TheIn VivoEffect of Tachykinins on Airway Mast Cells of the Rat

Abstract

The tachykinins substance P (SP) and neurokinin A (NKA) have been demonstrated in sensory airway nerves of animals and man and are thought to be neurotransmitters of local axon reflexes, generated by stimuli such as cigarette smoke, dust, histamine, and bradykinin. We previously showed that intravenous SP and NKA caused bronchoconstriction in anesthetized, mechanically ventilated rats. Pharmacologic studies suggested that this occurred by an indirect mechanism, probably mediated by acetylcholine and serotonin. In this study, we demonstrate that the bronchoconstriction caused by SP and NKA in Fisher 344 rats is accompanied by a dose-dependent release of histamine and serotonin in bronchoalveolar lavage (BAL) fluid. In rats depleted of mast cell mediators by pretreatment with compound 48/80, the effects of SP and NKA on lung resistance and serotonin in BAL fluid were abolished. Local instillation of NKA in the airways caused a significant dose-dependent increase in BAL histamine. After pretreatment with thiorphan, an inhibitor of neutral endopeptidase (NEP), the bronchoconstriction and the histamine and serotonin release in BAL fluid caused by SP and NKA were enhanced. After pretreatment with a combination of thiorphan and the angiotensin-converting enzyme inhibitor captopril, NKA and SP were almost equipotent in causing bronchoconstriction and serotonin release in the airways. This study indicates that mast cells are largely involved in the bronchoconstrictor effect of intravenously administered neurokinins in rats. As in the guinea pig, NEP is involved in the termination of the bronchoconstrictor effect of tachykinins. Moreover, NEP also affects the airway histamine and serotonin release caused by these tachykinins in the Fisher 344 rat.