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1 The effect of the calcitonin gene-related peptide antagonist (CGRP837, 400 nmol kg-', i.v.) on the increased blood flow induced by calcitonin gene related peptide (CGRP), vasodilator prostaglandins, and topical capsaicin was measured with a laser Doppler blood flow meter in rat abdominal skin.2 The saphenous nerve was electrically stimulated and the effect of CGRP8-37 (400 nmol kg-', i.v.) on the increased blood flow (measured by laser Doppler flowmetry) and oedema formation (measured by the extravascular accumulation of ['25f]-albumin) was investigated in the rat hind paw.3 CGRP8-37 (400 nmol kg-', i.v.) had no effect on basal cutaneous blood flow at uninjected sites and sites injected with Tyrode buffer, but acted selectively to inhibit the increased blood flow induced by intradermal CGRP (10 pmol/site, P< 0.05), but not that induced by prostaglandin E2 (PGE2, 300 pmol/ site) or carba-prostacyclin (cPGI2, 100 pmol/site). 4 Capsaicin (0.1-33 mM), applied topically, acted in a dose-related manner to increase blood flow. CGRP837 (400 nmol kg-', i.v.) almost totally inhibited blood flow induced by capsaicin (10 mM; P <0.05) but did not significantly inhibit blood flow induced by a higher dose of capsaicin (33 mM). 5 The increased blood flow induced by short stimulation of the saphenous nerve (10 V, 1 ms, 2 Hz for 30 s) was inhibited by 76%, 5 min after i.v. CGRP837 (400 nmol kg-', i.v., P<0.05). 6 A longer (5 min) electrical stimulation of the saphenous nerve caused oedema formation, in addition to increased blood flow. The oedema formation was significantly inhibited by CGRP8-37 (400 nmol kg-', i.v., P<0.05). 7 The results suggest that the potent microvascular vasodilator neuropeptide, CGRP, is responsible for the increased blood flow observed after short stimulation of the saphenous nerve and that endogenous CGRP contributes in a pro-inflammatory manner to neurogenic oedema formation in the rat hind paw.

The novel neuronal nitric oxide synthase inhibitors, 1-(2-trifluoromethylphenyl)imidazole (TRIM) and 7-nitro indazole (7-NI), were used to investigate the role of nitric oxide in a model of transient focal cerebral ischemia in vivo. In halothane-anesthetized rats, the middle cerebral artery (MCA) was occluded for 2 hours using an intravascular thread and then reperfused for 22 hours before histologic evaluation. TRIM (10, 20, or 50 mg/kg), 7-NI (60 mg/kg), TRIM (50 mg/kg) plus L-arginine (300 mg/kg), or L-arginine (300 mg/kg) alone was administered intraperitoneally, either at 5 or 90 minutes after MCA occlusion. Immediate administration (5 minutes after MCA occlusion) of TRIM produced a dose-related reduction in lesion size, which was reversed with L-arginine coadministration. Similarly, delayed administration of TRIM (90 minutes after MCA occlusion, 50 mg/kg) decreased total lesion volume by 48.4% +/- 13.0% in comparison to a reduction of 39.3% +/- 10.9% when TRIM (50 mg/kg) was administered immediately (5 minutes) after occlusion. 7-NI (60 mg/kg) reduced the total lesion volume by 38.5% +/- 13.7% when administered immediately (5 minutes) after MCA occlusion, but had no effect when administration was delayed (90 minutes). Neither TRIM (50 mg/kg) nor 7-NI (60 mg/kg), administered 5 minutes after MCA occlusion, had any significant effect on mean arterial blood pressure throughout the ischemic period or for up to 10 minutes after reperfusion. These results indicate that immediate or delayed administration of the selective neuronal NOS inhibitor TRIM reduces the lesion volume after transient MCA occlusion. In contrast, only immediate administration of 7-NI reduces lesion volume.

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Tumour necrosis factor-a (TNF-a) and interleukin 1b (IL-1b) have been implicated in the pathogenesis of asthma. The p38 kinase inhibitor, SB 203580 inhibits TNF-a and IL-1b production in vitro and in vivo. In this study the e ect of SB 203580 on allergen-induced airway TNF-a production and in¯ammatory cell recruitment was investigated in sensitized Brown Norway rats. The allergen-induced increase in bronchoalveolar lavage (BAL) TNF-a was inhibited by SB 203580 at every dose tested (10 ± 100 mg kg 71 , p.o.). In contrast, neither ovalbumin-induced eosinophilia or neutrophilia were inhibited by SB 203580 (10 ± 100 mg kg 71 , p.o.). In conclusion, SB 203580 inhibits BAL TNF-a production by 95% without inhibiting either antigen-induced airway eosinophilia or neutrophilia. This data suggests that either the residual TNF-a is su cent to drive allergen-induced in¯ammatory cell recruitment into the lung or that TNF-a is not involved in allergen-induced in¯ammatory cell recruitment.