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-1alpha) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-1alpha (0.3 pmol) were ineffective when given alone. When combined at these low doses, substance P and IL-1alpha interacted to produce an enhanced neovascular response. 2 By use of selective tachykinin NK1, NK2 and NK3 receptor agonists, ([Sar,Met(02)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-1alpha (10 pmol and 0.3 p mol day-1, respectively) was abolished by co-administration of (i) the selective peptide NK1 receptor antagonist, L-668,169 (I 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 mug day-1). In contrast, the selective NK2 receptor antagonist, L-659,874 (I nmol day-1) was ineffective. 4 The angiogenic action of substance P and IL-1alpha 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.