Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists

Br J Pharmacol. 1993 Sep;110(1):43-9. doi: 10.1111/j.1476-5381.1993.tb13769.x.


1. Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin-1 alpha (IL-1 alpha) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-1 alpha (0.3 pmol) were ineffective when given alone. When combined at these low doses, substances P and IL-1 alpha interacted to produce an enhanced neovascular response. 2. By use of selective tachykinin NK1, NK2 and NK3 receptor agonists, ([Sar9,Met(O2)11]substance P, [beta-Ala8]neurokinin A(4-10), Succ-[Asp6,MePhe8]substance P(6-11) (senktide), respectively), it was established that the activation of NK1 receptors is most likely to mediate the angiogenic response to substance P in this model. 3. The angiogenic activity of substance P and IL-1 alpha (10 pmol and 0.3 pmol day-1, respectively) was abolished by co-administration of (i) the selective peptide NK1 receptor antagonist, L-668,169 (1 nmol day-1), (ii) the selective non-peptide NK1 receptor antagonists, RP 67580 and (+/-)-CP-96,345 (both at 1 nmol day-1) or (iii) the IL-1 receptor antagonist, IL-1ra, (50 micrograms day-1). In contrast, the selective NK2 receptor antagonist, L-659,874 (1 nmol day-1) was ineffective. 4. The angiogenic action of substance P and IL-1 alpha was resistant to modification by mepyramine (1 nmol day-1) and/or cimetidine (10 nmol day-1), indomethacin (7 nmol day-1) or the platelet-activating factor (PAF) antagonist, WEB-2086 (22 nmol day-1), indicating that histamine, prostaglandins and PAF are not likely to be involved in this neovascular response. 5. The inhibition of the substance P/IL-1 angiogenic response by selective NK1 receptor antagonists or by an IL-1 receptor antagonist demonstrates that angiosuppression can be achieved by blocking the activity of angiogenic factors at the receptor level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / metabolism
  • Animals
  • Histamine / physiology
  • Histamine H1 Antagonists / pharmacology
  • Histamine H2 Antagonists / pharmacology
  • Indomethacin / pharmacology
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Interleukin-1 / pharmacology*
  • Male
  • Neovascularization, Pathologic / pathology*
  • Neurokinin-1 Receptor Antagonists*
  • Platelet Activating Factor / antagonists & inhibitors
  • Platelet Activating Factor / physiology
  • Prostaglandins / physiology
  • Rats
  • Rats, Wistar
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Receptors, Interleukin-1 / physiology
  • Receptors, Neurokinin-1 / physiology
  • Regional Blood Flow / drug effects
  • Substance P / pharmacology*
  • Xenon Radioisotopes


  • Histamine H1 Antagonists
  • Histamine H2 Antagonists
  • Interleukin-1
  • Neurokinin-1 Receptor Antagonists
  • Platelet Activating Factor
  • Prostaglandins
  • Receptors, Interleukin-1
  • Receptors, Neurokinin-1
  • Xenon Radioisotopes
  • Substance P
  • 6-Ketoprostaglandin F1 alpha
  • Histamine
  • Indomethacin