AJP - GI Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Gastrointest Liver Physiol 286: G698-G701, 2004; doi:10.1152/ajpgi.00529.2003
0193-1857/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
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 (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zavros, Y.
Right arrow Articles by Merchant, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zavros, Y.
Right arrow Articles by Merchant, J. L.

THEMES

Inflammation and Cancer III. Somatostatin and the innate immune system

Yana Zavros,1 John Y. Kao,1 and Juanita L. Merchant1,2

Departments of 1Internal Medicine and 2Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109


   ABSTRACT
TOP
 ABSTRACT
SOMATOSTATIN AND ITS RECEPTOR...
 GENETICALLY ENGINEERED MOUSE...
 IMMUNOREGULATION OF SOMATOSTATIN
 REFERENCES
 
In the stomach, somatostatin is secreted from D cells and is a potent inhibitor of gastrin-induced acid secretion. During bacterial infection, somatostatin expression and release are suppressed. As a result, gastric infection often induces hypergastrinemia that, in turn, stimulates gastric acid secretion, the stomach's most important antimicrobial agent. There are an abundance of data showing that inflammatory cytokines regulate somatostatin in immune and neural cells. However, it was not until recently that the immunoregulation of gastric somatostatin was studied in vivo. This theme article discusses the role of somatostatin as an immunoregulatory peptide during gastritis.

Helicobacter; gastritis; hypergastrinemia; interferon-{gamma}; interleukin-4

SOMATOSTATIN WAS FIRST IDENTIFIED in 1973 in the hypothalamus as growth hormone release inhibitory factor (6). In 1975, Arimura et al. (2) described the first radioimmunoassay for somatostatin. With a functioning radioimmunoassay, the tissue distribution and multiple molecular forms of somatostatin were documented. Since then, it has been revealed that somatostatin is not only produced in the hypothalamus but is present in a variety of endocrine and nonendocrine tissues. Moreover, its effect on each target cell is generally to inhibit peptide function. In the central nervous system, somatostatin acts as a neurotransmitter, whereas in peripheral tissues, it regulates endocrine and exocrine secretion and modulates motor activity in the gastrointestinal tract (17). Somatostatin also regulates hematopoietic cells involved in the immune defense pathways of several tissues including the stomach (22, 24).

In the stomach, somatostatin is the primary inhibitor of gastrin-stimulated acid secretion. Gastrin, released from antral G cells, is a major regulator of parietal cell acid secretion. Gastrin indirectly stimulates acid secretion through induction of histamine release from enterochromaffin-like (ECL) cells. Histamine subsequently stimulates gastric acid secretion through H2 receptors on parietal cells (18). Increased acid levels then stimulate putative chemoreceptors on antral D cells to secrete somatostatin and block further release of gastrin and gastric acid. Thus gastric acid secretion is regulated by a negative feedback mechanism involving somatostatin (17). During gastric bacterial infection, this negative feedback mechanism does not occur.

Chronic inflammation of the gastric mucosa (chronic gastritis) is caused by Helicobacter pylori or bacterial overgrowth in the hypochlorhydric stomach (5, 25). Infection with H. pylori mounts a T-helper (Th)1 immune response characterized by the recruitment of T lymphocytes expressing IFN-{gamma}, TNF-{alpha}, and IL-1{beta} but low levels of Th2 lymphocytes expressing IL-4 and IL-5 (15). IFN-{gamma}-null mice do not mount an inflammatory response even after 15 mo of H. pylori infection (19). In contrast, mice deficient in IL-4 exhibit a skewed Th1 immune response (19). Thus it is believed that IFN-{gamma} plays a pivotal role in orchestrating the mucosal damage observed during gastritis.

Chronic gastritis is also accompanied by reciprocal changes in the gastric neuroendocrine cell populations that regulate acid secretion (16). The number of G cells increases, whereas D cells decrease rendering Helicobacter-infected subjects hypergastrinemic (16). Although reciprocal changes between gastrin and somatostatin occur during bacterial colonization, the link to the immune system has been poorly defined. Recently, we have shown that the gastric immune system and acid regulatory peptides are not separate entities but rather, are part of an immunoregulatory circuit. This article summarizes the role of somatostatin in the gastric innate immune system.


   SOMATOSTATIN AND ITS RECEPTOR FAMILY
TOP
 ABSTRACT
 SOMATOSTATIN AND ITS RECEPTOR...
GENETICALLY ENGINEERED MOUSE...
 IMMUNOREGULATION OF SOMATOSTATIN
 REFERENCES
 
Somatostatin is synthesized from a 92-amino acid preprosomatostatin precursor molecule. Mammalian preprosomatostatin is processed predominantly at the COOH-terminal segment to generate two biologically active forms, somatostatin-14 and somatostatin-28. Both bioactive forms are synthesized in unpredictable amounts by somatostatin-producing cells due to differential precursor processing. Somatostatin-14 is predominantly found in pancreatic islets, stomach, peripheral, and enteric neurons. Somatostatin-28 accounts for 20–30% of the total somatostatin in brain and is the major immunoreactive form in the small intestine (21).

Molecular characterization of rodent and human somatostatin receptors have resulted in the identification of five different receptors (sstr1–5) that all belong to the G protein-coupled receptor superfamily. They are encoded by five different genes and are highly conserved between species (for example, sstr1 of mouse and human share 99% sequence identity). Within the same species, there is a 45–61% sequence identity between different receptor subtypes. Both somatostatin-14 and somatostatin-28 bind to sstr1–4 with equal affinity. However, somatostatin-28 has a higher affinity for sstr5 (10).

All five somatostatin receptors have been identified throughout the central nervous system and endocrine and exocrine glands. However, sstr2 is the predominant receptor localized on parietal and ECL cells, suggesting that it is through this receptor that somatostatin inhibits gastric acid secretion (1). Studies using the sstr2 knockout/lacZ knockin mice showed that the majority of epithelial cells in the midregion of the fundus express sstr2 and were identified as parietal cells by positive H+-K+-ATPase immunostaining (1). In addition, ECL cells located in the fundus and pylorus also express these sstr2 receptors (1). Consistent with its location, the sstr2 knockout mouse exhibits high gastric acid secretion due to a lack of a somatostatin-induced inhibitory effect on parietal and ECL cells (13). Somatostatin also inhibits IFN-{gamma} release from T cells (8). SSTR2 is the predominant receptor subtype expressed by granuloma lymphocytes isolated from mice with schistosomiasis infection (8). In particular, the sstr2A isoform accounts for 99% of inflammatory cell sstr2 mRNA and mediates the inhibitory effect of somatostatin on T cell IFN-{gamma} release (8).

Initial studies focused on the ability of somatostatin to inhibit acid secretion by suppressing adenyl cyclase/cAMP-dependent intracellular pathways. Subsequently, it was recognized that somatostatin could also act further downstream in the cell-signaling cascade. For example, one mechanism of somatostatin action involves inhibition of ERK activity, Elk-1 phosphorylation, and transcriptional activation of c-Fos and c-Jun (20). Somatostatin is also known to inhibit both basal and stimulated gastrin gene expression (3). EGF stimulation of gastrin transcription is mediated by an EGF response element (gERE) that lies between -68 and -54 in the gastrin promoter (14). Inhibition of the response by somatostatin is mediated by a cis-regulatory element located 5' to gERE at -82 to -69 (3). The putative somatostatin response element contains the E-box CATATGG, which typically binds helix-loop-helix transcription factors (3).


   GENETICALLY ENGINEERED MOUSE MODELS TO STUDY SOMATOSTATIN-INHIBITORY PATHWAYS
TOP
 ABSTRACT
 SOMATOSTATIN AND ITS RECEPTOR...
 GENETICALLY ENGINEERED MOUSE...
IMMUNOREGULATION OF SOMATOSTATIN
 REFERENCES
 
Originally developed to investigate the role of somatostatin as a mediator of growth hormone effects (11), somatostatin-deficient mice were found by our group to show higher circulating gastrin levels compared with wild-type mice (24). In contrast to somatostatin-deficient mice, sstr2 null mice do not show changes in circulating gastrin peptides (13). Collectively, these two results suggest that somatostatin plays a critical role in suppressing basal levels of gastrin (3) but that the inhibition of gastrin release is not mediated through the sstr2 receptor. In contrast to the sstr2-null mice, somatostatin null mice show the same basal gastric acid levels as those observed in wild-type C57BL/6 mice (24). So, in essence, the somatostatin effect on parietal cells and acid secretion occurs through sstr2, whereas the regulation of gastrin by somatostatin occurs through one of the other receptor family members. During Helicobacter felis infection in wild-type mice, we observed hypochlorhydria (24) consistent with what occurs in human subjects infected with H. pylori. In contrast, somatostatin-deficient mice infected with Helicobacter showed an increase in gastric acidity (24). Hyperacidity in the stomachs of null mice was explained by the lack of inhibition by somatostatin on the gastrin-secreting G cell during infection that, in turn, overwhelms any neutralizing effects from bacterial ammonia or cytokine inhibition of acid secretion (12). In addition, the results suggest that low or absent somatostatin levels are central to the development of gastric hyperacidity when the stomach is colonized by bacteria.


   IMMUNOREGULATION OF SOMATOSTATIN
TOP
 ABSTRACT
 SOMATOSTATIN AND ITS RECEPTOR...
 GENETICALLY ENGINEERED MOUSE...
 IMMUNOREGULATION OF SOMATOSTATIN
REFERENCES
 
Evidence for the immunoregulation of somatostatin originates from in vitro studies demonstrating somatostatin secretion from isolated rabbit and canine fundic D cells induced by TNF-{alpha} and IL-1{beta} (4). More recently, using isolated mouse gastric cells, we showed that somatostatin release is induced by IL-4 and inhibited by IFN-{gamma} (Fig. 1, A and B) (24). IFN-{gamma} stimulates the release of gastrin in part by suppressing somatostatin secretion (Fig. 1). In contrast, IL-4 directly stimulates the release of somatostatin that, in turn, suppresses gastrin secretion (Fig. 1) (24).



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 1. Reciprocal changes in gastrin and somatostatin (SOM) release by IFN-{gamma} from the isolated mouse gastric cells. The amount of gastrin released from gastric cells isolated from wild-type (SOM+/+) (A) and somatostatin null (SOM-/-) (B) mouse stomachs in response to treatment with 100 nM IFN-{gamma} or IL-4 for 6, 12, 18, and 24 h. The amount of SOM released from gastric cells isolated from SOM+/+ (C) and SOM-/- (D) mouse stomachs in response to 100 nM IFN-{gamma} or IL-4 for 6, 12, 18, and 24 h. The results are expressed as the %initial cell gastrin (350 pmol/l) or SOM (200 pmol/l) content. *P < 0.05, **P < 0.005 vs. PBS, n = 3 independent experiments performed in triplicate (24) (reproduced with permission from Proc Natl Acad Sci USA, 2003).

 

IL-4 directly stimulates somatostatin release through IL-4 receptors present on canine fundic D cells (24). Furthermore, stimulation of somatostatin by IL-4 is required to reduce inflammatory T cells recruited to the stomach during Helicobacter-induced gastritis. IFN-{gamma} expression, hypergastrinemia, and bacterial colonization were also inhibited by IL-4. However, the inhibition did not occur in IL-4-infused somatostatin-deficient mice infected with Helicobacter (24). Thus we concluded that somatostatin was both necessary and sufficient to prevent Helicobacter-induced gastritis (24). However, it is important to note that the levels of other proinflammatory cytokines (e.g., TNF-{alpha} and IL-1{beta}) that are also elevated in the inflamed gastric mucosa were not examined in the study. Indeed, IL-1{beta} or TNF-{alpha} has been shown to directly inhibit parietal cell function in studies using primary gastric cell preparations (23). Thus a major role of these cytokines, which are upregulated in response to bacterial infection, is likely to suppress acid secretion. The predominant Th2 cytokines elicited during helminth treatment of gastritis were IL-4, IL-10, and transforming growth factor (TGF)-{beta} but not IL-5, IL-6, or IL-12 (9). Regulatory T cells are thought to modulate H. pylori-mediated inflammation because IL-10 null mice mount a more aggressive inflammatory response to the organism than normal mice (7, 19). However, the mechanism by which IL-10 (regulatory T cells) and TGF-{beta} (Th3) oppose Th1-mediated inflammation has yet to be examined. Whereas experiments performed in the somatostatin-deficient mice demonstrate that somatostatin is both necessary and sufficient to resolve Helicobacter gastritis, treatment with Th2 cytokines other than IL-4 has not been investigated.

In summary, in the normal stomach, somatostatin inhibits gastrin release. However, IFN-{gamma} removes the inhibitory influence of somatostatin by suppressing its release from the D cells during inflammation (Fig. 2A). Systemic administration of a synthetic analog of somatostatin, such as octreotide, or infusion of the Th2 cytokine IL-4 increases the circulating levels of somatostatin. The Th1/Th2 equilibrium is reestablished through the reduction of IFN-{gamma}, inflammation, and, subsequently, gastrin expression (Fig. 2B). It is widely accepted that the neuropeptide somatostatin is an important regulator of the immune system in a number of tissues. However, the focus of somatostatin in the stomach has traditionally been on its ability to regulate gastric acid and gastrin secretion. In light of our recent results, we have shifted our focus from somatostatin as a regulator of acid secretion to its role as an important regulator of the innate immune system during gastritis (24). In particular, establishing a link between somatostatin and Th2 cytokines provides a possible explanation as to why Helicobacter gastritis is a Th1-predominant event. Establishing a critical link between somatostatin and the immune response may facilitate the generation of a Th2 response, development of novel therapies, and possibly vaccines.



View larger version (30K):
[in this window]
[in a new window]
  		Fig. 2. Model for immune regulation of gastrin and somatostatin secretion. A: gastrin is stimulated by the release of IFN-{gamma} during a T helper (Th)1 immune response to bacterial colonization. IFN-{gamma} downregulates the release of somatostatin by inhibiting the D cells and stimulating gastrin release (dotted line shown representing both direct and indirect pathways). This result relieves the inhibitory effect of somatostatin on gastrin. B: somatostatin is released in response to IL-4 and can mediate the resolution of Helicobacter-induced gastritis by suppressing Th1 immune cells. The inhibitory effect of IL-4 on the G cell occurs acutely by stimulating the release of somatostatin. However, in the absence of somatostatin (SOM-/-mice), a delayed inhibitory effect of IL-4 on the G cell was revealed (dotted line shown representing both direct and indirect pathways of the G cell) (24) (reproduced with permission from Proc Natl Acad Sci USA, 2003).

 


   ACKNOWLEDGMENTS
 
GRANTS

This work was supported, in part, by Public Health Service Grants PO1-62041, R01-61410, and R01-457129 (to J. L. Merchant) and Michigan Gastrointestinal Peptide Research Center Pilot Feasibility Grant DK-34933 (to Y. Zavros).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. L. Merchant, 1150 West Medical Ctr. Dr., MSRB I, 3510, Ann Arbor, MI 48109–0650 (E-mail: merchanj{at}umich.edu).


   REFERENCES
TOP
 ABSTRACT
 SOMATOSTATIN AND ITS RECEPTOR...
 GENETICALLY ENGINEERED MOUSE...
 IMMUNOREGULATION OF SOMATOSTATIN
 REFERENCES
 

  1. Allen JP, Canty AJ, Schulz S, Humphrey PP, Emson PC, and Young HM. Identification of cells expressing somatostatin receptor 2 in the gastrointestinal tract of Sstr2 knockout/lacZ knockin mice. J Comp Neurol 454: 329-340, 2002.[CrossRef][Web of Science][Medline]
  2. Arimura A, Sato H, Dupont A, Nishi N, and Schally AV. Somatostatin: abundance of immunoreactive hormone in rat stomach and pancreas. Science 189: 1007-1009, 1975.[Abstract/Free Full Text]
  3. Bachwich D, Merchant J, and Brand SJ. Identification of a cis-regulatory element mediating somatostatin inhibition of epidermal growth factor-stimulated gastrin gene transcription. Mol Endocrinol 6: 1175-1184, 1992.[Abstract/Free Full Text]
  4. Beales I, Calam J, Post L, Srinivasan S, Yamada T, and DelValle J. Effect of transforming growth factor {alpha} and interleukin 8 on somatostatin release from canine fundic D cells. Gastroenterology 112: 136-143, 1997.[CrossRef][Web of Science][Medline]
  5. Blaser MJ and Parsonnet J. Parasitism by the "slow" bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J Clin Invest 94: 4-8, 1994.[Web of Science][Medline]
  6. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, and Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179: 77-79, 1973.[Abstract/Free Full Text]
  7. Eaton KA, Mefford M, and Thevenot T. The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice. J Immunol 166: 7456-7461, 2001.[Abstract/Free Full Text]
  8. Elliott DE, Li J, Blum AM, Metwali A, Patel YC, and Weinstock JV. SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-{gamma} release. Eur J Immunol 29: 2454-2463, 1999.[CrossRef][Web of Science][Medline]
  9. Fox JG, Beck P, Dangler CA, Whary MT, Wang TC, Shi HN, and Nagler-Anderson C. Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy. Nat Med 6: 536-542, 2000.[CrossRef][Web of Science][Medline]
  10. Krantic S. Peptides as regulators of the immune system: emphasis on somatostatin. Peptides 21: 1941-1964, 2000.[CrossRef][Web of Science][Medline]
  11. Low MJ, Otero-Corchon V, Parlow AF, Ramirez JL, Kumar U, Patel YC, and Rubinstein M. Somatostatin is required for masculinization of growth hormone-regulated hepatic gene expression but not of somatic growth. J Clin Invest 107: 1571-1580, 2001.[Web of Science][Medline]
  12. Marshall BJ, Barrett LJ, Prakash C, McCallum RW, and Guerrant RL. Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gastroenterology 99: 697-702, 1990.[Web of Science][Medline]
  13. Martinez V, Curi AP, Torkian B, Schaeffer JM, Wilkinson HA, Walsh JH, and Tache Y. High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice. Gastroenterology 114: 1125-1132, 1998.[CrossRef][Web of Science][Medline]
  14. Merchant JL, Demediuk B, and Brand SJ. A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol 11: 2686-2696, 1991.[Abstract/Free Full Text]
  15. Mohammadi M, Czinn S, Redline R, and Nedrud J. Helicobacter-specific cell-mediated immune responses display a predominant Th1 phenotype and promote a delayed-type hypersensitivity response in the stomachs of mice. J Immunol 156: 4729-4738, 1996.[Abstract]
  16. Moss SF, Legon S, Bishop AE, Polak JM, and Calam J. Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease. Lancet 340: 930-932, 1992.[CrossRef][Web of Science][Medline]
  17. Patel YC. Somatostatin and its receptor family. Front Neuroendocrinol 20: 157-198, 1999.[CrossRef][Web of Science][Medline]
  18. Prinz C, Sachs G, Walsh JH, Coy DH, and Wu SV. The somatostatin receptor subtype on rat enterochromaffinlike cells. Gastroenterology 107: 1067-1074, 1994.[Web of Science][Medline]
  19. Smythies LE, Waites KB, Lindsey JR, Harris PR, Ghiara P, and Smith PD. Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-{gamma}, gene-deficient mice. J Immunol 165: 1022-1029, 2000.[Abstract/Free Full Text]
  20. Todisco A, Takeuchi Y, Yamada J, Sadoshima JI, and Yamada T. Molecular mechanisms for somatostatin inhibition of c-fos gene expression. Am J Physiol Gastrointest Liver Physiol 272: G721-G726, 1997.[Abstract/Free Full Text]
  21. Trent DF and Weir GC. Heterogeneity of somatostatin-like peptides in rat brain, pancreas, and gastrointestinal tract. Endocrinology 108: 2033-2038, 1981.[Abstract/Free Full Text]
  22. Weinstock JV and Elliott D. The somatostatin immunoregulatory circuit present at sites of chronic inflammation. Eur J Endocrinol 143, Suppl 1: S15-S19, 2000.[Abstract/Free Full Text]
  23. Yasunaga Y, Shinomura Y, Kanayama S, Higashimoto Y, Yabu M, Miyazaki Y, Murayama Y, Nishibayashi H, Kitamura S, and Matsuzawa Y. Mucosal interleukin-1{beta} production and acid secretion in enlarged fold gastritis. Aliment Pharmacol Ther 11: 801-809, 1997.[CrossRef][Web of Science][Medline]
  24. Zavros Y, Rathinavelu S, Kao JY, Todisco A, Del Valle J, Weinstock JV, Low MJ, and Merchant JL. Treatment of Helicobacter gastritis with IL-4 requires somatostatin. Proc Natl Acad Sci USA 100: 12944-12949, 2003.[Abstract/Free Full Text]
  25. Zavros Y, Rieder G, Ferguson A, Samuelson LC, and Merchant JL. Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology 122: 119-133, 2002.[CrossRef][Web of Science][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
E. Mensah-Osman, Y. Zavros, and J. L. Merchant
Somatostatin stimulates menin gene expression by inhibiting protein kinase A
Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G843 - G854.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
W. Motomura, T. Yoshizaki, K. Ohtani, T. Okumura, M. Fukuda, J. Fukuzawa, K. Mori, S.-J. Jang, N. Nomura, I. Yoshida, et al.
Immunolocalization of a Novel Collectin CL-K1 in Murine Tissues
J. Histochem. Cytochem., March 1, 2008; 56(3): 243 - 252.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
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 (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zavros, Y.
Right arrow Articles by Merchant, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zavros, Y.
Right arrow Articles by Merchant, J. L.

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