Role of tachykinins in sephadex-induced airway hyperreactivity and inflammation in guinea pigs.

We have studied the effect of selective tachykinin NK(1) and NK(2) receptor antagonists on airway hyperreactivity to acetylcholine and increase of inflammatory cells on bronchoalveolar lavage fluid induced by sephadex beads (20 mg/kg, i.v.) in guinea pigs. Airway hyperreactivity was assessed by measuring the increase of bronchial insufflation pressure to acetylcholine (0.01-30 micromol/kg, i.v.) at 3 h (early phase) and 24 h (late phase) after sephadex administration. An increase in inflammatory cells in bronchoalveolar lavage fluid (eosinophils and macrophages) was detected at 24 h (from 11.6 x 10(6) to 49.3 x 10(6) cells) but not at 3 h from sephadex administration. Neurokinin A and substance P levels in bronchoalveolar lavage fluid showed a significant increase at 24 h (from 31.7+/-11.6 to 561+/-231 pg/ml and from 5.9+/-2.6 to 29.3+/-4.1 pg/ml for neurokinin A and substance P, respectively). At this time point, the tachykinin in bronchoalveolar lavage cellular content was depleted from 232+/-43 to 21+/-20 pg/sample and from 56.6+/-6.7 to 2+/-2 pg/sample for neurokinin A and substance P, respectively. Capsaicin pretreatment abolished the early but not the late phase of airway hyperreactivity induced by sephadex without modifying bronchoalveolar lavage total cells number and bronchoalveolar lavage levels of neurokinin A and substance P. Administration of the tachykinin NK(2) (nepadutant) and/or the NK(1) receptor antagonist (MEN 11467 or (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N[N-(p-tolylacetyl)-N-(methyl)-D-3(2-naphthyl)alanyl)diaminocyclohexane)), 5 min before sephadex, prevented the early phase of airway hyperreactivity to acetylcholine but only nepadutant prevented the late phase. Nepadutant was able to abolish the early phase of airway hyperreactivity if given after sephadex administration and reduced by about 50% the increase of cell number in bronchoalveolar lavage fluid during the late phase, without affecting the levels of neurokinin A and substance P. These findings indicate an involvement of endogenous tachykinins in the genesis of airway hyperreactivity in a guinea-pig model of non-allergic asthma. Early airway hyperreactivity apparently involves release of tachykinins from capsaicin-sensitive afferent nerves acting via tachykinin NK(1)/NK(2) receptors. Late airway hyperreactivity involves tachykinins acting via tachykinin NK(2) receptors: inflammatory cells activated/recruited in response to sephadex challenge appear a likely source of tachykinins involved in the late phase of the response.

Pharmacological profile of the novel mammalian tachykinin, hemokinin 1.

1. The effects of the novel mammalian tachykinin, hemokinin 1 (HEK-1), have been investigated by radioligand binding and functional in vitro and in vivo experiments. 2. Similar to SP (K(i)=0.13 nM), HEK-1 inhibited in a concentration-dependent manner and with high affinity [(3)H]-substance P (SP) binding to human NK(1) receptor (K(i)=0.175 nM) while its affinity for [(125)I]-neurokinin A (NKA) binding at human NK(2) receptor was markedly lower (K(i)=560 nM). 3. In isolated bioassays HEK-1 was a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors. In the rat urinary bladder (RUB) HEK-1 was about 3 fold less potent than SP. In the rabbit pulmonary artery (RPA) HEK-1 and in the guinea-pig ileum (GPI), HEK-1 was about 500 fold less potent than NKA and NKB, respectively. 4. The responses to HEK-1 were antagonized by GR 82334 in RUB (pK(B)=5.6+/-0.07), by nepadutant in RPA (pK(B)=8.6+/-0.04) and by SR 142801 in GPI (pK(B)=9.0+/-0.2) with apparent affinities comparable to that measured against tachykinin NK(1), NK(2) and NK(3) receptor-selective agonists, respectively. 5. Intravenous HEK-1 produced dose-related decrease of blood pressure in anaesthetized guinea-pigs (ED(50)=0.1 nmol kg(-1)) and salivary secretion in anaesthetized rats (ED(50)=6 nmol kg(-1)) with potencies similar to that of SP. All these effects were blocked by the selective tachykinin NK(1) receptor antagonist, SR 140333. 6. We conclude that HEK-1 is a full agonist at tachykinin NK(1), NK(2) and NK(3) receptors, possesses a remarkable selectivity for NK(1) as compared to NK(2) or NK(3) receptors and acts in vivo experiments with potency similar to that of SP.