Stimulation of angiogenesis by substance P and interleukin-1 in the rat and its inhibition by NK1 or interleukin-1 receptor antagonists.
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.
Fan
T P
TP
Department of Pharmacology, University of Cambridge.
Hu
D E
DE
Guard
S
S
Gresham
G A
GA
Watling
K J
KJ
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D006632:Histamine / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology*; D064729:Neurokinin-1 Receptor Antagonists; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000494:pharmacology*; D014980:Xenon Radioisotopes
D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D007375:Interleukin-1; D064729:Neurokinin-1 Receptor Antagonists; D010972:Platelet Activating Factor; D011453:Prostaglandins; D017472:Receptors, Interleukin-1; D018040:Receptors, Neurokinin-1; D014980:Xenon Radioisotopes; D013373:Substance P; D015121:6-Ketoprostaglandin F1 alpha; D006632:Histamine; D007213:Indomethacin