INVOLVEMENT OF TACHYKININ NK1 AND NK2 RECEPTORS IN SUBSTANCE-P-INDUCED MICROVASCULAR LEAKAGE HYPERSENSITIVITY AND AIRWAY HYPERRESPONSIVENESS IN GUINEA-PIGS

Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness (AHR) and airway inflammation, However, it is unknown which tachykinin receptors mediate these biological act ivities, The effects of two antagonists of tachykinin neurokinin-1 (NK 1) and tachykinin neurokinin-2 (NK2) receptors, SR 140333 and SR 48968 , respectively, were investigated on substance P (SP)-induced airway h yperresponsiveness and potentiation of the histamine-induced increase in microvascular leakage, in phosphoramidon-pretreated guinea-pigs. Gu inea-pigs were pretreated with phosphoramidon (0.1 mM aerosol for 15 m in) and exposed 15 min later to saline solution alone or to saline sol ution containing SP (0.1 mg . mL(-1) for 30 min), Twenty four hours la ter, the animals were anaesthetized and prepared for the recording of the pulmonary inflation pressure (PIP) to acetylcholine or for the inv estigation of microvascular leakage to histamine. Pretreatment of the guinea-pigs with a single dose of SR 48968 (1 mg . kg(-1), i.p.) 30 mi n before SP exposure, significantly prevented the development of AHR, whereas SR 140333 (1 mg . kg(-1), i.p.) did not. In a second set of ex periments, phosphoramidon-pretreated guinea-pigs exposed to SP present ed a significant potentiation of the histamine-induced increase in mic rovascular leakage in pulmonary airways, When the guinea-pigs were pre treated with SR 140333, an inhibition of the increased microvascular l eakage to histamine was observed, In contrast, no significant inhibito ry activity was noted when the guinea-pigs were pretreated with SR 489 68. The present data demonstrate the importance of tachykinin NK2 rece ptor stimulation in the development of airway hyperresponsiveness and that of tachykinin NK1 receptor stimulation in microvascular leakage h ypersensitivity in phosphoramidon-pretreated and substance P-exposed g uinea-pigs, The results also suggest a dissociation between the presen ce of microvascular leakage and the occurrence of airway hyperresponsi veness.