RSD931, a novel anti-tussive agent acting on airway sensory nerves.
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.
Adcock
J J
JJ
Pneumolabs (UK) Ltd, NPIMR, Y Block, Watford Road, Harrow, Middlesex HA1 3UJ, UK.
Douglas
G J
GJ
Garabette
M
M
Gascoigne
M
M
Beatch
G
G
Walker
M
M
Page
C P
CP
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000996:Antitussive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000294:innervation; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D002211:Capsaicin; D002336:Carnosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008012:Lidocaine / Q000008:administration & dosage / Q000494:pharmacology* / Q000031:analogs & derivatives; D008168:Lung / Q000187:drug effects* / Q000294:innervation; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013997:Time Factors
D000336:Aerosols; D000996:Antitussive Agents; D019343:Citric Acid; D002336:Carnosine; D008012:Lidocaine; D002211:Capsaicin; C006110:carcainium chloride