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

Abstract

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

Antagonism by lipophilic quaternary ions of the K+ channel opener, levcromakalim, in vascular smooth muscle

“…We have recently shown that imidazol(id)ine based compounds, such as alinidine, are antagonists of K+ channel openers such as cromakalim, in both vascular and non-vascular smooth muscle (McPherson & Angus, 1989;1990;Challinor & McPherson, 1993). The antagonism displayed by imidazol(id)ine compounds is characterized by a shift to the right in the cromakalim concentration-effect curve associated with a flattening of the curve at higher concentrations ( > 10 9AM) and a reduction in the maximum response (McPherson & Angus, 1989;1990; see also Murray et al, 1989;Good et al, 1992). This type of antagonism was also displayed by the active quaternary ions.…”

Postjunctional effect of pinacidil on contractility of isolated bovine trachealis

“…MCCAIG and DE JONCKHEERE [3] reported that cromakalim attenuated contractions induced by peripheral vagus nerve stimulation in the isolated guinea-pig trachea, but it had no effect on contractions induced by EFS or exogenous ACh, suggesting a ganglionic effect [3]. By contrast, BURKA et al [4] and GOOD et al [5] found in isolated guinea-pig trachea that cromakalim [4] or lemakalim [5] inhibited EFSinduced contractions more than ACh-induced contractions, suggesting pre-and postjunctional effects. Consistent with the latter results is the observation made in vivo by ICHINOSE and BARNES [6] that cromakalim inhibited bronchoconstriction induced by vagal stimulation more than that induced by exogenous ACh.…”

“…Eur Respir J., 1996Respir J., , 9, 2057Respir J., -2063 In smooth muscle, potassium channel openers (KCOs) increase K + efflux across the cell membrane, resulting in cell membrane hyperpolarization, reduction of Ca 2+ influx through L-type voltage-dependent Ca 2+ -channels [1, 2], and relaxation. There is disagreement about whether the effects of KCOs occur directly at the muscle cell (postjunctional) or at the muscle cell and nerve level (pre-and postjunctional) [3][4][5][6]. For instance, in guinea-pig trachealis the adenosine triphosphate (ATP)-sensitive K + -channel (KATP) opener, cromakalim, affects the excitatory nonadrenergic noncholinergic (eNANC) nervous system [4].…”

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

“…Studies in vivo have activators will attenuate the release of neuropeptides (such as confirmed that when administered by a variety of different substance P and neurokinin A) from excitatory nonroutes such compounds protect animals from the bronchoadrenergic, non-cholinergic (eNANC) unmyelinated nerves spastic effects of a variety of stimuli (Arch et al, 1988; (C fibres) (Ichinose & Barnes, 1990; Lewis & Raeburn, 1990;Paciorek et al, 1990a;Bowring et al, 1991;Raeburn & Burka et al, 1991;Good et al, 1992). In particular, inhibi- Karlsson, 1991;Englert et al, 1992).…”