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

Abstract

1 Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin-1 alpha (IL-1α) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-1α (0.3 pmol) were ineffective when given alone. When combined at these low doses, substance P and IL-1α 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, [β-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-1α (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 μg 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-1α 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.