis that the cold-induced activation of the ET system is mediated by the RAS warrants further investigation.

Our previous studies indicated that cold-induced cardiac hypertrophy was independent of high BP, because prevention or reduction of CIH failed to attenuate the development of cardiac hypertrophy (41, 44, 45). It has been reported that the ET system can contribute to cardiac hypertrophy (7, 16, 20, 29, 34). ET-1 added directly to cardiomyocytes in culture increases the size of the cells and increases actin production (17). The most recent report indicates that ET-1 produced locally by cardiomyocytes is an important mediator for myocardial hypertrophy induced by thyroid hormone (38). Although ET-1 levels in the heart were not elevated until 5 wk of exposure to cold, the ratio of cardiac ETA to ETB receptors was markedly increased as early as 1 wk of exposure to cold. It was reported that ETA receptor-mediated action plays an important role in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension and cardiac hypertrophy (29). However, the ETB receptor-mediated action protects against vascular and end-organ damage in this model of hypertension. An increase in the ETA-to-ETB receptor ratio points out the necessity to determine whether the alteration in the ET system in the heart is involved in cold-induced cardiac hypertrophy.

The kidney is one of the most important organs in the regulation of systemic hemodynamics and is a key target organ for ET-1 as well as a major site of ET-1 production. In addition to its effect on renal hemodynamics, ET-1 directly regulates tubular handling of electrolytes and water (1). The cold-induced increase in renal ET-1 occurred predominantly in the renal cortex. An increase in ET-1 levels in the renal cortex decreases renal blood flow and glomerular filtration rate (1, 10), resulting in antidiuresis and antinatriuresis. This effect is mediated by cortical vasoconstrictor effects of ETA receptors, which were also increased by cold exposure. In the renal medulla, however, ET-1 inhibits Na+-K+-ATPase activity and blocks the stimulatory effects of vasopressin on water reabsorption and, thereby, induces natriuresis and diuresis (1, 22, 23). This effect is mediated by ETB receptors through increases in nitric oxide release and cellular cGMP levels (2). Thus the effects of ET-1 on Na+ and water reabsorption in the medulla are different from those in the cortex. ET-1 levels in the medulla did not increase until 5 wk, but medullary ETB receptor protein expression was decreased throughout exposure to cold. Thus the differential regulation of the ET system in the cortex and medulla tends to increase reabsorption of Na+ and water, thereby causing the fluid retention that is seen in cold-exposed rats (40). In addition, ET-1 has proliferative effects that may contribute to cold-induced renal hypertrophy. The present data also demonstrated that the renal cortex was predominantly occupied by ETA receptors, whereas in the renal medulla ETB receptors were heavily distributed throughout the tubules.

The cold-induced downregulation of ETB receptors in the heart and renal medulla was probably due to increased ET-1 levels in these tissues. However, cold exposure upregulated ETA receptors in the heart and renal cortex against the background of unchanged or increased ET-1. The mechanism responsible for this unique regulation of ETA receptors during cold exposure is still under investigation. Recent advances in receptor physiology indicate that a receptor can be regulated by many factors in addition to its ligand (32, 42, 43, 46, 48, 54). It is known that cold exposure increases the secretion of thyroid hormones, which may activate the cardiac ET system (38). Therefore, it is worthwhile to test whether thyroid hormones mediate the cold-induced upregulation of ETA receptors.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grant HL-077490 and in part by American Heart Association-National Grant 0130387N (to Z. Sun).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Xiuqing Wang and Lucile Skelley for technical support with tissue extraction, Western blotting, and histology.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Z. Sun, Depts. of Medicine and Physiology, Box 100274, College of Medicine, Univ. of Florida, 1600 SW Archer Rd., Gainesville, FL 32610-0274 (e-mail: zsun{at}phys.med.ufl.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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  1. Abassi ZA, Ellahham S, Winaver J, and Hoffman A. The intrarenal endothelin system and hypertension. News Physiol Sci 16: 152–157, 2001.[Abstract/Free Full Text]
  2. Abassi ZA, Gurbanov K, Rubinstein I, Better OS, Hoffman A, and Winaver J. Regulation of intrarenal blood flow in experimental heart failure: role of endothelin and nitric oxide. Am J Physiol Renal Physiol 274: F766–F774, 1998.[Abstract/Free Full Text]
  3. Ahn D, Ge Y, Stricklett PK, Gill P, Taylor D, Hughes AK, Yanagisawa M, Miller L, Nelson RD, and Kohan DE. Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. J Clin Invest 114: 504–511, 2004.[CrossRef][Web of Science][Medline]
  4. Alexander BT, Cockrell KL, Rinewalt AN, Herrington JN, and Granger JP. Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol Regul Integr Comp Physiol 280: R1388–R1392, 2001.[Abstract/Free Full Text]
  5. Baker-Blocker A. Winter weather and cardiovascular mortality in Minneapolis-St. Paul. Am J Public Health 72: 261–265, 1982.[Abstract/Free Full Text]
  6. Ballew JR and Fink GD. Role of ETA receptors in experimental ANG II-induced hypertension in rats. Am J Physiol Regul Integr Comp Physiol 281: R150–R154, 2001.[Abstract/Free Full Text]
  7. Cullen JP, Bell D, Kelso EJ, and McDermott BJ. Use of A-192621 to provide evidence for involvement of endothelin ETB-receptors in endothelin-1-mediated cardiomyocyte hypertrophy. Eur J Pharmacol 417: 157–168, 2001.[CrossRef][Web of Science][Medline]
  8. D'Orleans-Juste P, Labonte J, Bkaily G, Choufani S, Plante M, and Honore JC. Function of the endothelinB receptor in cardiovascular physiology and pathophysiology. Pharmacol Ther 95: 221–238, 2002.[CrossRef][Web of Science][Medline]
  9. D'Orleans-Juste P, Plante M, Honore E, Carrier E, and Labonte J. Synthesis and degradation of endothelin-1. Can J Physiol Pharmacol 81: 503–510, 2003.[CrossRef][Web of Science][Medline]
  10. Dvorak P, Kramer HJ, Backer A, Maly J, Kopkan L, Vaneckova I, Vernerova Z, Opocensky M, Tesar V, Bader M, Ganten D, Janda J, and Cervenka L. Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats. Kidney Blood Press Res 27: 248–258, 2004.[CrossRef][Web of Science][Medline]
  11. Fregly MJ, Kikta DC, Threatte RM, Torres JL, and Barney CC. Development of hypertension in rats during chronic exposure to cold. J Appl Physiol 66: 741–749, 1989.[Abstract/Free Full Text]
  12. Fujiwara T, Kawamura M, Nakajima J, Adachi T, and Hiramori K. Seasonal differences in diurnal blood pressure of hypertensive patients living in a stable environmental temperature. J Hypertens 13: 1747–1752, 1995.[Web of Science][Medline]
  13. Hara K, Kobayashi N, Nakano S, Mori Y, Tsubokou Y, and Matsuoka H. Effects of TCV-116 on endothelin-1 and PDGF A-chain expression in angiotensin II-induced hypertensive rats. Hypertens Res 24: 55–64, 2001.[CrossRef][Web of Science][Medline]
  14. Hata T, Ogihara T, Maruyama H, Mikami H, Nakamaru M, Naka T, Kumahara Y, and Nugent CA. The seasonal variation of blood pressure in patients with essential hypertension. Clin Exp Theory Pract A4: 341–354, 1982.
  15. Haynes WG and Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 16: 1081–1098, 1998.[CrossRef][Web of Science][Medline]
  16. Ito H, Hiroe M, Hirata Y, Fujisaki H, Adachi S, Akimoto H, Ohta Y, and Marumo F. Endothelin ETA receptor antagonist blocks cardiac hypertrophy provoked by hemodynamic overload. Circulation 89: 2198–2203, 1994.[Abstract/Free Full Text]
  17. Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, and Marumo F. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 69: 209–215, 1991.[Abstract/Free Full Text]
  18. Jolma P, Koobi P, Kalliovalkama J, Saha H, Fan H, Jokihaara J, Moilanen E, Tikkanen I, and Porsti I. Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure. Nephrol Dial Transplant 18: 2560–2569, 2003.[Abstract/Free Full Text]
  19. Katwa LC. Cardiac myofibroblasts isolated from the site of myocardial infarction express endothelin de novo. Am J Physiol Heart Circ Physiol 285: H1132–H1139, 2003.[Abstract/Free Full Text]
  20. Kedzierski RM and Ynagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 41: 851–876, 2001.[CrossRef][Web of Science][Medline]
  21. Kim JY, Jung KY, Hong YS, Kim JI, Jang TW, and Kim JM. The relationship between cold exposure and hypertension. J Occup Health 45: 300–306, 2003.[CrossRef][Web of Science][Medline]
  22. Kohan DE and Padilla E. Endothelin-1 production by rat inner medullary collecting duct: effect of nitric oxide, cGMP, and immune cytokines. Am J Physiol Renal Fluid Electrolyte Physiol 266: F291–F297, 1994.[Abstract/Free Full Text]
  23. Kohan DE. Endothelins in the normal and diseased kidneys. Am J Kidney Dis 29: 2–26, 1997.[Web of Science][Medline]
  24. Lepert J, Ringqvist A, Karlberg BE, and Ringqvist I. Whole-body cooling increases plasma endothelin-1 levels in women with primary Raynaud's phenomenon. Clin Physiol 18: 420–425, 1998.[CrossRef][Web of Science][Medline]
  25. Levin ER. Endothelins. N Engl J Med 333: 356–363, 1995.[Free Full Text]
  26. Mangiafico RA, Malatino LS, Santonocito M, Spada RS, and Tamburino G. Plasma endothelin-1 concentrations during cold exposure in essential acrocyanosis. Angiology 47: 1033–1038, 1996.[Web of Science][Medline]
  27. Markewitz BA and Kohan DE. Role of intrarenal endothelin in the generation and maintenance of hypertension. Miner Electrolyte Metab 21: 342–352, 1995.[Web of Science][Medline]
  28. Mateo AO and Artinano AA. Highlights on endothelins. Pharmacol Res 36: 339–351, 1997.[CrossRef][Web of Science][Medline]
  29. Matsumura Y, Hashimoto N, Taira S, Kuro T, Kitano R, Ohkita M, Opgenorth TJ, and Takaoka M. Different contributions of endothelin-A and endothelin-B receptors in the pathogenesis of deoxycorticosterone acetate-salt-induced hypertension in rats. Hypertension 33: 759–765, 1999.[Abstract/Free Full Text]
  30. Minami J, Kawano Y, Ishimitsu T, Yoshimi H, and Takisita S. Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension. J Hypertens 14: 1421–1425, 1996.[CrossRef][Web of Science][Medline]
  31. Moreau P and Schifrin EL. Role of endothelins in animal models of hypertension: focus on cardiovascular protection. Can J Physiol Pharmacol 81: 511–521, 2003.[CrossRef][Web of Science][Medline]
  32. Peng JF and Phillips MI. Opposite regulation of brain angiotensin type 1 and 2 receptors in cold-induced hypertension. Regul Pept 297: 91–102, 2001.
  33. Peng JF, Kimura B, Fregly MJ, and Phillips MI. Reduction of cold-induced hypertension by antisense oligodeoxynucleotides to angiotensinogen mRNA and AT1-receptor mRNA in brain and blood. Hypertension 31: 1317–1323, 1998.[Abstract/Free Full Text]
  34. Piuhola J, Szokodi I, Kinnunen P, Ilves M, deChatel R, Voulteenaho O, and Ruskoaho H. Endothelin-1 contributes to the Frank-Starling response in hypertrophic rat hearts. Hypertension 41: 93–98, 2003.[Abstract/Free Full Text]
  35. Schiffrin EL. A critical review of the role of endothelial factors in the pathogenesis of hypertension. J Cardiovasc Pharmacol 38 Suppl 2: S3–S6, 2001.
  36. Seretakis D, Lagiou P, Lipworth L, Signorello LB, Rothman KJ, and Trichopoulos D. Changing seasonality of mortality from coronary heart disease. JAMA 278: 1012–1014, 1997.[Abstract/Free Full Text]
  37. Sheth T, Nair C, Muller J, and Yusuf S. Increased winter mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol 33: 1916–1919, 1999.[Abstract/Free Full Text]
  38. Shohet RV, Kisanuki YY, Zhao X, Siddiquee Z, Franco F, and Yanagisawa M. Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy. Proc Natl Acad Sci USA 101: 2088–2093, 2004.[Abstract/Free Full Text]
  39. Sun Z, Cade JR, and Fregly MJ. Cold-induced hypertension. A model of mineralocorticoid-induced hypertension. Ann NY Acad Sci 813: 682–688, 1997.[Medline]
  40. Sun Z, Cade R, Katovich MJ, and Fregly MJ. Body fluid distribution in rats with cold-induced hypertension. Physiol Behav 65: 879–884, 1999.[CrossRef][Medline]
  41. Sun Z, Cade JR, Fregly MJ, and Rowland NE. Effect of chronic treatment with propranolol on the cardiovascular responses to chronic cold exposure. Physiol Behav 62: 379–384, 1997.[CrossRef][Medline]
  42. Sun Z, Cade R, and Tatum C. Central imidazoline and angiotensin II receptors in cardiovascular responses to chronic cold exposure in rats. J Therm Biol 26: 513–518, 2001.[CrossRef][Web of Science]
  43. Sun Z, Cade R, and Morales C. Role of central angiotensin II receptors in cold-induced hypertension. Am J Hypertens 15: 85–92, 2002.[CrossRef][Web of Science][Medline]
  44. Sun Z, Cade R, Zhang Z, Alouidor J, and Van H. Angiotensinogen gene knockout delays and attenuates cold-induced hypertension. Hypertension 41: 322–327, 2003.[Abstract/Free Full Text]
  45. Sun Z, Fregly MJ, and Cade JR. Effect of renal denervation on elevation of blood pressure in cold-exposed rats. Can J Physiol Pharmacol 73: 72–78, 1995.[Web of Science][Medline]
  46. Sun Z, Fregly MJ, Rowland NE, and Cade JR. Comparison of changes in blood pressure and dipsogenic responsiveness to angiotensin II in male and female rats chronically exposed to cold. Physiol Behav 60: 1543–1549, 1996.[CrossRef][Medline]
  47. Sun Z, Wang X, Wood CE, and Cade JR. Genetic AT1A receptor deficiency attenuates cold-induced hypertension. Am J Physiol Regul Integr Comp Physiol 288: R433–R439, 2005.[Abstract/Free Full Text]
  48. Sun Z and Cade R. Cold-induced hypertension and diuresis. J Therm Biol 25: 105–109, 2000.
  49. Touyz RM and Schiffrin EL. Role of endothelin in human hypertension. Can J Physiol Pharmacol 81: 533–541, 2003.[CrossRef][Web of Science][Medline]
  50. Tschudi MR, Mesaros S, Luscher TF, and Malinski T. Direct in situ measurement of nitric oxide in mesenteric resistance arteries. Increased decomposition by superoxide anion production. Hypertension 27: 32–35, 1996.[Abstract/Free Full Text]
  51. Turner AJ, Barnes K, Schweizer A, and Valdenaire O. Isoforms of endothelin-converting enzyme: why and where? Trends Pharmacol Sci 19: 483–486, 1998.[CrossRef][Medline]
  52. Vogel Backer A, Heller J, and Kramer HJ. The renal endothelin system in the Prague hypertensive rat, a new model of spontaneous hypertension. Clin Sci (Lond) 97: 91–98, 1999.[Medline]
  53. Wang X, Cade R, and Sun Z. Human eNOS gene delivery attenuates cold-induced elevation of blood pressure in rats. Am J Physiol Heart Circ Physiol 289: H1161–H1168, 2005.[Abstract/Free Full Text]
  54. Wilson KM, Sumners C, Hathaway S, and Fregly MJ. Mineralocorticoids modulate central angiotensin II receptors in rats. Brain Res 382: 87–96, 1986.[CrossRef][Web of Science][Medline]
  55. Zhu Z, Zhu S, Zhu J, van der Giet M, and Tepel M. Endothelial dysfunction in cold-induced hypertensive rats. Am J Hypertens 15: 176–180, 2002.[CrossRef][Web of Science][Medline]



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