Saredutant

The contractile effects of tachykinins on the gastrointestinal tract are well-known, but how they modulate slow-waves, particularly in species capable of emesis, remains largely unknown. We aimed to elucidate the effects of tachykinins on myoelectric and contractile activity of isolated gastrointestinal tissues of the Suncus murinus.

The effects of substance P (SP), neurokinin (NK)A, NKB and selective NK₁ (CP122,721, CP99,994), NK₂ (SR48,968, GR159,897) and NK₃ (SB218,795, SB222,200) receptor antagonists on isolated stomach, duodenum, ileum and colon segments were studied. Mechanical contractile activity was recorded using isometric force displacement transducers. Electrical pacemaker activity was recorded using a microelectrode array.

Compared with NKA, SP induced larger contractions in stomach tissue and smaller contractions in intestinal segments, where oscillation magnitudes increased in intestinal segments, but not the stomach. CP122,721 and GR159,897 inhibited electrical field stimulation-induced contractions of the stomach, ileum and colon. NKB and NK₃ had minor effects on contractile activity. The inhibitory potencies of SP and NKA on the peristaltic frequency of the colon and ileum, respectively, were correlated with those on electrical pacemaker frequency. SP, NKA and NKB inhibited pacemaker activity of the duodenum and ileum, but increased that of the stomach and colon. SP elicited a dose-dependent contradictive pacemaker frequency response in the colon.

This study revealed distinct effects of tachykinins on the mechanical and electrical properties of the stomach and colon vs. the proximal intestine, providing a unique aspect on neuromuscular correlation in terms of the effects of tachykinin on peristaltic and pacemaker activity in gastrointestinal-related symptoms.

Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E₂ (PGE₂, 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hyperventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE₂ receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK₁R and NK₂R) respectively. This study aimed to define the impacts of CA- and PGE₂-exposure on pulmonary SP and NKA levels and the roles of NK₁R and NK₂R in modulating CA- and PGE₂-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE₂-exposure; (2) effects of CP-99994 and SR-48968 (a NK₁R and a NK₂R antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE₂-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK₁R/NK₂R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE₂-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently suppressed the cough responses to CA with less impact on the cough response to PGE₂. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE₂. Moreover, NK₁R and NK₂R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA- and PGE₂-exposure play important roles in generating the cough and ventilatory responses to CA and PGE₂, at least in part, via activation of NK₁R and NK₂R expressed in vagal C-neurons (pulmonary C-neurons).