Inhibition of citric acid- and capsaicin-induced cough by novel TRPV-1 antagonist, V112220, in guinea-pig

Abstract

Background: Cough reflex can be induced by the pepper extract capsaicin and by low pH in guinea-pig airways. Transient receptor potential vanniloid-1 (TPRV-1) is expressed in the sensory and afferent nerve fibres in airways.

Objective: We hypothesized that a novel pyridazinylpiperazine analog TPRV-1 inhibitor can effectively reduce cough reflex stimulated by citric acid and capsaicin.

Methods: Guinea pigs were injected with specific TPRV-1 inhibitor, V112220, a pyridazinylpiperazine analog of N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide (BCTC) (3 mg/kg) intra-peritoneally. One hour before cough response assessment. Coughs were recorded using a recorder system that identified cough sound and accompanying expiratory flows, distinct from sneezes. Guinea-pigs exposed to citric acid (0.4 M) and to capsaicin (10-4M) aerosols, in succession separately by 2 hours.

Results: V112220 significantly inhibited the number of coughs induced by citric acid (73 +/- 11%, p < 0.01) and capsaicin (70 +/- 9.4%, p < 0.05) compared to vehicle control.

Conclusion: A novel pyridazinylpiperazine analog TPRV-1 inhibitor can inhibit the cough reflex, induced by both low pH and capsaicin, suggesting that it could be clinically beneficial in treatment of cough.

Figure 1

Number of coughs per 10 min in conscious guinea-pigs on pre-screen, following exposure to citric acid and to capsaicin. Left panel shows the response in the control group, the central panel the response from vehicle-treated group, and the right panel the effect of treatment with V112220.

Figure 2

Number of coughs following citric acid or capsaicin exposure. Left panel show results from citric acid exposure while the right panel the results from capsaicin exposure. Data shown as mean ± 95% CI (*, ** p < 0.05 and 0.01 compared to vehicle treatment).