Journal of Applied Physiology Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 96: 809-813, 2004. First published October 3, 2003; doi:10.1152/japplphysiol.00684.2003
8750-7587/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
96/2/809    most recent
00684.2003v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lam, S. Y.
Right arrow Articles by Leung, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lam, S. Y.
Right arrow Articles by Leung, P. S.

HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease

Regulation of the angiotensin-converting enzyme activity by a time-course hypoxia in the carotid body

Siu Yin Lam,1 Man-Lung Fung,2 and Po Sing Leung1

1Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, and 2Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong

Submitted 3 July 2003 ; accepted in final form 1 October 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Chronic hypoxia activates a local angiotensin-generating system in the carotid body. Here, we test the hypothesis that the activity of the critical enzyme for this system, angiotensin-converting enzyme (ACE), in the carotid body is subject to regulation by a time-course hypoxia. Results from the carotid body assays showed that ACE activity was markedly increased under the hypoxic stress of 7-, 14-, 21-, and 28-day exposures. The changes in ACE activity of 7-day (15.00 vs. 30.95 x 10-5 nmol·µg-1·min-1), 14-day (8.73 vs. 30.25 x 10-5 nmol·µg-1·min-1), and 21-day (11.41 vs. 31.83 x 10-5 nmol·µg-1·min-1) hypoxia treatments were enhanced significantly. However, ACE activity in 28-day (13.18 vs. 24.53 x 10-5 nmol·µg-1·min-1) hypoxia treatment was observed to increase insignificantly when compared with results in the respective control groups. Captopril inhibited all rises in ACE activity in both the control and experimental groups. Results clearly indicate an activation of the enzymatic activity of ACE, the critical enzyme for determining the conversion of angiotensin I into the physiologically active angiotensin II, by chronic hypoxia in the carotid body. An increase in the ACE activity may increase the local production of angiotensin II in the carotid body and thus its agonist action at the AT1 receptor. This may be important in the modulation of cardiopulmonary adaptation in the hypoxic ventilatory response as well as for electrolyte and water homeostasis during chronic hypoxia.

renin-angiotensin system; chronic hypoxia; angiotensin II; captopril

THE ANGIOTENSIN-CONVERTING ENZYME (ACE) is a dipeptidyl carboxyl peptidase, which is a membrane-bound ectoenzyme, first identified as a key component of the renin-angiotensin system (RAS). It cleaves angiotensin I (ANG I) at His-Leu dipeptidyl residue from the carboxyl terminus to form ANG II, the biologically active peptide of the RAS. This enzymatic action takes place in the lung where the large total surface area of the whole pulmonary vasculature facilitates the rapid conversion process and makes it accessible to circulating macromolecules (44). ACE is, to a lesser extent, also produced in other sites, such as the kidney, liver, and systemic vascular bed. Because ACE is a membrane-bound peptidase with a zinc ectoenzyme facing the lumen, conversion of ANG II occurs extracellularly in the lungs. There are also a number of dipeptide bonds and tripeptide bonds that can be cleaved by ACE, such as bradykinin (11, 37).

It is known that the circulating RAS plays an important role in hemodynamic regulation (5, 46, 51). In addition to the circulating RAS, there is ever-increasing evidence for the existence of local RAS in multiple tissues and organs. In this respect, locally produced angiotensins act frequently in a paracrine or autocrine manner (4, 12, 13, 47). These local systems are also responsive to various stimuli of physiology and pathophysiology, such as hypoxia and pancreatitis (recently reviewed in Refs. 29 and 33). Of particular interest are the expression and localization of ANG II receptors, predominantly the AT1-receptor subtype, in the chemosensitive (glomus) cells of the carotid body (16, 32). ANG II increases intracellular calcium levels in the glomus cells, and the calcium response can be blocked by losartan, an AT1 antagonist (16, 17). In addition, chronic hypoxia is associated with an upregulation of AT1 receptor expression in the glomus cells, thereby enhancing the carotid afferent nerve activity to ANG II stimulation (17, 32). During chronic hypoxia, the carotid body changes its hypoxic sensitivity and is responsible for the ventilatory acclimatization to hypoxia, which involves an initial rapid increase in ventilation followed by a progressive hyperventilation (25, 48, 52). The locally synthesized ANG II and the upregulated AT1 receptors may play active roles in modulating the excitability of the carotid chemoreceptors during chronic hypoxia. In addition to the functional changes, the volume of the carotid body increases during chronic hypoxia due to structural changes, including increased vascularization, hypertrophy, and hyperplasia of the glomus cells (25, 48, 52). The well-known effect of ANG II on stimulating cell growth and proliferation during tissue remodeling may underlie the structural changes of the carotid body during chronic hypoxia. Intriguingly, our recent study (26) has provided solid evidence for a locally generated angiotensin system in the carotid body, which might be operated via a renin-independent pathway. Such a local angiotensin-generating system could be notably activated at the level of angiotensinogen, an obligatory component for the RAS, by chronic hypoxia (27).

Notwithstanding the emerging role of this local system in modulating the carotid body function and adaptation in chronic hypoxia, the importance of ACE activity in the carotid body during chronic hypoxia remains almost unexplored. The present study was designed specifically to examine the hypothesis that the activity of this critical enzyme, which is responsible for determining the generation of physiologically active ANG II, is regulated by a time-course hypoxia in the carotid body. This was achieved by a specific assay for ACE activity coupled with an internally quenched fluorogenic substrate, methoxycarbonyl (Meoc)-DL-Amp-Gly-Lys[dinitrophenylhydrazine ({epsilon}-DNP)]-Gln-OH.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental animals and isolation of carotid body. Adult male Sprague-Dawley rats aged 28 days were used. The animals were bred and raised under pathogen-free conditions, with a controlled ambient temperature of 20 ± 1°C, relative humidity of 60-80%, and a 14:10-h light-dark cycle in the Laboratory Animal Services Centre of the Chinese University of Hong Kong. Standard rat chow and tap water were supplied ad libitum. Ethical approval for the animal model and experimental protocols were obtained from the Animal Experimentation Ethic Committee of the Chinese University of Hong Kong, Hong Kong. After a deep anesthesia with halothane, Sprague-Dawley rats were decapitated, and carotid bodies were dissected from the bifurcation and the superior sympathetic ganglion in PBS, pH 7.4.

Chronic hypoxia rats. In the rat model of chronic hypoxia, the animals were kept in a moderate level (10%) of oxygen, which is relevant to clinical and physiological situations as described previously (17, 27, 32). Briefly, experimental rats were exposed to an isobaric hypoxia chamber for a period of up to 4 wk. The oxygen level was continuously monitored by an oxygen analyzer (Vacumetries) and was maintained by a servo-feedback control of solenoid valves that gated the inflow of pure nitrogen. The nitrogen was then allowed to mix with room air that was generated into the chamber by a pump at a speed of 1-2 l/min. Inside of each chamber, desiccator and soda lime were used to maintain the humidity and carbon dioxide condition. Each chamber was opened for ~15 min for regular maintenance every 2-3 days. To examine the time-course effect of hypoxic treatment on experimental rats, animals at aged 28 days were conditioned in the above environment for 7, 14, 21, and 28 days. Time- and age-matched rats kept in the same housing but with normal room air supply were used as the normoxic controls.

Specific assay for ACE activity. The purification and characterization of microvillar membrane-bound ACE from porcine kidney cortex were described previously (20). A specific assay for ACE activity that uses an internally quenched fluorogenic substrate, Meoc-DL-Amp-Gly-Lys({epsilon}-DNP)-Gln-OH, has been recently developed (22). Briefly, an internally quenched tetrapeptide substrate for ACE fluorogenic that used the fluorescent amino acid 2-amino-3-(7-methoxy-4-coumaryl) propanoic acid, quenched by a dinitrophenyl group, was attached to a lysine residue. The peptide [N-Meoc-DL-Amp-Gly-Lys({epsilon}-DNP)-Gln-OH] was synthesized and characterized as reported previously (22). To prepare membrane protein for measurement of ACE activity, 10 carotid bodies obtained from five animals were pooled for an assay. The carotid bodies and lungs were homogenized in 1:9 (wt/vol) PBS (pH 7.4) containing 1 mM PMSF (28). The homogenate was subject to sedimentation at 1,000 g for 10 min at 4°C. The membrane fraction within the supernatant portion was collected by centrifugation at 30,000 g for 30 min at 4°C. The protein concentration was measured by the Bio-Rad protein assay. The measurement of ACE activity was performed as described previously (22). Briefly, membrane proteins (5 µg) were preincubated with Tris buffer (100 mM Tris·HCl, pH 8.0, and 300 mM NaCl) in a final volume of 950 µl at 37°C for 30 min. For the control setting, 15 mM captopril (Sigma Chemical, St. Louis, MO) was added to inhibit the ACE activity. After preincubation, 50 µl of 0.4 mM fluorogenic ACE substrate (0.32 mg/ml in Tris buffer) were added to the mixtures and incubated again at 37°C for 60 min. The fluorescence of the mixtures was measured by a fluorometer. A mixture of 50 µl of ACE substrate and 950 µl of Tris buffer was used as the blank and was used to set zero with excitation at 328 nm and emission at 392 nm of the fluorometer. Fluorescent standard of 0.1 mM (37.8 mg/l in Tris buffer) was diluted to give 1 µM solution as a reference reading for calculating the ACE activity (in nmol·µg of protein-1·min-1).

Statistical analysis. ACE activities were expressed as nanomoles per micrograms of protein per minute. Results were expressed as means ± SE (n = 5 assays) for the controls and the chronically hypoxic groups. Differences were compared by an unpaired t-test, analyzed by one-way ANOVA, and followed by Duncan's multiple range test to detect intergroup differences. P values of <0.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
The changes of enzymatic ACE activities in the carotid body by chronic hypoxia were investigated by using a specific assay for ACE activity. The activities of carotid body ACE in each group of experiments were calculated (in nmol·µg-1·min-1 x 10-5), and lungs were collected from the normoxic rats and used as a positive control for the expression of ACE activity in the present study. The effects of chronic hypoxia on the ACE activities were observed in a time-dependent manner with 7-, 14-, 21- and 28-day hypoxia, when compared with their respective normoxic controls (Table 1). With the use of an internally quenched fluorogenic substrate, ACE activities in rat carotid bodies that underwent 7-, 14-, 21-, and 28-day treatment under normoxic condition were found to be 15.00 x 10-5, 8.73 x 10-5, 11.41 x 10-5, and 13.18 x 10-5 nmol·µg-1·min-1, respectively. Chronic hypoxia markedly increased the ACE activity of rat carotid bodies up to 30.95 x 10-5, 30.25 x 10-5, 31.83 x 10-5, and 24.53 x 10-5 nmol·µg-1·min-1 in the 7-, 14-, 21- and 28-day treatments, respectively. The specific activities of ACE in the 7-day (Fig. 1), the 14-day (Fig. 2), and the 21-day (Fig. 3) hypoxic rat carotid bodies were shown to be significantly different from their respective normoxic controls; however, the 28-day hypoxic carotid bodies showed an insignificant difference compared with results from their normoxic controls (Fig. 4). Almost no ACE activity was detected when captopril, a specific ACE inhibitor, was added to any of the samples tested, both in the carotid bodies and in the lung tissues (Figs. 1, 2, 3, 4). This clearly shows that the intrinsic peptidase present in the carotid body is a specific substrate for ACE. There were ~2.06-, 3.47-, 2.79-, and 1.86-fold increases in the ACE activities in rat carotid bodies subjected to 7-, 14-, 21-, and 28-day hypoxia, respectively, compared with results from controls (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Regulation of ACE activities from normoxic and hypoxic carotid bodies during varying period of chronic hypoxia study

 


View larger version (10K):
[in this window]
[in a new window]
  		Fig. 1. Effect of 7-day hypoxia on angiotensin-converting enzyme (ACE) activity in carotid bodies. C7, ACE activity in 7-day normoxic carotid bodies; H7, ACE activity in 7-day hypoxic carotid bodies; Lung, ACE activity in normoxic lung; C7-inhibitor, ACE activity with ACE inhibitor in 7-day control carotid bodies; H7-inhibitor, ACE activity with ACE inhibitor in 7-day hypoxic carotid bodies; L-inhibitor, ACE activity with ACE inhibitor in lung. ACE activity was expressed in nmol·µg-1·min-1 of 7-day normoxic and hypoxic carotid bodies. Data are expressed as means ± SE (n = 5 assays for each group). **Statistical significance when compared with the normoxic group (P < 0.05). *Statistical significance when compared with activity in corresponding group without application of inhibitor (P < 0.05).

 


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 2. Effect of 14-day hypoxia on ACE activity in carotid bodies. C14, ACE activity in 14-day normoxic carotid bodies; H14, ACE activity in 14-day hypoxic carotid bodies; Lung, ACE activity in lung; C14-inhibitor, ACE activity with ACE inhibitor in 14-day control carotid bodies; H14-inhibitor, ACE activity with ACE inhibitor in 14-day hypoxic carotid bodies; L-inhibitor, ACE activity with ACE inhibitor in lung. ACE activity was expressed in nmol·µg-1·min-1 of 14-day normoxic and hypoxic carotid bodies. Data are expressed as means ± SE (n = 5 assays for each group). **Statistical significance when compared with the normoxic group (P < 0.05). *Statistical significance when compared with activity in corresponding group without application of inhibitor (P < 0.05).

 


View larger version (10K):
[in this window]
[in a new window]
  		Fig. 3. Effect of 21-day hypoxia on ACE activity in carotid bodies. C21, ACE activity in 21-day normoxic carotid bodies; H21, ACE activity in 21-day hypoxic carotid bodies; Lung, ACE activity in lung; C21-inhibitor, ACE activity with ACE inhibitor in 21-day control carotid bodies; H21-inhibitor, ACE activity with ACE inhibitor in 21-day hypoxic carotid bodies; L-inhibitor, ACE activity with ACE inhibitor in lung. ACE activity was expressed in nmol·µg-1·min-1 of 21-day normoxic and hypoxic mature carotid bodies. Data are expressed as means ± SE (n = 5 assays for each group). **Statistical significance when compared with the normoxic group (P < 0.05). *Statistical significance when compared with activity in corresponding group without application of inhibitor (P < 0.05).

 


View larger version (10K):
[in this window]
[in a new window]
  		Fig. 4. Effect of 28-day hypoxia on ACE activity in carotid bodies. C28, ACE activity in 14-day normoxic carotid bodies; H28, ACE activity in 28-day hypoxic carotid bodies; Lung, ACE activity in lung; C28-inhibitor, ACE activity with ACE inhibitor in 28-day control carotid bodies; H28-inhibitor, ACE activity with ACE inhibitor in 28-day hypoxic carotid bodies; L-inhibitor, ACE activity with ACE inhibitor in lung. ACE activity expressed in nmol·µg-1·min-1 of 28-day normoxic and hypoxic carotid bodies. Data are expressed as means ± SE (n = 5 assays for each group). *Statistical significance when compared with activity in corresponding group without application of inhibitor (P < 0.05).

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Hypoxia is known to be one of the pivotal factors that renders a regulatory effect on the expression and function of local RAS components from various tissues and organs. These include, to name a few, the lung (7, 40, 42, 56), the kidney (43), the heart (41), the epididymis (30), and the pancreas (6, 21). Of great importance is the recent evidence for the existence of an intrinsic RAS in the carotid body (26). The key components of such a local RAS are subject to the fine regulation by chronic hypoxia (17, 27, 32). In those studies, mRNA expression for individual components, such as the ANG II receptors (AT1a, AT1b, and AT2-receptor subtypes), angiotensinogen, and ACE, was found to be present in the carotid body. Interestingly, mRNAs of angiotensinogen and ACE were expressed, whereas renin mRNA was absent in the carotid body, suggesting that a renin-independent angiotensin system might be operating in the carotid body (26). On the other hand, these RAS components such as AT1 receptors (17, 32) and angiotensinogen (27) could be finely upregulated to different degrees after exposure to chronic hypoxia.

Notwithstanding the importance of such a local system in the carotid body, the regulation of ACE activity and its potential role in the production of ANG II during chronic hypoxia remain equivocal. In view of this fact, the present study has focused on ACE activity, ACE being a critical enzyme for the determination of the conversion of ANG I into physiologically active ANG II and the degradation of bradykinin in the carotid body during exposure to chronic hypoxia. Results showed that ACE activity exhibited a time-dependent increase during 7, 14, 21, and 28 days of chronic hypoxia. There was a significant increase in the ACE activity of rat carotid bodies under the stress of chronic hypoxia starting at day 7 and sustaining at day 14 to day 21 in the hypoxic groups. Afterward, however, this began to level off during further hypoxic treatment. Indeed, the increase in the 28-day hypoxic group was found to be statistically insignificant when compared with its respective normoxic controls. These results prompt us to suggest that enhanced activity of ACE could be responsible for the increased generation of ANG II in the carotid body from as early as day 7 to ~1-mo of chronic hypoxia. The resultant level of ANG II together with upregulated expression of AT1 receptors may be physiologically important in the modulation of excitability of carotid chemoreceptor activity and thus the ventilatory drive during chronic hypoxia. However, the relative importance of ACE and importance of the alternative enzymes to renin as well as angiotensinogen in the carotid body, finally dictating the biosynthetic cascade of ANG II production, need further investigation.

The carotid body acts as the first gate for detecting the rapid changes in oxygen tension and composition in the arterial blood. Its local RAS components together with the activity of ACE were upregulated by chronic hypoxia. In this regard, there was a differential effect on the regulation of the ACE activity by chronic hypoxia, notably in various tissues or organs. Previous studies have shown that the serum ACE activity is reduced in human subjects at high altitude (35, 36). ACE activity decreases in the lung (23, 24, 45), whereas it increases in the kidney (45) and pancreas (22) of chronically hypoxic rats. Our results showed that there was an abrupt and significant effect on the ACE activity in the rat carotid bodies that underwent 7, 14, and 21 days of hypoxia, suggesting that the effect of chronic hypoxia on the ACE activity is organ specific. In this context, our previous study (27) has also shown an increase in the mRNA expression of ACE in the carotid body in hypoxia. Thus the elevated ACE activity may be due to an increased level of ACE protein in the carotid body during chronic hypoxia.

It is noted that the rat carotid bodies with 28-day hypoxia showed a statistically insignificant increase in the ACE activity. The adaptation and compensation by the carotid body might account for the change in ACE activity during chronic hypoxia. In fact, the increase in ACE activity is associated with an increased volume of the carotid body due to remodeling in vasculature, development of cellular hypertrophy, and increased mitotic activities in the chemosensitive cells during chronic hypoxia (25, 48, 52). It has been reported that elevation of ACE activity in pulmonary artery smooth muscle cells by hypoxia may play an important role in the development of hypoxic pulmonary hypertension (54). An increase in ANG II levels via the pathway of ANG II formation by ACE may also play an important role in the cardiac hypertrophy of hamster caused by the overloaded state (34). Therefore, the upregulation of ACE activity in rat carotid body by chronic hypoxia should be of physiological and clinical relevance, for example, for high-altitude physiology and in some clinical conditions of congenital heart defects and chronic lung disease (14, 15).

The local RAS in the carotid body might play a crucial role in the hemodynamic and pathophysiological changes in hypoxia. The increased ACE activity can elevate local production of ANG II, thus enhancing the excitability of the carotid chemoreceptor. In addition to the increase in the ventilatory drive during hypoxia, studies have shown that the activation of carotid chemoreceptor can cause sodium and water diuresis, thus leading to a reduction in plasma volume and an increase in hemoconcentration in early hypoxia (19). In addition, basal levels of and exercise-induced elevation in plasma renin activity and aldosterone are less in mountaineers (49, 55), high-altitude natives, and patients with chronic lung diseases (8), suggesting that hypoxia interferes with the circulating RAS. This downregulation may reduce the sodium and water retention that may occur at high altitude. On the other hand, the upregulation of the local RAS in the carotid body may be compensatory to the suppressive effect of hypoxia on the circulating RAS for the maintenance of sympathetic activities. The outcomes of these adaptive changes are centrally linked to the physical performance and development of pulmonary hypertension and acute mountain sickness at high altitude. Indeed, it was found that the levels of serum ACE activity and the insertion/deletion polymorphism of the ACE gene are associated with athletic performance and arterial oxygen saturation at high altitude (3, 18, 39, 53) and a number of cardiopulmonary diseases (1, 2, 9, 10, 38, 50). Thus changes of local ACE activity in the carotid body by prolonged hypoxia might be potentially important in high altitude and in athlete physiology, in addition to having pathophysiological relevance (31).


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
We thank the financial support from the Research Grants Councils of Hong Kong (Project CUHK 4075/00M AND CUHK 4116/01M) and the Direct Grant of the Chinese University of Hong Kong (Project 2041013).


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. S. Leung, Dept. of Physiology, Faculty of Medicine, The Chinese Univ. of Hong Kong, Shatin, N.T., Hong Kong (E-mail: psleung{at}cuhk.edu.hk).

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
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, and Morrell NW. Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med 166: 1396-1402, 2002.[Abstract/Free Full Text]
  2. Alvarez R, Reguero JR, Batalla A, Iglesias-Cubero G, Cortina A, Alvarez V, and Coto E. Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res 40: 375-379, 1998.[Abstract/Free Full Text]
  3. Alvarez R, Terrados N, Ortolano R, Iglesias-Cubero G, Reguero JR, Batalla A, Cortina A, Fernandez-Garcia B, Rodriguez C, Braga S, Alvarez V, and Coto E. Genetic variation in the renin-angiotensin system and athletic performance. Eur J Appl Physiol 82: 117-120, 2000.[CrossRef][Web of Science][Medline]
  4. Campell DJ. Tissue renin-angiotensin system: sites of angiotensin formation. J Cardiovasc Pharmacol 10: 1-8, 1987.[Medline]
  5. Catt KJ, Cain MD, Coghlan JP, Zimmet PZ, Cran E, and Best JB. Metabolism and blood levels of angiotensin II in normal subjects, renal disease, and essential hypertension. Circ Res 27: 177-193, 1970.[Medline]
  6. Chan WP, Fung ML, Nobiling R, and Leung PS. Activation of local renin-angiotensin system by chronic hypoxia in rat pancreas. Mol Cell Endocrinol 160: 107-114, 2000.[CrossRef][Web of Science][Medline]
  7. Chassagne C, Eddahibi S, Adamy C, Rideau D, Marotte F, Dubois-Rande JL, Adnot S, Samuel JL, and Teiger E. Modulation of angiotensin II receptor expression during development and regression of hypoxic hypertension. Am J Respir Cell Mol Biol 22: 323-332, 2000.[Abstract/Free Full Text]
  8. Colice GL, Lawrason J, Munsef A, Bittle P, Dietz J, and Ramirez G. Hormonal response to exercise in high altitude natives and COPD patients. Aviat Space Environ Med 64: 512-516, 1993.[Medline]
  9. Danser AH, Schalekamp MA, Bax WA, van den Brink AM, Saxena PR, Riegger GA, and Schunkert H. Angiotensin-converting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 92: 1387-1388, 1995.[Abstract/Free Full Text]
  10. Danser AH and Schunkert H. Renin-angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases. Eur J Pharmacol 410: 303-316, 2000.[CrossRef][Web of Science][Medline]
  11. Doggrell SA. Angiotensin AT-1 receptor antagonism: complementary or alternative to ACE inhibition in cardiovascular and renal disease? Expert Opin Pharmacother 3: 1543-1556, 2001.
  12. Dzau VJ. Vascular renin-angiotensin: a possible autocrine or paracrine system in control of vascular function. J Cardiovasc Pharmacol 6: 377-382, 1984.
  13. Dzau VJ, Burt DW, and Pratt RE. Molecular biology of the renin-angiotensin system. Am J Physiol Renal Fluid Electrolyte Physiol 255: F563-F573, 1988.[Abstract/Free Full Text]
  14. Fletcher EC. Physiological and genomic consequences of intermittent hypoxia. J Appl Physiol 90: 1600-1605, 2001.[Abstract/Free Full Text]
  15. Fletcher EC, Bao G, and Li R. Renin activity and blood pressure in response to chronic episodic hypoxia. Hypertension 34: 309-314, 1999.[Abstract/Free Full Text]
  16. Fung ML, Lam SY, Chen Y, Dong X, and Leung PS. Functional expression of angiotensin II receptors in type-I cells of the rat carotid body. Pflügers Arch 441: 474-480, 2001.[CrossRef][Web of Science][Medline]
  17. Fung ML, Lam SY, Dong X, Chen Y, and Leung PS. Postnatal hypoxemia increases angiotensin II sensitivity and up-regulates AT1a angiotensin receptors in rat carotid body chemoreceptors. J Endocrinol 173: 305-313, 2002.[Abstract]
  18. Gayagay G, Yu B, Hambly B, Boston T, Hahn A, Celermajer DS, and Trent RJ. Elite endurance athletes and the ACE I allele—the role of genes in athletic performance. Hum Genet 103: 48-50, 1998.[CrossRef][Web of Science][Medline]
  19. Honig A. Peripheral arterial chemoreceptors and control of sodium and water homeostasis. Am J Physiol Regul Integr Comp Physiol 257: R1282-R1302, 1989.[Abstract/Free Full Text]
  20. Hooper NM, Keen J, Pappin DJ, and Turner AJ. Pig kidney angiotensin converting enzyme. Purification and characterization of amphipathic and hydrophilic forms of the enzyme establishes C-terminal anchorage to the plasma membrane. Biochem J 247: 85-93, 1987.[Web of Science][Medline]
  21. Ip SP, Chan YW, and Leung PS. Effects of chronic hypoxia on the circulating and pancreatic renin-angiotensin system. Pancreas 25: 296-300, 2002.[CrossRef][Web of Science][Medline]
  22. Ip SP, Kwan PC, Williams CH, Pang S, Hooper NM, and Leung PS. Changes of angiotensin-converting enzyme activity in the pancreas of chronic hypoxia and acute pancreatitis. Int J Biochem Cell Biol 35: 944-954, 2003.[CrossRef][Web of Science][Medline]
  23. Jederlinic P, Hill NS, Ou LC, and Fanburg BL. Lung angiotensin converting enzyme activity in rats with differing susceptibilities to chronic hypoxia. Thorax 43: 703-707, 1988.[Abstract/Free Full Text]
  24. Kay JM, Keane PM, Suyama KL, and Gauthier D. Lung angiotensin converting enzyme activity in chronically hypoxic rats. Thorax 40: 587-591, 1985.[Abstract/Free Full Text]
  25. Lahiri S, Di Giulio C, and Roy A. Lessons from chronic intermittent and sustained hypoxia at high altitudes. Respir Physiol Neurobiol 130: 223-233, 2002.[CrossRef][Web of Science][Medline]
  26. Lam SY and Leung PS. A locally generated angiotensin system in rat carotid body. Regul Pept 107: 97-103, 2002.[CrossRef][Web of Science][Medline]
  27. Lam SY and Leung PS. Chronic hypoxia activates a local angiotensin-generating system in rat carotid body. Mol Cell Endocrinol 203: 147-153, 2003.[CrossRef][Web of Science][Medline]
  28. Leung PS, Chan WP, and Nobiling R. Regulated expression of pancreatic renin-angiotensin system in experimental pancreatitis. Mol Cell Endocrinol 166: 121-128, 2002.
  29. Leung PS and Chappell MC. A local pancreatic renin-angiotensin system: endocrine and exocrine roles. Int J Biochem Cell Biol 35: 838-846, 2003.[CrossRef][Web of Science][Medline]
  30. Leung PS, Fung ML, and Sernia C. Chronic hypoxia induced down-regulation of angiotensinogen expression in rat epididymis. Regul Pept 96: 143-149, 2001.[CrossRef][Web of Science][Medline]
  31. Leung PS, Fung ML, and Tam SC. Renin-angiotensin system in the carotid body. Int J Biochem Cell Biol 35: 847-854, 2003.[CrossRef][Web of Science][Medline]
  32. Leung PS, Lam SY, and Fung ML. Chronic hypoxia upregulates the expression and function of AT1 receptor in rat carotid body. J Endocrinol 167: 517-524, 2000.[Abstract]
  33. Leung PS and Sernia C. The renin-angiotensin system and male reproduction: new functions for old hormones. J Mol Endocrinol 30: 263-270, 2003.[Abstract]
  34. Li P, Chen PM, Wang SW, and Chen LY. Time-dependent expression of chymase and angiotensin converting enzyme in the hamster heart under pressure overload. Hypertens Res 25: 757-762, 2002.[CrossRef][Web of Science][Medline]
  35. Milledge JS and Catley DM. Angiotensin converting enzyme response to hypoxia in man: its role in altitude acclimatization. Clin Sci (Lond) 67: 453-456, 1984.[Medline]
  36. Milledge JS, Catley DM, Blume FD, and West JB. Renin, angiotensin-converting enzyme, and aldosterone in humans on Mount Everest. J Appl Physiol 55: 1109-1112, 1983.[Abstract/Free Full Text]
  37. Molinaro G, Adam A, Lepage Y, Hammerschmidt D, Koenigbauer U, and Eastlund T. Hypotensive reaction during staphylococcal protein A column therapy in a patient with anomalous degradation of bradykinin and Des-Arg9-bradykinin after contact activation. Transfusion 42: 1458-1465, 2002.[CrossRef][Web of Science][Medline]
  38. Montgomery HE, Clarkson P, Dollery CM, Prasad K, Losi MA, Hemingway H, Statters D, Jubb M, Girvain M, Varnava A, World M, Deanfield J, Talmud P, McEwan JR, McKenna WJ, and Humphries S. Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation 96: 741-747, 1997.[Abstract/Free Full Text]
  39. Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman DE, Jubb M, World M, Thomas EL, Brynes AE, Saeed N, Barnard M, Bell JD, Prasad K, Rayson M, Talmud PJ, and Humphries SE. Human gene for physical performance. Nature 393: 221-222, 1998.[CrossRef][Medline]
  40. Morrell NW, Atochina EN, Morris KG, Danilov SM, and Stenmark KR. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. J Clin Invest 96: 1823-1833, 1995.[Web of Science][Medline]
  41. Morrell NW, Danilov SW, Satyan KB, Morris KG, and Stenmark KR. Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension. Cardiovasc Res 34: 393-403, 1997.[Abstract/Free Full Text]
  42. Morrell NW, Morris KG, and Stenmark KR. Role of angiotensin converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol Heart Circ Physiol 269: H1186-H1194, 1995.[Abstract/Free Full Text]
  43. Neylon M, Marshall J, and Johns EJ. The role of the renin-angiotensin system in the renal response to moderate hypoxia in the rat. J Physiol 491: 479-499, 1996.[Abstract/Free Full Text]
  44. Ng KKF and Vane JR. Conversion of angiotensin to angiotensin II. Nature 216: 762-766, 1967.[CrossRef][Medline]
  45. Oparil S, Narkates AJ, Jackson RM, and Ann HS. Altered angiotensin-converting enzyme in lung and extrapulmonary tissues of hypoxia-adapted rats. J Appl Physiol 65: 218-227, 1988.[Abstract/Free Full Text]
  46. Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev 57: 313-370, 1977.[Free Full Text]
  47. Phillips MI, Speakman EA, and Kimura B. Levels of angiotensin and molecular biology of the tissue renin angiotensin systems. Regul Pept 43: 1-20, 1993.[CrossRef][Web of Science][Medline]
  48. Prabhakar NR. Oxygen sensing by the carotid body chemoreceptors. J Appl Physiol 88: 2287-2295, 2000.[Abstract/Free Full Text]
  49. Ramirez G, Hammond M, Agosti SJ, Bittle PA, Dietz JR, and Colice GL. Effects of hypoxemia at sea level and high altitude on sodium excretion and hormonal levels. Aviat Space Environ Med 63: 891-898, 1992.[Medline]
  50. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, and Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343-1346, 1990.[Web of Science][Medline]
  51. Vane JR. The fate of angiotensin I. In: Handbook of Experimental Pharmacology, Angiotensin, edited by Page IH and Bumpus FM. New York: Springer-Verlag, 1974, vol. 37, p. 17-39.
  52. Wang ZY and Bisgard GE. Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59: 168-177, 2002.[CrossRef][Web of Science][Medline]
  53. Woods DR, Pollard AJ, Collier DJ, Jamshidi Y, Vassiliou V, Hawe E, Humphries SE, and Montgomery HE. Insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and arterial oxygen saturation at high altitude. Am J Respir Crit Care Med 166: 362-366, 2002.[Abstract/Free Full Text]
  54. Yu TZ and Ma CT. Effect of hypoxia on angiotensin-converting enzyme activity and gene expression of intrapulmonary artery smooth muscle cells. Sheng Li Xue Bao 50: 623-628, 1998.[Medline]
  55. Zaccaria M, Rocco S, Noventa D, Varnier M, and Opocher G. Sodium regulating hormones at high altitude: basal and post-exercise levels. J Clin Endocrinol Metab 83: 570-574, 1998.[Abstract/Free Full Text]
  56. Zhao L, al-Tubuly R, Sebkhi A, Owji AA, Nunez DJ, and Wilkins MR. Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung. Br J Pharmacol 119: 1217-1222, 1996.[Web of Science][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. S. Gilmartin, R. Tamisier, M. Curley, and J. W. Weiss
Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H778 - H785.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
T. V. Serebrovskaya, E. B. Manukhina, M. L. Smith, H. F. Downey, and R. T. Mallet
Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension?
Experimental Biology and Medicine, June 1, 2008; 233(6): 627 - 650.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. Tamisier, B. E. Hunt, G. S. Gilmartin, M. Curley, A. Anand, and J. W. Weiss
Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans
Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3027 - H3035.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
H. D. Schultz, Y. L. Li, and Y. Ding
Arterial Chemoreceptors and Sympathetic Nerve Activity: Implications for Hypertension and Heart Failure
Hypertension, July 1, 2007; 50(1): 6 - 13.
[Full Text] [PDF]

Home page
 Exp PhysiolHome page
J. W. Weiss, M. D. Y. Liu, and J. Huang
Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Physiological basis for a causal relationship of obstructive sleep apnoea to hypertension
Exp Physiol, January 1, 2007; 92(1): 21 - 26.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
P. S. Leung
Novel roles of a local angiotensin-generating system in the carotid body
J. Physiol., August 15, 2006; 575(1): 4 - 4.
[Full Text] [PDF]

Home page
 J. Physiol.Home page
Y.-L. Li and H. D. Schultz
Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II
J. Physiol., August 15, 2006; 575(1): 215 - 227.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. D Ganfornina, M. T Perez-Garcia, G Gutierrez, E Miguel-Velado, J. R Lopez-Lopez, A Marin, D Sanchez, and C Gonzalez
Comparative gene expression profile of mouse carotid body and adrenal medulla under physiological hypoxia
J. Physiol., July 15, 2005; 566(2): 491 - 503.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. Tamisier, A. Anand, L. M. Nieto, D. Cunnington, and J. W. Weiss
Arterial pressure and muscle sympathetic nerve activity are increased after two hours of sustained but not cyclic hypoxia in healthy humans
J Appl Physiol, January 1, 2005; 98(1): 343 - 349.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
96/2/809    most recent
00684.2003v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lam, S. Y.
Right arrow Articles by Leung, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lam, S. Y.
Right arrow Articles by Leung, P. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.