Pharmacologic Characterization 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.