RSD931, a novel anti-tussive agent acting on airway sensory nerves

Abstract

1 The anti-tussive effects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. 2 Pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml(-1) reduced the number of citric acid-induced coughs by 9.3, 32.6 and 40.9% (P>0.05) for lidocaine and by 25.3% (P>0.05), 40.4% (P>0.05) and 97.6% (P<0.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml(-1) only. In addition, RSD931 at 10 mg ml(-1) reduced citric acid-evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1+/-5.1 to 2.7+/-0.9 coughs (P<0.01). 3 Acute pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 10.0 and 30.0 mg ml(-1) reduced the number of capsaicin-evoked coughs by 42.2 and 10.3% (P>0.05) (lidocaine) and by 25% (P>0.05) and 76.9% (P<0.01) (RSD931), respectively. Lidocaine had little effect on the latency of cough onset at either 10.0 or 30.0 mg ml(-1), however, RSD at 30.0 mg ml(-1) significantly (P<0.05) prolonged the latency of cough onset. 4 RSD931 (10.0 mg ml(-1)) significantly (P<0.05-<0.01) reduced the spontaneous and histamine-evoked discharges in Adelta-fibres originating from airway, rapidly adapting stretch receptors (RARs) without affecting histamine-evoked bronchoconstriction. Lidocaine at 10.0 mg ml(-1) also significantly (P<0.05) inhibited the spontaneous and histamine-induced discharges of RARs without affecting histamine-evoked bronchoconstriction. 5 Aerosols of RSD931 (10.0 mg ml(-1)) caused a transient, but significant (P<0.05), activation of pulmonary C-fibre endings 2.5 min after administration started. RSD931 had no significant (P>0.05) effects on discharges in bronchial C-fibres originating from bronchial C-fibre endings, capsaicin-evoked discharges of either pulmonary or bronchial C-fibre endings or on capsaicin-evoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml(-1)) significantly (P<0.05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin-evoked bronchoconstriction. 6 These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in Adelta-fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti-tussive agent.

Figure 1

The chemical structures of lidocaine and carcainium chloride.

Figure 2

Effect aerosols of distilled H₂O, lidocaine and RSD931 on citric acid-evoked cough responses in conscious guinea-pigs (n=5 per group). Results are expressed as total number of coughs in the 15 min period following the start of citric acid aerosol against concentration. Distilled H₂O, lidocaine (0.1–10 mg ml⁻¹) and RSD931 (0.1–10 mg ml⁻¹) were administered by aerosol for 5 min before citric acid. Values are mean±s.e.mean in each case. +P<0.05 and ++P<0.01, compared to RSD931 at 10 mg ml⁻¹; ***P<0.05, compared to lidocaine and P<0.001, compared to distilled H₂O (ANOVA followed by Tukey–Kramer multiple comparison test). dist H₂O=distilled water.

Figure 3

Effect aerosols of distilled H₂O (vehicle), lidocaine and RSD931 on capsaicin-evoked cough responses in conscious guinea-pigs (n=12 per group). Results are expressed as total number of coughs in the 15 min period following the start of capsaicin aerosol against concentration. Distilled H₂O, lidocaine (10 and 30 mg ml⁻¹) and RSD931 (10 and 30 mg ml⁻¹) were administered by aerosol for 5 min before capsaicin. Values are mean±s.e.mean in each case. **P<0.01, compared to matched vehicle pre-treated group; +P<0.05, compared to matched lidocaine pre-treated group (ANOVA followed by Tukey–Kramer multiple comparison test).

Figure 4

Effect of aerosols of distilled H₂O and RSD931 on citric acid-evoked cough responses in conscious rabbits (n=11 per group). Results are expressed as total number of coughs in the 10 min period following the start of citric acid aerosol. Distilled H₂O and RSD931 (10 mg ml⁻¹) were administered by aerosol for 5 min before citric acid. Values are mean±s.e.mean in each case. **P<0.01, compared to distilled H₂O (Mann–Whitney U-test).

Figure 5

Effect of aerosols of distilled H₂O, lidocaine and RSD931 on discharges in Aδ-fibres originating from RARs in the respiratory tract of anaesthetized, paralysed, artificially ventilated rabbits (n=12). Results are expressed as imp. s⁻¹ against time (min). Distilled H₂O and lidocaine (10 mg ml⁻¹) were administered sequentially in the one group of animals (n=6) at time 0. Distilled H₂O and RSD931 (10 mg ml⁻¹) were administered sequentially in a second group of animals (n=6) at time 0. Administration of distilled H₂O aerosols had no significant effects on the spontaneous discharge of RARs in the RSD931 group (0). However, in the lidocaine group the RARs were significantly activated at 2.5 and 5.0 min after the start of the H₂O aerosol dH₂O. Administration of an aerosol of RSD931 or lidocaine significantly inhibited the spontaneous discharges of RARs at both 10 and 20 min after the administration. Values are mean±s.e.mean in each case. Statistical significance was assessed for each treatment compared to time −5 (ANOVA followed by Dunnett's Multiple Comparison Test), *P<0.5, **P<0.01. dH₂O=distilled water.

Figure 6

Effect or aerosols of distilled H₂O, lidocaine and RSD931 on discharges in C-fibres originating from bronchial C-fibre endings in the respiratory tract of anaesthetized, paralyzed, artificially ventilated rabbits (n=12). Results are expressed as imp. s⁻¹ against time (min). Distilled H₂O and lidocaine (10 mg ml⁻¹) were administered sequentially in the one group of animals (n=6) at time 0. Distilled H₂O and RSD931 (10 mg ml⁻¹) in a second group of animals (n=6) at time 0. Administration of vehicle, distilled H₂O aerosols had no significant (P>0.05) effects on the spontaneous discharge of bronchial c-fibres in either the RSD931 or the lidocaine group of animals. Similarly, administration of an aerosol of RSD931 had no significant effects on the discharge of bronchial c-fibres. However, aerosols of lidocaine significantly (P<0.05) reduced the spontaneous discharge of bronchial c-fibres at 10 and 20 min after the start of administration. Values are mean±s.e.mean in each case. Statistical significance was assessed for each treatment compared to time −5 (ANOVA followed by Dunnett's Multiple Comparison Test), *P<0.5. dH₂O=distilled water.

Figure 7

Effect of aerosols of distilled H₂O, lidocaine and RSD931 on discharges in C-fibres originating from pulmonary C-fibre endings in the respiratory tract of anaesthetized, paralysed, artificially ventilated rabbits (n=12). Results are expressed as imp. s⁻¹ against time (min). Distilled H₂O and lidocaine (10 mg ml⁻¹) were administered sequentially in the one group of animals (n=6) at time 0. Distilled H₂O and RSD931 (10 mg ml⁻¹) in a second group of animals (n=6) at time 0. Values are mean±s.e.mean in each case. Statistical significance was assessed for each treatment compared to time −5 (ANOVA followed by Dunnett's Multiple Comparison Test), *P<0.5, **P<0.01. dH₂O=distilled water.