Neurokinin 1 and 2 Receptors Differently Modulate PEG 2 ‐ and Citric Acid‐Induced Cough and Ventilatory Responses

Inhalation of aerosolized citric acid (CA) or prostaglandin E 2 (PGE 2 ) provokes distinct cough patterns (Type I vs. II) and ventilatory responses (substantial hyperventilation vs. slight tachypnea) in humans and guinea pigs. Substance P (SP) and neurokinin A (NKA) are peripherally released mainly by pulmonary sensory fibers and capable of facilitating CA‐induced cough and modulating ventilation via preferentially activating neurokinin 1 and 2 receptors (NK 1 R and NK 2 R) respectively. The goal of this study was to determine the effects of CA and PGE 2 exposure on pulmonary SP and NKA levels and the roles of NK 1 R and NK 2 R in CA‐ and PGE 2 ‐evoked cough and ventilatory responses. In unanesthetized guinea pigs, we compared: (1) pulmonary SP and NKA contents after inhalation of aerosolized vehicle, CA or PGE 2 for 10 min; (2) effects of CP‐99994 and SR‐48968 (a NK 1 R and a NK 2 R antagonist) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA‐ and PGE 2 ‐evoked cough and ventilation; and (3) expression of NK 1 R/NK 2 R in vagal pulmonary C‐neurons labeled by TRPV1 (responsible for Type I cough) or EP 3 receptors (a PGE 2 receptor responsible for Type II cough) using immunocytochemical approaches. We found that CA and PGE 2 exposure evoked Type I and II cough respectively associated with different degree of increases in pulmonary SP and NKA. CP‐99994 and SR‐48968 via IP or IH depressed the cough responses to CA more than those to PGE 2 exposure. The antagonists substantially inhibited or blocked the evoked ventilatory responses. Moreover, NK 1 R and NK 2 R co‐express in vagal pulmonary C‐neurons labeled by TRPV1 or EP 3 receptors. These results suggest that endogenously released SP and NKA (pulmonary) play important roles in CA‐ and PGE 2 ‐evoked cough and ventilatory responses.