Pharmacologic characteriztion of bronchospasm induced by substance P [SP] and SP fragments in guinea - pig

ABSTRACT

Using pharmacologic approach, neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea-pigs was characterized. Thus, the bronchospastic effects of substance P [SP] and SP fragments [all administrated intravenously] before and after giving vehicle or selective neurokinin receptor antagonists were compared. Ranking order of potency of SP or SP fragments for induction of bronchoconstriction was SP4-11 >> SP5-11 = SP3-11 = SP2-11 > SP = SP6-11 [the number of amino acid in the sequence of SP fragments are shown by superscript]. The neurokinin 1 [NK1] receptor antagonists [CP 96,345 or CP 99,994, 3 mg kg-1, iv] did not change baseline values of pulmonary flow resistance [RL] and dynamic pulmonary elastance [EL] and did not eliminate bronchopulmonary responses to these peptides but decreased changes in RL and EL in response to SP and SP fragments. The neurokinin 2 [NK2] receptor antagonist SR 48,968 [1 mg kg-1, iv] failed to induce a rightward shift in dose-response curves to SP or SP fragments except to SP4-11. Combinations of NK1 and NK2 receptor antagonists shifted dose-response curves to SP and SP fragments more than that of NK1 receptor antagonists alone. These findings reveal that SP-induced bronchoconstriction is mediated by its C-terminal sequence and this response is mainly via NK1 receptors. Moreover, bronchopulmonary responses to SP and its C-terminal fragments are complex and there may be interactions between NK1 and NK2 receptors in the lungs