The relaxant action of BRL 34915 in rat uterus

Abstract

1 BRL 34915 (0.04-1.3 tiM) caused concentration-dependent inhibition of spontaneous phasic spasms of the isolated uterus of the term pregnant rat and this effect was not antagonized by propranolol. Spasms evoked by low concentrations of KC1 (< 20 mM) were inhibited by BRL 34915 but those evoked by higher concentrations ( >40 mM) were unaffected.2 In experiments using extracellular electrical recording, BRL 34915 (1O fM) selectively inhibited oxytocin-induced phasic spasms and the associated spike activity but had little effect on the tonic component of the spasms. BRL 34915, as an inhibitor of phasic spasms to oxytocin (0.2 nM), was antagonized by procaine (0.3 and 1 mM). 3 BRL 34915 (10 EM) did not inhibit Ca2+-induced spasm of saponin-skinned thin myometrial strips.4 Intracellular microelectrode recording from myometrial strips showed that BRL 34915 (10I jM) inhibited action potentials and phasic spasms in the presence of oxytocin (0.2 nM) and produced a hyperpolarization of 5 mV. 5In single myometrial cells under current or voltage clamp, BRL 34915 (0I jAM) had no effect on action potentials and inward current in Ca2+-or Ba2+-containing media in the presence of tetraethylammonium, 4-aminopyridine and .caesium chloride. In the absence of these K+-channel inhibitors, BRL 34915 had no effect on resting membrane potential, membrane resistance, action potentials, inward current or outward current.6 BRL 34915 (1 or 1O IM) had no effect on '8Rb efflux from myometrial strips. 86Rb efflux was increased by oxytocin (0.2 and 20 nM). 7 The relaxant profile of BRL 34915 in the rat uterus is similar to that described for other smooth muscles where an action to open membrane K+-channels has been proposed. BRL 34915 inhibited spike production but produced only a small hyperpolarization without a detectable increase in 86Rb efflux. Membrane resistance and transmembrane currents were unaffected. These results suggest that in the uterus the effects of BRL 34915 may be restricted to K+-channels involved in the production of pacemaker activity.

Effects of several potassium channel openers and glibenclamide on the uterus of the rat

“…However, it should be noted that there is no direct evidence to support the involvement of K+ channels in the actions of these drugs in the uterus of the oestrogen-treated rats. A similar situation with regard to the uterus of late-pregnant rat has been discussed previously (Hollingsworth et al, 1987;.…”

“…Cromakalim is a relaxant of the isolated uterus of the term-pregnant rat (Hollingsworth et al, 1987; where it exhibits similar properties to those seen in other smooth muscles in terms of potency, rate of onset of action, reversibility and sensitivity to non-selective blockers of K+ channels such as tetraethylammonium. However, in the uterus of the term-pregnant rat, in contrast to other smooth muscles, cromakalim does not increase the efflux of 86Rb+ or 42K+, produce a marked hyperpolarization or augment the outward K + current in isolated myometrial cells (Hollingsworth et al, 1987;. Recently, it has been shown that glibenclamide is a selective antagonist of these K + channel openers in vitro (Buckingham et al, 1989;Cavero et al, 1989;Eltze, 1989;Wilson, 1989;Winquist et al, 1989;Newgreen et al, 1990).…”

Effects of cromakalim on the contraction and the membrane potential of the circular smooth muscle of guinea‐pig stomach

“…To explain the cromakalim-induced inhibition of spontaneous activity without hyperpolarization in the rat portal vein and uterus (Hamilton et al, 1986;Hollingsworth et al, 1987), these workers suggest that K+ channels associated with the pacemaker activity in these tissues were more sensitive to this agent than those responsible for determining the resting membrane potential. This may not be the case in the guinea-pig stomach, because the frequency of the spontaneous slow waves was not changed by cromakalim at concentrations which inhibited spike generation.…”

“…The dissociation between electrical effects and mechanical effects of cromakalim was also observed by Tomita & Brading (1990), who showed that cromakalim suppressed the contraction of guinea-pig stomach in spite of the persistance of the slow wave. It was shown that cromakalim does not change the Ca2"-sensitivity of smooth muscles (Allen et al, 1986;Hollingsworth et al, 1987). Therefore, the possible inhibition by cromakalim of an increase in [Ca2+]i through potentialindependent mechanisms, for example inhibition of intracellular Ca2+ refilling (Bray et al, 1991), is suggested.…”

Characteristics of the contractile response of rabbit aorta produced by cromakalim in calcium‐free solution

“…Elevation of extracellular K depolarizes the smooth muscle cells and shifts the potassium equilibrium potential (EK) to a less negative value (Hamilton et al, 1986). Under these experimental conditions the relaxant efficacy of cromakalim is markedly reduced or even abolished as has been widely reported for a variety of smooth muscles (Allen et al, 1986;Hamilton et al, 1986;Hollingsworth et al, 1987;Foster et al, 1989). Likewise, in the present study cromakalim failed to produce any contractile response in rabbit aortic strips following pre-incubation in Ca-free PSS containing an elevated [KCI] of 65.9 mM.…”