The gastrointestinal tract may be considered to contain three muscle
layers. These are the outer longitudinal and circular muscle
layers that comprise the muscularis propria
and an inner muscle
layer beneath the mucosa (the intestinal lining) called the muscularis
(meaning "muscle of the mucosa
"). The muscularis
propria is primarily involved in propelling ingested substances along the
length of the intestine whereas, the role of the muscularis mucosae has
not yet been so clearly established. It has been suggested that this
muscle may be involved in maintaining structural integrity in some regions
of the gut whereas, in other areas it may modulate absorption and/or
secretion by altering the surface area of the mucosa. Research in the GI
Neuropharmacology Laboratory is largely focused on the muscularis mucosae
in an attempt to clearly define its physiological role and to assess
the mechanisms underlying the damage it may sustain in certain
intestinal disease processes.
Currently, two major projects involving the role of the muscularis mucosae
in gastrointestinal function are being conducted. In the first, the
pharmacological properties of this muscle are being studied in an attempt
to assess its functional relationship to the mucosal epithelium. In the
second, events leading to altered muscularis mucosae and
epithelial function in intestinal inflammation are being investigated.
Details of these projects appear below:
It is the overall aim of the first research project to investigate the
mechanisms that regulate the integrated function of the muscularis mucosae
and the mucosal epithelium in the small and large intestine. A more
thorough understanding of the properties of the muscularis mucosae and how
its relationship with the mucosal epithelium varies along the length of
the gut is a necessary adjunct to our understanding of how the function of
these dissimilar structures within the intestine are integrated, such that
they are both able to contribute to the performance of a common goal,
i.e., mucosal absorption and secretion. In the first part of the
project we are using a novel in vitro technique to measure how
contraction and relaxation of the muscularis mucosae influences mucosal
function and to assess how different luminal stimuli (altered pH,
osmolarity, distension and irritation) alter muscularis mucosae motor
activity. In the second portion of this study we are attempting to
characterize the nature of the neurotransmitters released by the nerves of
the submucosal plexus that innervate the muscularis mucosae and the
mucosal epithelium in different regions of the intestine. The third
component of this investigation involves performing a comprehensive
classification of the receptor subtypes associated with the
neurotransmitters found to influence muscularis mucosae and mucosal
epithelial function at these sites. From the results of these experiments
it will be possible to determine the extent to which the functions of the
muscularis mucosae and mucosal epithelium are linked. The data will also
allow us to characterize the neurotransmitters and receptors involved in
coordinated muscularis mucosae movement and epithelial ion/nutrient
transport in successive regions of the gut.
Based upon the experiments described above, we are also working to
determine how inflammation, such as may be seen in ulcerative colitis or
Crohn's disease, alters the integrated function of the muscularis mucosae
and mucosal epithelium in the colon.
In the second research project we have been able to demonstrate that in a
well characterized model of Inflammatory
Bowel Disease (IBD) the individual functions of each of the
mucosal epithelium, the muscularis mucosae and the submucosal plexus are
disrupted in the earliest stages of the inflammatory process. Now, through
the use of a novel in vitro technique developed at the University
of South Dakota School of Medicine, it is possible to measure
simultaneously how this developing inflammation affects the ability of the
mucosal epithelium to absorb and secrete and the ways in which it disrupts
modulation of these processes by the motor activity of the muscularis
mucosae and the submucosal plexus. This is an important area of study
because IBD is characterized by periods of chronic diarrhea that are
consistent with severe mucosal dysfunction. These studies are specifically
designed to investigate the relationship between muscularis mucosae
movement and mucosal function in both the control and the colitic colon
in vitro and to determine how the role of the submucosal plexus in
coordinating these events is altered by the onset of inflammation. The
data obtained in this study will provide new insights into mechanisms of
colonic function in the earliest stages of colitis about which essentially
nothing is presently known. In addition, because the muscularis mucosae is
pharmacologically distinct from the other muscle layers of the gut, these
experiments will help us to identify potential therapeutic agents designed
to selectively restore the function of this muscle to pre-inflammation
levels. By doing this we hope to be able to assist in a return to normal
mucosal epithelial activity. This is a preferable approach to the
pharmacologic agents and surgical procedures currently employed in
treating IBD, because these attempt to influence colonic function once the
inflammatory process has reached a more advanced and less reversible
first research poster, British Pharmacological Society meeting, Oxford
This is me and some of
the people who have been involved in the GI Neuropharmacology Research
Program at the University of South Dakota.
Presenting research data at the International Motility Society, Lorne, Victoria,
at the American Gastroenterological Association Meeting, Chicago, IL,
Courses for Fall and Spring 2015/2016
Introduction to Pharmacology
Medical Foundations 1
GI & Hepatobiliary Systems
Memberships of Professional Societies:
Publications (selected from 39):
- Burakoff, R., Zhao, L., Celifarco, A.J., Rose, K., Donovan, V. &
Percy, W.H.: Effects of purified C. difficile toxin A on rabbit
distal colon. Gastroenterology 109:
- Goldhill, J.M., Rose, K. & Percy, W.H.: Effects of antibiotics on
epithelial ion transport in the rabbit distal colon in vitro. J.
Pharm. Pharmacol. 48: 651-656, 1996.
- Percy, W.H., Miller, A.J. & Brunz, J.T.: Pharmacologic
characteristics of rabbit esophageal muscularis mucosae in vitro.
Dig. Dis. Sci. 42: 2537-2546,
- Percy, W.H., Burakoff, R., Rose, K., Desai, H.P., Pothoulakis, C. &
Eglow, R.: In vitro evidence that rabbit distal colonic muscularis
mucosae has a Clostridium difficile toxin A receptor. Am. J.
Physiol. 275: G402-G409, 1998.
- Appleyard, C.B., Williams, J.L., Hathaway, C.A. & Percy, W.H.:
Temporal patterns of colonic blood flow and tissue damage in an animal
model of colitis. Dig. Dis. Sci. 44:
- Hathaway, C.A., Appleyard, C.B., Percy, W.H. & Williams, J.L.:
Experimental colitis increases blood-brain barrier permeability in
rabbits. Am. J. Physiol. 276:
- Percy, W.H., Warren, J.M. & Brunz, J.T.: Characteristics of the
muscularis mucosae in the acid secreting region of the rabbit stomach.
Am. J. Physiol. 276: G1213-G1220, 1999.
- Hathaway, C.A., Percy, W.H. & Williams, J.L.: The effects of free
radicals and leukocytes on increases in blood-brain barrier permeability
during colitis. Dig. Dis. Sci. 45: 967-975,
- Percy, W.H., Brunz, J.T., Burgers, R.E., Fromm, T.H., Merkwan, C.L. &
vanDis, J.: Inter-relationship between colonic muscularis mucosae activity
and changes in transmucosal potential difference. Am. J. Physiol. 281: G479-G489, 2001.
- Percy, W.H., Kittelsrud, J.M. & Brunz, J.T.: Types of adrenoreceptors
mediating responses of rabbit gastric muscularis mucosae. Dig. Dis. Sci. 47: 356-364, 2002.
- Appleyard, C.B., Alvarez, A. & Percy, W.H.: Temporal changes in
colonic vascular architecture and inflammatory mediator levels in animal
models of colitis. Dig. Dis. Sci. 47:
- Percy, W.H., Fromm, T.H. & Wangsness, C.E.: Muscularis mucosae
contraction evokes colonic secretion via prostaglandin synthesis and nerve
stimulation. Am. J. Physiol. 284:
- Goodman, B.E. & Percy, W.H.: CFTR in cystic fibrosis and cholera: From
membrane transport to clinical practice. Adv.
Physiol. Ed. 29: 75-82, 2005.
- Appleyard, C.B., Morales, M. & Percy, W.H.: Regional variations in
neurokinin receptor subtype contributions to muscularis mucosae and
epithelial function in rat colon. Dig. Dis. Sci.
51: 506-516, 2006.
- Percy, W.H. & Keupp, S.: Adrenergic responses of rat colonic
muscularis mucosae. J. Pharm. Pharmacol. 60: 1097-1103, 2008.
- Percy, W.H. and Christensen, J.: Some drug actions on the activity
of the colonic muscularis mucosae of the opossum in vitro. Proc.
5th British Society for Gastroenterology/SK & F International workshop on
clinical pharmacology and the gut. Ed. M.J.S. Langman: Published by SK&F
Laboratories, England. pp 59-65, 1984.
- Burakoff, R., Percy, W.H., Nastos, E. and Won, S.: The
pharmacologic basis of the mechanism of action of leukotrienes B4 and D4
and prostaglandins E2 and F2alpha on distal colonic motility in the rabbit
in vivo. In- Inflammatory Bowel Disease: current status and future
approach. Ed. R. P. MacDermott: Elsevier Science Publishers. pp 317-322,
- Percy, W.H., Burton, M.B., Jacobowitz, Y. & Burakoff, R.: An
investigation in vitro of the properties of the individual muscle
layers of the rabbit colon in an induced colitis. In-Effects of immune
cells and inflammation on smooth muscle and enteric nerves. Eds. S.M.
Collins & W.J. Snape: CRC Press. pp 95-108, 1990.
- Percy, W.H.: The use of in vitro techniques for the study of
gastrointestinal motility. In-Methods in Gastrointestinal Pharmacology: A
Handbook. Ed. T.S. Gaginella: CRC Press. pp189-223, 1995.
Abstracts (selected from 92):
- Percy, W.H., Brunz, J.T & Burgers, R.E.: Inter-relationship
between rabbit distal colonic muscularis mucosae movement and alterations
in transepithelial potential difference. Gastroenterology 116:
- Percy, W.H., Brunz, J.T., Burgers, R.E & van Dis, J.: Modulation of
muscularis mucosae and epithelial function in the rabbit distal colon
in vitro. Neurogastroenterol. & Motil. 11: 280, 1999.
- Percy, W.H. & Fromm, T.H.: Tachykinin-induced responses of rat colonic
muscularis mucosae are governed by regional variations in neurokinin
receptor subtypes. Gastroenterology 118: A836, 2000.
- Appleyard, C.B., Alvarez, A. & Percy, W.H.: Inflammation-induced
in vascular architecture in animal models of colitis. Gastroenterology
118: A1113, 2000.
- Percy, W.H. & Fromm, T.: Simultaneous analysis of the effects of
bradykinin on rabbit distal colonic muscularis mucosae and epithelium.
Neurogastroenterol. & Motil. 12: 491, 2000.
- Appleyard, C.B. & Percy, W.H.: Regional variations in neurokinin
receptor subtype contributions to muscularis mucosae and epithelial
function in the rat colon. Neurogastroenterol. & Motil. 12: 477,
- Percy, W.H. & Wangsness, C.E.: Colonic muscularis mucosae contraction
elicits mucosal secretion via prostaglandin production and non-cholinergic
nerve stimulation. Gastroenterology 120: A329, 2001.
- Percy, W.H., Fromm, T.H. & Wangsness, C.E.: Prostaglandin production
and neural pathways integrate muscularis mucosae and mucosal function in
rabbit distal colon. Proceedings of the 34th International
Physiological Sciences, Christchurch, New Zealand, 2001.
- Percy, W.H., Wangsness, C.E. & Fromm, T.H.: Colonic muscularis mucosae
contraction drives mucosal secretion via prostaglandin production and
neural pathways. Neurogastroenterol. & Motil. 13: 421, 2001.
- Percy, W.H., Wangsness, C.E. & Fromm, T.H.: TNBS colitis alters
colonic muscularis mucosae-mucosa interactions in the rabbit.
Gastroenterology 122: T1079, 2002.
- Percy, W.H. & Fromm, T.H.: Acute TNBS colitis alters muscularis
mucosae-mucosa communication in vitro. Neurogastro. & Motil.
15: 589, 2003.
- Percy, W.H.: Rabbit colonic muscularis mucosae-mucosa communication is
altered in acute TNBS colitis. Neurogastro. & Motil. 16: 678, 2004.
- Appleyard, C.B., Morales, M. & Percy, W.H.: Rat colonic muscularis
mucosae and mucosa each possess three neurokinin (NK) receptor subtypes,
but only one mediates responses to substance P in each structure.
Gastroenterology 128: A270, 2005.
- Percy, W.H.: Region-specific mechanisms underlying the excitatory
effects of bradykinin and ATP on rat colonic muscularis mucosae.
Neurogastro. & Motil. 17: 33, 2005.
- Percy, W.H.: Responses of rat proximal, mid and distal colonic
muscularis mucosae to ATP and bradykinin are mediated by different
mechanisms. Gastroenterology 130: A287-288, 2006.
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whp 7/96: Last Updated 09/03/2015
The views and opinions expressed in these pages are strictly those of Dr. William Percy.
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