Inhibition of compound 48/80 — induced vascular protein leakage by pretreatment with capsaicin and a substance P antagonist

Summary

• 1. Intravenous injection of compound 48/80 (1 mg×kg⁻¹) induced an acute increase in vascular permeability to plasma proteins in various organs of rats.

• 2. The compound 48/80 response was partly inhibited by histamine H₁ and H₂ receptor blockade in the urinary bladder and in the duodenum, but not in the trachea, the oesophagus, the ureter and the paw skin. Blockade of 5-hydroxytryptamine receptors with methysergide led to a reduction of the permeability response in the oesophagus and in the urinary bladder, leaving responses in other organs unchanged.

• 3. Pretreatment of neonatal rats with capsaicin almost abolished the 48/80 response in all organs except in the duodenum. Pretreatment of rats with [D-Arg¹, D-Trp^7,9, Leu¹¹]-substance P, a substance P antagonist, also caused a partial inhibition of the permeability response to compound 48/80 in several organs.

• 4. Topical administration of compound 48/80 (1 mg×ml⁻¹) onto the tracheal mucosa induced local Evans blue extravasation. This response was resistant to pretreatment with histamine receptor antagonists, but was largely inhibited after neonatal capsaicin pretreatment. Topical administration of compound 48/80 (1 mg×ml⁻¹ or 10 mg×ml⁻¹) into the eye did not cause visible Evans blue extravasation in the conjunctiva, nor any signs of pain reaction as indicated by the absence of the wiping response, usually seen upon noxious chemical stimuli in the eye.

• 5. In guinea-pigs, 10 mg×kg⁻¹ compound 48/80 i.v. were required to induce vascular protein leakage in different organs. This response was blocked by pretreatment with H₁ and H₂ receptor antagonists, but only slightly reduced after systemic capsaicin pretreatment of guinea-pigs.

• 6. Pretreatment of rats with compound 48/80 for 3 consecutive days lead to an almost complete depletion of histamine in the paw skin and to a partial depletion of histamine in the trachea. In the lung and in the duodenum, however, histamine concentrations remained unchanged. Simultaneously, there was an about 25%–30% reduction of substance P concentrations in the paw skin and in the trachea, but not in the lung or in the spinal cord. In compound 48/80 pretreated rats, there was no change of the permeability response to intravenous substance P, nor any change of the behavioural nociceptive response upon topical capsaicin application in the eye.

• 7. It is concluded that intravenous compound 48/80 administration induces an acute increase in vascular permeability in various organs of rats mainly via a histamine independent activation of capsaicin sensitive, most probably substance P containing sensory neurones. In guineapigs, the permeability response to intravenous compound 48/80 is mainly caused by histamine, acting both directly and indirectly via sensory neurones. Pretreatment of rats with compound 48/80 causes, besides histamine depletion from mast cells, a reduction of substance P in sensory nerves. This may reflect a long lasting stimulation of sensory nerve endings by mast cell constituents or a direct action of compound 48/80 on sensory nerves.