Effect of nedocromil sodium on allergen‐, PAF‐, histamine‐ and bradykinin‐induced airways vasodilatation and pulmonary obstruction in the pig

Abstract

1 The influence of nedocromil sodium on the nasal and bronchial effects induced by allergen, plateletactivating factor (PAF), capsaicin, histamine and bradykinin aerosol challenge in ascaris-sensitized and pentobarbitone-anaesthetized pigs was studied. Blood flow changes in the bronchial and nasal circulation were measured with ultrasonic flow probes around the supplying arteries, and vascular resistance was calculated. Changes in pulmonary resistance (Rpul.), dynamic compliance (Cdy.), mean arterial pressure (MAP) and heart rate (HR) were also determined. 2 Allergen and PAF aerosol challenge in the lung produced similar effects consisting of both bronchial and nasal vasodilatation, bronchoconstriction (increase in Rpuim and decrease in CdY,) and increases in MAP and HR. Local pretreatment with nedocromil sodium (80mg, aerosol) reduced the peak and duration of both the bronchial vasodilatation and increase in Rpuim, while only the duration of the change in Cdyn was significantly decreased. Nedocromil sodium did not alter the increases in MAP and HR. The nasal vasodilatation evoked by PAF, but not allergen, challenge in the lung was reduced by nedocromil sodium. 3 Allergen challenge in the nose induced vasodilatation of long duration which was reduced by local nedocromil sodium pretreatment (50,pg kg-1, intra-arterially). 4 The vasodilator response to histamine aerosol was attenuated in the nasal, but not the bronchial circulation by local nedocromil sodium pretreatment. Histamine-induced bronchoconstriction was not altered by nedocromil sodium. 5 Bradykinin aerosol-induced vasodilatation in the nasal and bronchial circulation was markedly and equally reduced by local nedocromil sodium and systemic capsaicin (50mgkg-1, s.c. 2 days before) pretreatment. The vasodilatation caused by i.v. bradykinin challenge was not reduced by capsaicin pretreatment. Capsaicin aerosol-induced vasodilatation in the nasal and bronchial circulation was not affected by local nedocromil sodium pretreatment. 6 In conclusion, nedocromil sodium blocks some local vascular and bronchial effects, but not increases in MAP and HR, induced by allergen and PAF aerosol in the pig. Bradykinin-induced vasodilatation in the airways, which seems to be largely dependent on capsaicin-sensitive sensory nerves, is markedly inhibited by nedocromil sodium pretreatment, whereas capsaicin-induced vasodilatation is not affected by nedocromil sodium. It may be suggested that nedocromil sodium acts by inhibiting some common process involved in the release of mediators from inflammatory cells (when stimulated by allergen and PAF) and sensory nerves (when stimulated by bradykinin and histamine, but not capsaicin).

The roles of the prostaglandin D2 receptors DP1 and CRTH2 in promoting allergic responses

“…The ability of PGD 2 to induce nasal air flow resistance is blocked by the vasoconstrictor oxymetazoline highlighting the importance of a vascular event in mediating this response ( Howarth et al , 1991 ). Production of PGD 2 in response to allergen in pigs has been proposed to mediate a long‐lasting component of airway vasodilatation resistant to antihistamines ( Alving et al , 1991 ). This conclusion is based on the ability of PGD 2 to mimic the long‐lasting airways vasodilatation induced by allergen and the inhibitory effect of the cyclooxygenase inhibitor diclofenac on allergen‐induced blood flow changes.…”

The effect of a bradykinin B2 receptor antagonist, NPC-567, on allergen-induced airway responses in a porcine model

“…In the pig model, BK challenge does not induce bronchoconstriction [4]. In a sheep study, however, BK was shown to be bronchoconstrictive [27].…”

“…This supports the idea that substance P can act as a link between bradykinin and mast cell activation. Furthermore, it has previously been suggested that nedocromil sodium inhibits mast cell and sensory nerve activation by common mechanisms, thus explaining this compound´s larger inhibitory effect on histamine release in vivo than in to isolated mast cells in vitro [4,11].…”

“…Bradykinin is known to be a potent vasodilator, and as inhalation of bradykinin causes an increase in bronchial blood flow in pigs [4], one might expect a smaller increase in bronchial blood flow after antigen challenge in NPC-567-treated animals than in controls. However, we observed a higher bronchial vascular conductance in the NPC-567-treated pigs during the late-phase reaction, even though there were no significant differences between the groups.…”

“…Bradykinin may be an inflammatory mediator of importance in asthma as it causes contraction of smooth muscle, arteriolar dilatation, increased vascular permeability, and sensory nerve activation in the airways [4,23]. In asthmatics, inhalation of bradykinin causes bronchoconstriction [13] and in BAL fluid from asthmatics subjected to allergen challenge, the concentrations of kallikrein and kinins are increased [9].…”