Early angiogenesis is a key step in the transition from acute to persistent inflammation. The nervous system has long been known to play a role in inflammation, in part through the release of substance P from peripheral nerve terminals (neurogenic inflammation). Application of substance P can stimulate vessel growth in a variety of angiogenesis assays, although it was previously not known whether endogenous substance P released from sensory nerves could modulate angiogenesis. We hypothesized that endogenous substance P can initiate angiogenesis during acute neurogenic inflammation. Here we show that 10 nmol of substance P can stimulate angiogenesis within the rat knee synovium, as shown by increased endothelial cell proliferation index [PCNA index, 19% (95% confidence interval (CI), 17 to 20%)] compared with saline injected knees [6% (95% CI, 4% to 8%), p Ͻ 0.05]. Moreover, this was prevented by coadministration of an antagonist of the neurokinin-1 (NK 1 ) subtype of neurokinin receptor SR140333 (nolpitantium), 1 mol [8% (95% CI, 5% to 11%)]. Capsaicin 0.5%, which stimulates release of endogenous substance P from sensory nerves, was also found to enhance synovial angiogenesis, [PCNA index 17% (95% CI, 14% to 19%)] compared with saline injected control knees [2% (95% CI, 1% to 3%), p Ͻ 0.05], and this also was inhibited by 1 mol of SR140333 [11% (95% CI, 8 to 16%)]. Inhibition of capsaicin-enhanced angiogenesis was incomplete, and this may indicate a contribution of other neuropeptides, in addition to substance P-NK 1 receptor interactions, in capsaicin-enhanced angiogenesis. NK 1 receptor antagonists could have therapeutic potential in conditions where neurogenic angiogenesis contributes to disease.

During acute synovitis, early angiogenesis may enhance inflammation by facilitating edema formation and cellular infiltration. We have investigated the in vivo modulation by bradykinin of neurally enhanced early angiogenesis in rat models of knee synovitis. The increased endothelial cell proliferation that was observed 24 h after intra-articular injection of substance P (10 nmols) was completely blocked by either NK1 or B2 receptor antagonists (SR140333 or FR172357, respectively). In mild synovitis induced by 0.03% Carrageenan, but not in naïve animals, injection of bradykinin (100 nmols) increased endothelial cell proliferation. In moderate synovitis induced by 3% kaolin and 3% carrageenan, the combined blockade of both NK1 and B2 receptors inhibited 64% of the synovitis-enhanced endothelial cell proliferation. Synovitis-enhanced endothelial cell proliferation was also inhibited by the B2 receptor antagonist alone (27%) but not by the NK1 receptor antagonist alone. B1 receptor agonist (des-Arg9-bradykinin) and antagonist (SR240612A) did not significantly modulate endothelial cell proliferation. B2 receptor mRNA was constitutively expressed in both mild and moderate inflammation, whereas B1 mRNA production was induced in the moderate inflammation model. These findings demonstrate that substance P and bradykinin can act on NK1 and B2 receptors, respectively, to promote endothelial cell proliferation in acute synovitis.

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The role of calcium-independent phospholipase A 2 (iPLA 2 )-produced arachidonic acid (AA) in acetylcholine (ACh)-mediated, endothelium-dependent vascular relaxation was investigated. ACh-induced relaxation of phenylephrine-constricted isolated rat mesenteric resistance arteries was attenuated following pretreatment with (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL; 1 M; p Ͻ 0.01), a highly selective suicide substrate inhibitor of iPLA 2 . Following BEL, the ACh relaxation could be completely restored following pretreatment with picomolar quantities of the cell-permeant methyl ester analog of AA (arachidonic acid methyl ester, AAMe). Higher amounts of AA-Me (1 M) had a direct endothelium-dependent relaxing action, which was inhibited by the nitric-oxide synthase inhibitor (N -nitro-L-arginine; 100 M), independent of ACh, and unaffected by BEL. Neither the ACh relaxation restoring action nor the direct relaxing action of AA-Me was affected by preincubation with inhibitors of the lipoxygenase (esculetin, 10 M) or cytochrome P450 monooxygenase (17-octadecynoic acid; 10 M) pathways; and both actions of AA-Me were enhanced following preincubation with the cyclooxygenase inhibitor indomethacin (10 M; p Ͻ 0.05). The results of the present study indicate that iPLA 2 -produced AA plays an essential role in ACh-mediated endothelium-dependent relaxation in rat mesenteric resistance arteries.Vascular endothelium modulates blood pressure and flow by producing and releasing factors, which regulate the tone of the underlying smooth muscle. The pivotal role of endothelium-derived relaxing factor, now known to be nitric oxide (NO) generated from the metabolism of L-arginine, is well established (Palmer et al., 1987). In addition, other factors including AA and its metabolites may also contribute significantly to endothelium-mediated relaxation (for reviews, see Quilley et al

Please be advised that this information was generated on 2018-05-12 and may be subject to change.,f NERAL AND COMPARATIVE ENDOCRINOLOGY 75, 3 9^5 (1989) Prolactin Cell Activity and Sodium Fluxes in Tilapia (Oreochromis mossambicus) after Long-Term Acclimation to Acid Water G e r t F l i k ,* J o a n A. v a n d e r V e l d e n , ! H e in C. In tilapia exposed for 3 months to water of pH 4.5, prolactin cell activity, as estimated by ultrastructural morphometry and determination of prolactin synthesis in vitro, was signifi cantly higher than in controls from neutral water. Sodium influx from the water was 50% lower than in the controls, indicating impaired branchial sodium uptake mechanisms. In contrast to predictions based on the results of short-term exposure to acid water-which is known to induce an increase of sodium efflux-the sodium efflux rate was reduced to 70% of the control value. It is concluded that tilapia are able to acclimate to acid water by successful control-probably via prolactin-of diffusional sodium losses across the integu ment, in particular the gill surface. This compensates for the impaired sodium uptake, and enables the fish to reestablish a positive sodium balance in acid water.

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Infections lead to substantial morbidity during treatment of acute lymphoblastic leukemia (ALL). During ALL treatment, the adaptive immune system gets severely affected, leading to, amongst other things, declining serum immunoglobulin (IgG) levels. Theoretically, one may partially overcome the infection risk by supplementing the low IgG levels with intravenous immunoglobulins (IVIG).