Education:

• B.Sc.(Honors) Pharmacology, The University of Aberdeen, Scotland, U.K. 1978

• Ph.D. Pharmacology, The University of Aberdeen, Scotland, U.K. 1982

Current Appointment:

• Associate Professor, Physiology and Pharmacology & Assistant Director for Preclinical Medical Education, Sanford School of Medicine, The University of South Dakota

Research Interests:

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 mucosae (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 stage.

Presenting my first research poster, British Pharmacological Society meeting, Oxford University, England, 1981.

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, Australia, 1998.

Presenting research data at the American Gastroenterological Association Meeting, Chicago, IL, 2005.

Courses for Fall and Spring 2018/2019

PHAR 552: Introduction to Pharmacology

Memberships of Professional Societies:

American Physiological Society

Publications (selected from 39):

1. 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: 348-354, 1995.

2. 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.

3. Percy, W.H., Miller, A.J. & Brunz, J.T.: Pharmacologic characteristics of rabbit esophageal muscularis mucosae in vitro. Dig. Dis. Sci. 42: 2537-2546, 1997.

4. 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.

5. 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: 431-438, 1999.

6. 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: G1174-G1180, 1999.

7. 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.

8. 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, 2000.

9. 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.

10. 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.

11. 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: 2007-2014, 2002.

12. 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: G213-G220, 2003.

13. 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.

14. 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.

15. Percy, W.H. & Keupp, S.: Adrenergic responses of rat colonic muscularis mucosae. J. Pharm. Pharmacol. 60: 1097-1103, 2008.

Book Chapters:

1. 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.

2. 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, 1988.

3. 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.

4. 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):

1. 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: A1063, 1999.

2. 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.

3. 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.

4. Appleyard, C.B., Alvarez, A. & Percy, W.H.: Inflammation-induced changes in vascular architecture in animal models of colitis. Gastroenterology 118: A1113, 2000.

5. 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.

6. 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, 2000.

7. 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.

8. 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 34^th International Congress of Physiological Sciences, Christchurch, New Zealand, 2001.

9. 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.

10. Percy, W.H., Wangsness, C.E. & Fromm, T.H.: TNBS colitis alters colonic muscularis mucosae-mucosa interactions in the rabbit. Gastroenterology 122: T1079, 2002.

11. Percy, W.H. & Fromm, T.H.: Acute TNBS colitis alters muscularis mucosae-mucosa communication in vitro. Neurogastro. & Motil. 15: 589, 2003.

12. Percy, W.H.: Rabbit colonic muscularis mucosae-mucosa communication is altered in acute TNBS colitis. Neurogastro. & Motil. 16: 678, 2004.

13. 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.

14. Percy, W.H.: Region-specific mechanisms underlying the excitatory effects of bradykinin and ATP on rat colonic muscularis mucosae. Neurogastro. & Motil. 17: 33, 2005.

15. 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.

Links to Favorite Internet Sites:

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Federation of American Societies for Experimental Biology

City of Glasgow, Scotland, UK

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whp 7/96: Last Updated 10/29/2018

The views and opinions expressed in these pages are strictly those of Dr. William Percy.
The content of these pages has not been reviewed or approved by The University of South Dakota