title: Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model.
abstract: BACKGROUND
  We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins.
  
  
  METHODS
  Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA).
  
  
  RESULTS
  A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group.
  
  
  CONCLUSIONS
  The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced substances, out of which the tachykinins conform to one substance family, may play a role in mediating effects in the tissue in a muscle that is subjected to pronounced overuse.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Song
authors.forename: Per S
authors.initials: PS
authors.lastname: Stål
authors.forename: Ji-Guo
authors.initials: JG
authors.lastname: Yu
authors.forename: Ronny
authors.initials: R
authors.lastname: Lorentzon
authors.forename: Clas
authors.initials: C
authors.lastname: Backman
authors.affiliation: Department of Integrative Medical Biology, Section for Anatomy, Umeå University, 901 87 Umeå, Sweden. sture.forsgren@anatomy.umu.se.
authors.forename: Sture
authors.initials: S
authors.lastname: Forsgren
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D012090:Cumulative Trauma Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D007267:Injections; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009220:Myositis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013373:Substance P / Q000008:administration & dosage / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D018040:Receptors, Neurokinin-1; D013373:Substance P
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