Electrical and mechanical effects of BRL34915 in guinea‐pig isolated trachealis

Abstract

1 BRL34915 (0.1–10 μM) suppressed the spontaneous tone of guinea-pig isolated trachealis in a concentration-dependent manner. BRL34915 was not antagonized by propranolol (1 μM). 2 In trachea where spontaneous tone was suppressed by indomethacin (2.8 μM) but subsequently restored to the same level with acetylcholine or histamine, the relaxant potency of BRL34915 was reduced. 3 In Krebs solution containing K⁺ (120 mM), isolated trachealis muscle developed near-maximal tension. The relaxant effects of BRL34915 were virtually abolished in this medium. 4 Concentration-effect curves for KCl, acetylcholine and histamine were constructed in tissues treated with indomethacin (2.8 μM). BRL34915 (10 μM) depressed the foot of the concentration-effect curve for KCl and caused minor rightward shifts in the concentration-effect curves of acetylcholine and histamine. 5 Four K⁺-channel inhibitors were tested. Apamin (0.1 μM) did not modify the action of BRL34915. Tetraethylammonium (8 mM) had little effect but procaine (5 mM) and 4-aminopyridine (5 mM) each significantly inhibited the relaxant action of BRL34915. 6 Intracellular electrophysiological recording showed that BRL34915 (0.1 μM) caused very minor relaxation and little, if any, electrical change. Higher concentrations (1–10 μM) evoked relaxation, suppression of spontaneous electrical slow waves and marked hyperpolarization of the trachealis cells. In the presence of TEA (8 mM) or procaine (5 mM) the hyperpolarization induced by BRL34915 was significantly reduced. 7 In trachealis skinned of its plasma membranes, tension development induced by Ca²⁺ (20 μM) was unaffected either by BRL34915 (10 μM) or by nicorandil (1 mM). 8 In studies of the efflux of ⁸⁶Rb⁺ from muscle-rich strips of trachea, BRL34915 (1 and 10 μM) increased the effux rate constant. 9 It is concluded that BRL34915 evokes relaxation of the trachealis by a mechanism that involves neither β-adrenoceptor activation nor direct reduction of the sensitivity of the intracellular contractile machinery to cytosolic free Ca²⁺. The action of BRL34915 may depend on the opening of K⁺ channels in the plasma membrane which are permeable to ⁸⁶Rb⁺. The opening of these channels, or the effects of their opening, may be reduced by K⁺-channel inhibitors such as 4-aminopyridine, procaine and TEA but not by apamin.