The contribution of nitric oxide to endotoxin‐induced ocular inflammation: interaction with sensory nerve fibres

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Abstract
1 The actions of nitric oxide (NO) have been investigated in an endotoxin-evoked ocular inflammatory model in the rabbit, with particular emphasis on the relationship between NO, sensory nerves (C-fibres) and the C-fibre neuropeptides, calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating peptide (PACAP). 2 Endotoxin, injected intravitreally, evoked inflammatory responses, i.e. conjunctival hyperaemia, miosis and protein extravasation, reflected by the aqueous flare response (AFR). In control rabbits, the maximum AFR was 66.5 ± 9.5 (arbitrary units). Pretreatment with the NO synthase (NOS) inhibitor, NG-nitro-l-arginine (L-NAME, 200 mg kg−1) given by intravenous injection, inhibited the endotoxin-evoked responses; the AFR was 16.5 ± 1.9 (n = 8, P < 0.001) and the conjunctival hyperaemia was abolished. 3 Endotoxin-evoked ocular inflammation is associated with the release of CGRP and PACAP from C-fibres. In the eyes challenged with endotoxin, the concentrations of PACAP-27, −38 and CGRP in the aqueous humour were 58.2 ± 10.9, 54.4 ± 12.4 and 5526 ± 519 (pmoll−1), respectively. L-NAME inhibited the release of PACAP-27, −38 and CGRP; the concentrations were 14.3 ± 2.5, 13.5 ± 2.5 and 510 ± 67 (pmoll−1), respectively (n = 8, P < 0.01 or 0.001). 4 Intravitreal injection of 0.3 nmol CGRP induced conjunctival hyperaemia and AFR; the maximum AFR was 140.2 ± 11.4. L-NAME suppressed the response induced by CGRP; the AFR was 23.4 ± 5.5 (n = 8, P < 0.001). L-NAME abolished the conjunctival hyperaemia induced by PACAP-27 and −38 (0.3 nmol) and reduced the AFR. 5 The inflammatory cells that infiltrated the uvea, cornea and aqueous humour in large numbers in response to intravitreal injection of endotoxin were found to express inducible NOS. L-NAME prevented the appearance of such cells. 6 Our findings suggest that NO plays an important role in the endotoxin-evoked ocular inflammation in the rabbit: NO activates C-fibres causing release of C-fibre neuropeptides into the aqueous humour. In addition, NO mediates some of the ocular effects of CGRP and PACAP, since L-NAME suppressed the AFR induced by these peptides.