Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing

Foot Ankle Int. 2005 Oct;26(10):832-9. doi: 10.1177/107110070502601008.


Background: In the last few years much research has been conducted in methods to promote tendon healing. The aim of this study was to determine if the healing process after operative repair of rat Achilles tendons could be stimulated by the paratendinous injection of a sensory peptide, substance P (SP).

Methods: Ninety-six male Sprague-Dawley rats were randomly allocated to four groups: (I) control buffer injections, (II) injections of SP 10(-6) mol/kg body weight combined with a carrier, (III) injections of SP 10(-8) mol/kg BW with the carrier, and (IV) injections with the carrier only (thiorphan 1 micromol/kg BW and captopril 30 micromol/kg BW, both neutral endopeptidase inhibitors). The influence on tissue repair was determined from the histologic measurement of fibroblast proliferation, angiogenesis, and collagen organization. On days 7, 14, 28 and 42, animals were sacrificed and histologic evaluations were performed on the injured Achilles tendon constructs.

Results: The two groups subjected to SP injections showed a significant initial fibroblast proliferation on day 7 (p < 0.05), which rapidly declined by day 14 to the level of cellular proliferation observed with the use of thiorphan and captopril. Capillary proliferation showed a similar evolution, except that in the second week angiogenesis in the treated groups was below the level of the control group. Strikingly, collagen orientation increased faster in the groups injected with SP. This was obvious from the second week already and the difference remained until the completion of the study.

Conclusion: This is the first study to demonstrate that paratendinous injections of SP after operative repair of the Achilles tendon in rats appears to provide a boost to the initial stages of healing and significantly accelerate the reparative phase of the healing process.

MeSH terms

  • Achilles Tendon / blood supply
  • Achilles Tendon / injuries*
  • Achilles Tendon / physiopathology
  • Animals
  • Captopril / pharmacology
  • Cell Proliferation / drug effects
  • Collagen / physiology
  • Disease Models, Animal
  • Drug Combinations
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Male
  • Neovascularization, Physiologic / drug effects
  • Neprilysin / antagonists & inhibitors*
  • Protease Inhibitors / pharmacology
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Rupture
  • Substance P / pharmacology*
  • Tendon Injuries / drug therapy*
  • Tendon Injuries / physiopathology
  • Thiorphan / pharmacology
  • Treatment Outcome
  • Wound Healing / drug effects*
  • Wound Healing / physiology


  • Drug Combinations
  • Protease Inhibitors
  • Substance P
  • Collagen
  • Captopril
  • Thiorphan
  • Neprilysin