Comparative effects of BRL 38227, nitrendipine and isoprenaline on carbachol‐ and histamine‐stimulated phosphoinositide metabolism in airway smooth muscle

Abstract

LEI 9HN and *SmithKline Beecham Pharmaceuticals, Great Burgh, Epsom, Surrey KT18 5XQ1 The ability of BRL 38227 and nitrendipine to affect muscarinic agonist and histamine-stimulated [3H]-inositol phosphate accumulation in slices of bovine tracheal smooth muscle has been studied and compared with the established inhibitory effects of isoprenaline on this pathway.2 Pre-addition of BRL 38227 (5 J4M), nitrendipine (1 I1M) or isoprenaline (10 IJM) significantly inhibited the subsequent inositol phosphate response to histamine at all concentrations studied (10-1000 AM).BRL 38227 and nitrendipine also significantly inhibited the [3H]-inositol phosphate response to low (1 tiM), but not high (100 AM) concentrations of carbachol. Isoprenaline had no effect at any concentration of carbachol studied. 3 Nitrendipine (IC50 = 95 nM) and BRL 38227 (IC50 = 322 nM) caused concentration-related inhibitions of the inositol phosphate response to histamine (100 JM). Similar maximal inhibitions were caused by each agent (55-58%). Inhibitory effect of BRL 38227 was reduced in potency (ICM = 5.5 JiM), but not magnitude, in the presence of glibenclamide (O.5 JAM). 4 Time-course studies comparing the effects of BRL 38227 addition 15 min before, and 10 min after histamine challenge showed that for pre-addition a distinct (<2 min) lag occurred following histamine addition before the inhibitory effect of BRL 38227 was manifest. In contrast, when BRL 38227 was added O min after histamine, an inhibitory effect was immediately apparent. 5 Further evidence for an initial, 'protected' phase of inositol phosphate accumulation was provided by the finding that BRL 38227 pre-addition had no effect on the early (0-300 s) time-course of inositol 1,4,5-trisphosphate mass accumulation. 6 The inhibitory effect of BRL 38227, but not that of nitrendipine or isoprenaline, on histaminestimulated [3H]-inositol phosphate accumulation was completely prevented in the presence of an elevated extracellular K+ (65 mM) concentration. 7 The results demonstrate that membrane hyperpolarization, and/or blockade of voltage-operated Ca2"-channels can regulate agonist-stimulated phosphoinositide metabolism in airway smooth muscle.The possible contribution of this regulatory mechanism to the relaxant properties of these agents is discussed.

Correlation of cyclic AMP accumulation and relaxant actions of salmeterol and salbutamol in bovine tracheal smooth muscle

“…It has been suggested that the ability of 13-adrenoceptor agonists to inhibit Hist-stimulated [3H]-InsP accumulation arises as a consequence of the membrane hyperpolarizing action of these agents which reduce voltagesensitive Ca2"-influx in this tissue (Challiss et al, 1993). Thus in common with K+-channel openers, the inhibitory effects of ,B-adrenoceptor agonists on Hist-stimulated [3H]-InsP accumulation can be completely negated by preventing hyperpolarization (Challiss, 1992;Challiss et al, 1992). It is interesting to note that recent studies have provided evidence that whilst Salb and Iso can cause membrane hyperpolarization of guineapig trachealis and increased Rb+-efflux from bovine trachealis (Dougall et al, 1991).…”

H2S relaxes isolated human airway smooth muscle cells via the sarcolemmal KATP channel

“…Few studies have focused on the mechanistic actions of H 2 S in the lung-resident cells. Even though the role of K ATP channels in regulating airway functions has been reported [21; 22; 23], the effects of H 2 S on airway smooth muscle (ASM), the end-effector of acute airway narrowing, are largely unexplored.…”

Effects of ATP-sensitive potassium channel openers on the contractile and phosphatidylinositol responses of the rat trachea

“…These data are inconsistent with the previous reports of inhibition of IP 3 production by K ATP channel openers in the arteries and trachea. Challiss et al [4] reported that pre-addition of lemakalim significantly inhibited the PI response to 1 µM CCh, but not to 10 µM CCh or greater, in slices of bovine tracheal smooth muscle. Since the doses of 50% effect (ED 50 ) of CCh in bovine tracheal smooth muscle is about 5.5 µM [13], the 1 µM CCh used in their study was less than the ED 50 of CCh [4].…”

“…However, since the K ATP channel seems not to be so important in airway smooth muscle, few studies, except for those of Challiss et al [4] and Kamei et al [5], have evaluated the effects of K ATP channel openers on the airway smooth muscle of bovines or dogs. These authors found that K ATP channel openers inhibited inositol phosphate or IP 3 accumulations.…”