Effects of cromakalim on neurally‐mediated responses of guinea‐pig tracheal smooth muscle

1 In guinea-pig isolated bronchus treated with indomethacin (2.8 gM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 JM)-sensitive, biphasic contraction comprising a rapid, atropine (1 tLM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10lM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response.2 BRL 38227 (0.3-3 AM), salmeterol (0.003-3 pM) and ketotifen (1.0-300 AM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3 Substance P (SP; 1 ,M) and neurokinin A (NKA; 0.07 Mm) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 pM), but not by BRL 38227 (3 Mm) or ketotifen (100 AM). 4 Acetylcholine (ACh; 6 AM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 AM) slightly inhibited responses to ACh (6 pM). Salmeterol (1 pM) and ketotifen (100 MM) markedly inhibited responses to ACh (6 Mm). 5 In bronchial rings pre-contracted with ACh (100 pM), BRL 38227 (0.1-30 pM), salmeterol (0.001-3tMM) and ketotifen (0.1-100 MM) 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 MM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227. The K+-channel

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of BRL 38227 on neurally‐mediated responses in the guinea‐pig isolated bronchus

Good

Clapham

Hamilton

1992

“…This may result from the pharmacokinetic properties of BRL55834 and here the observed longlasting effects of BRL55834 compared to those of levcromakalim may be significant. An additional factor is that BRL55834 may depress NANC excitatory neurotransmission in concentrations lower than those required to relax smooth muscle, an effect reported by Burka et al (1991) using levcromakalim. The possibility that such an action of BRL55834 could account for its bronchodilator effects in the absence of the anticipated hypotensive effects (Arch et al, 1994) …”

Section: Discussionmentioning

confidence: 99%

Effects of BRL55834 in rat portal vein and bovine trachea: evidence for the induction of a glibenclamide‐resistant, ATP‐sensitive potassium current

Edwards

Schneider

Niederste-Hollenberg

et al. 1995

1 The effects of the benzopyran K-channel opener, BRL55834, on mechanical activity in bovine trachealis and rat portal vein were studied together with membrane currents in freshly-isolated single cells derived from these tissues. 2 BRL55834 (3 nM-1 iM) produced a concentration-dependent relaxation of bovine trachealis precontracted with 100 gM histamine and reduced the spontaneous mechanical activity of rat portal veins, effects which were antagonized by glibenclamide (1 -10 gM) but were not reversible on washing. In contrast, charybdotoxin (250 nM) did not modify the spasmolytic effect of BRL55834 in bovine trachealis.3 BRL55834 (10 nM-10 gM) did not relax segments of bovine trachealis precontracted with 80 mM KCl.4 In some freshly-isolated single cells from bovine trachealis held at -10 mV, BRL55834 (3 giM) induced a time-independent outward K-current which was partially resistant to inhibition by glibenclamide (10 giM). In other cells, a very noisy, outwardly-rectifying and charybdotoxin-sensitive current developed in the presence of BRL55834 (3 giM) and in time-matched control cells. 5 In freshly-isolated single cells from rat portal vein held at -10 mV, BRL55834 (3 gM) induced a timeand calcium-independent outward K-current which was partially resistant (approximately 25% inhibition at + 40 mV) to subsequent inhibition by glibenclamide (10 gM). In contrast, levcromakalim induced a time-independent outward K-current which was completely inhibited by glibenclamide 10 gM. 6 With the non-hydrolysable ATP analogue, AMP-PCP (5 mM), in the pipette, the ability of BRL55834 to induce a time-independent K-current in portal vein cells was markedly reduced (approximately 80% inhibition at + 40 mV) whereas the effects of 10 gM levcromakalim were totally inhibited. 7 The glibenclamide-resistant current component induced by BRL55834 was totally inhibited by phentolamine (100 gM), a concentration that had no effect on the peak current (IBK(Ca)) induced by NS1619 (33 giM).8 Stationary fluctuation analysis of the noise associated with the glibenclamide-insensitive K-current induced by BRL55834 in rat portal vein cells indicated that the unitary current flowing through the underlying channels was 0.26 pA at -10 mV, a value inconsistent with the involvement of BKca.9 It is concluded that the relaxations of both bovine trachea and rat portal vein produced by BRL55834 are associated with the opening of K-channels. These are probably identical to the ATPsensitive K-channel opened by levcromakalim, although the involvement of an additional K-channel cannot be excluded. The reduced sensitivity of the BRL55834-induced changes to glibenclamide and to AMP-PCP may result from avid binding of BRL55834 to its site of action.

“…One suggestion is that cromakalim inhibits neural mechanisms underlying airways hyper-responsiveness, since available data suggest that cromakalim and other potassium channel activators affect hyper-responsiveness at doses that have no bronchoprotective effect in normal airways (Chapman et al, 1991;Burka et al, 1991). However, irrespective of the effects of the potassium channel activators on airways hyperresponsiveness, they are unequivocally relaxants of normal airways smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the airways relaxant and hypotensive potencies of the potassium channel activators BRL 55834 and levcromakalim (BRL 38227) in vivo in guinea‐pigs and rats

Bowring

Arch

Buckle

et al. 1993

SmithKline Beecham Pharmaceuticals, Yew Tree Bottom Road, Epsom, Surrey KT1 8 SXQ 1 BRL 55834, a novel potassium channel activator, has been compared with levcromakalim (BRL 38227) for its relaxant effects in vivo on the airways and vasculature of the guinea-pig and rat. 2 When administered intravenously 2min prior to challenge, BRL 55834 and levcromakalim each inhibited histamine-induced increases in airways resistance (Raw) in the anaesthetized guinea-pig, with BRL 55834 showing a 4.5 fold greater potency than levcromakalim (ED25 = 2.5 jig kg-' and 11.3 Ag kg-' respectively). By contrast, both compounds had similar hypotensive potencies (ED18 = 8.5 lgg kg'-and 6.5 gLg kg-respectively). 3 In the same guinea-pig model, intraduodenally administered BRL 55834 (100 and 250 Ag kg-') and levcromakalim (500 lAg kg-') each protected against histamine-induced changes in Raw and dynamic lung compliance (Cdyn), both compounds showing a rapid onset of action that persisted for more than 50 min.The lower dose of BRL 55834 had a similar bronchodilator effect to that of levcromakalim, yet both doses of BRL 55834 elicited substantially smaller effects than levcromakalim on mean arterial blood pressure. 4 In the anaesthetized rat, BRL 55834 and levcromakalim each evoked a dose-related inhibition of inhaled methacholine-induced changes in Raw and Cd. when given i.v., with BRL 55834 showing some four fold greater potency than levcromakalim (BRL 55834: Raw ED35 = 3.7 iLg kg'-, Cdyn ED35 = 5.9 Ag kg-'; levcromakalim: Raw ED35 =16 jig kg-', Cdyn ED35= 23.5 jig kg-'). As in the guinea-pig, BRL 55834 had a reduced propensity to lower mean arterial blood pressure (ED,, = 8 jg kg-' for BRL 55834, 11 ± 3% being its maximum effect; ED,,= 16 iLg kg-', maximum effect= 34 ± 6% for levcromakalim.5 When administered intraduodenally to anaesthetized rats, BRL 55834 (10, 20 and 100 lg kg-') evoked rapid and dose-related inhibitions of methacholine-induced Raw and Cdyn changes which persisted for over 30 min. At the lower and middle dose there was little effect on mean arterial blood pressure (<10% fall). Levcromakalim (500 jg kg-') by contrast elicited transient airways responses that diminished rapidly after 5 min, while the effects on blood pressure were well maintained (>20% at 65 min). Levcromakalim (1I00 Lg kg-') did not affect airways responses but also evoked a marked and sustained fall in blood pressure.6 BRL 55834, administered per os, prolonged the time to histamine-induced dyspnoea in conscious guinea-pigs. The greatest effect of BRL 55834 was observed when it was administered 60 min prior to challenge, a dose of 0.20 mg kg-' doubling the mean time to collapse. A similar level of protection was afforded by levcromakalim (1.25 mg kg-'), with maximal activity occurring between 30 and 60 min.7 The present studies in guinea-pigs and rats indicate that BRL 55834 is the first potassium channel activator to exhibit greater bronchodilator potency than levcromakalim but reduced tendency to lower arterial blood pressure. It is suggested that BR...