Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade.
1. This study investigates the effects of capsaicin-induced depletion of sensory neuropeptides and of neurokinin1 (NK1) receptor blockade on delayed-type hypersensitivity (DTH)-induced changes of vascular permeability in the small intestine of the mouse. 2. The DTH reaction in the small intestine was elicited by dinitrofluorobenzene (DNFB)-contact sensitization followed by oral dinitrobenzene sulphonic acid (DNBS) challenge. To assess vascular leakage the accumulation of the plasma marker, Evans blue (EB), was measured 2, 24 and 48 h after the challenge. 3. The small intestinal DTH reaction was characterized by a significant increase in vascular permeability 24 h after the challenge of previously sensitized mice when compared to vehicle-sensitized mice (P < 0.05, ANOVA). Capsaicin-induced depletion of sensory neuropeptides, two weeks before the sensitization, completely inhibited the DTH-induced increase in small intestinal vascular permeability at 24 h (P < 0.05, ANOVA). Vehicle/control: 108.2 +/- 8.6 ng EB mg-1 dry weight; vehicle/DTH 207.8 +/- 25.1 ng EB mg-1 dry weight; capsaicin/control: 65.8 +/- 11.9 ng EB mg-1 dry weight; capsaicin/DTH: 84.3 +/- 7.6 ng EB mg-1 dry weight. 4. The tachykinins, substance P and neurokinin A (1.5 to 50 x 10(-11) mol per mouse, i.v.), induced an increase in vascular leakage in the small intestine of naive mice. The specific NK1 receptor antagonist, RP67580 (10(-9) mol per mouse, i.v.) was the most effective in reducing the substance P-induced plasma extravasation when compared with other NK receptor antagonists, FK224 and FK888. 5. Treatment of DNFB-sensitized mice with RP67580 (10-9 mol per mouse, i.v.) immediately before and 1 h after the DNBS challenge resulted in a significant reduction of the DTH-induced increase in vascular permeability at 24 h (vehicle/control: 107.5 +/- 8.8 ng EB mg-1 dry weight; RP67580/control:95.4 +/- 5.4 ng EB mg-1 dry weight; vehicle/DTH: 206.6 +/- 22.6 ng EB mg-1 dry weight; RP67580/DTH:132.6 +/- 13.6 ng EB mg-1 dry weight, P<0.05, ANOVA).6. These results suggest that sensory nerves are involved in the development of small intestinal DTH reactions in the mouse. NK1 receptors could play an important role in the initiation of the DTH-induced changes in vascular leakage.
Kraneveld
A D
AD
Department of Pharmacology, Utrecht University, The Netherlands.
Buckley
T L
TL
van Heuven-Nolsen
D
D
van Schaik
Y
Y
Koster
A S
AS
Nijkamp
F P
FP
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007211:Indoles / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects*; D054833:Isoindoles; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology
D004151:Dipeptides; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D009479:Neuropeptides; D010456:Peptides, Cyclic; C075570:FK 224; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C078949:FK 888; D002211:Capsaicin