Effects of BRL 38227 on neurally-mediated responses in the guinea-pig isolated bronchus.
1. In guinea-pig isolated bronchus treated with indomethacin (2.8 microM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 microM)-sensitive, biphasic contraction comprising a rapid, atropine (1 microM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10 microM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response. 2. BRL 38227 (0.3-3 microM), salmeterol (0.003-3 microM) and ketotifen (1.0-300 microM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3. Substance P (SP; 1 microM) and neurokinin A (NKA; 0.07 microM) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 microM), but not by BRL 38227 (3 microM) or ketotifen (100 microM). 4. Acetylcholine (ACh; 6 microM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 microM) slightly inhibited responses to ACh (6 microM). Salmeterol (1 microM) and ketotifen (100 microM) markedly inhibited responses to ACh (6 microM). 5. In bronchial rings pre-contracted with ACh (100 microM), BRL 38227 (0.1-30 microM), salmeterol (0.001-3 microM) and ketotifen (0.1-100 microM) each produced concentration-dependent relaxation. Unlike ketotifen, BRL 38227 and salmeterol only partially (18.8 +/- 2.1% and 51.8 +/- 3.9% respectively) reversed the ACh-induced contraction. 6. The (+)-analogue of BRL 38227, BRL 38226 (0.3-100 microM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227. The K+-channel activators pinacidil (3.0-30 microM) and RP 52891 (3.0-30 microM) exerted similar inhibitory actions on responses to EFS as BRL 38227, but were less potent. Glibenclamide (0.1-1.O microM) and phentolamine (3 microM) antagonized the inhibitory effects of BRL 38227 on responses to EFS.7. It is concluded that BRL 38227 and ketotifen can inhibit NANCe neuroeffector transmission at concentrations exerting little or no inhibitory effects on responses to exogenously applied tachykinins.By contrast, in addition to suppressing NANCe responses to EFS, salmeterol also markedly inhibits responses to SP and NKA. At concentrations markedly suppressing cholinergic neuroeffector transmission, BRL 38227 has only minor effects on responses to exogenously-applied ACh. Salmeterol and ketotifen both depress responses to ACh within the concentration-range over which they inhibit cholinergic responses to EFS. The inhibitory effects of BRL 38227 on responses to EFS exhibit stereo-specificity and may involve the opening of a neuronal K+-channel. This K+-channel is glibenclamide-and phentolamine-sensitive and appears similar to the smooth muscle K+-channel which is modulated by BRL 38227.
Good
D M
DM
SmithKline Beecham Pharmaceuticals, Harlow, Essex.
Clapham
J C
JC
Hamilton
T C
TC
D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology; D019806:Cromakalim; D004558:Electric Stimulation; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D010646:Phentolamine; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D000068299:Salmeterol Xinafoate
D001578:Benzopyrans; D001993:Bronchodilator Agents; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D005905:Glyburide; D007665:Ketotifen; D010646:Phentolamine