Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein

Self Cite

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.

Section: Rb Effluxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The relaxant action of BRL 34915 in rat uterus

Hollingsworth

Amédée

Edwards

et al. 1987

Self Cite

“…The efflux of operated Ca2+ channels (VOC). Thus cromakalim K+ ions from the vascular smooth muscle cell hyperinhibits contractions induced by KCl, although high polarises the membrane towards the K+ equilibrium concentrations (>60mM) of KCl, produce contracpotential (Hamilton et al, 1986; tions which are resistant to cromakalim Clapham & Wilson, 1987 Cromakalim also inhibits contractions induced by receptor agonists such as noradrenaline, histamine, 5-hydroxytryptamine (5-HT) and angiotensin II (Clapham & Wilson, 1987;Cain & Nicholson, 1988;Cook et al, 1988;Wilson, 1988), even though contractions to these agents are less dependent on depolarisation than the equivalent contractions to KCI (Mulvany et al, 1982;Bolton et al, 1984;Haeusler, 1985;Neild & Kotecha, 1987). Unlike contractions to KCl, contractions to all concentrations of the receptor agonists are inhibited.…”

Section: Introductionmentioning

confidence: 99%

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca²⁺

Wilson

Cooper

1989

1 The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2 In normal Krebs solution, cromakalim (1 M) produced a 39.1% reduction in area under the curve (AUG) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 pM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3 LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (ECG90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 pM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4 Pinacidil (3pM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3pM) plus LaC13 ( mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%).5 In both normal and Ca2"-free Krebs solution, cromakalim (0.1, 1.0 and 10pM) produced concentration-related inhibition of the contraction to caffeine (10mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3pM). Similarly, pinacidil (0.3, 3.0 and 30 pM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.OpM) and sodium nitroprusside (0.03, 0.3 and 3.0 pM) had no significant effect on caffeine contractions. 6 The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.

“…It is thought that the ability of cromakalim to open smooth muscle cell membrane K+ channels underlies its relaxant effect not only in rabbit, rat and guinea-pig isolated blood vessels (Coldwell & Howlett, 1986;Hamilton et al, 1986;Quast, 1987), but also in rat isolated uterus (Hollingsworth et al, 1987), guineapig trachealis (Allen et al, 1986) and guinea-pig and pig urinary bladder (Foster & Brading, 1987).…”

Section: Introductionmentioning

confidence: 99%

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Buckingham

Hamilton

Howlett

et al. 1989

117

In rat isolated thoracic aortic rings pre‐contracted with noradrenaline (10−6 m), cromakalim (3 × 10−7‐3 × 10−5 m) produced concentration‐related relaxation. This effect was progressively inhibited by increasing concentrations of the anti‐diabetic sulphonylurea drug, glibenclamide (10−6‐10−5 m). In rat isolated portal veins, cromakalim (3 × 10−8‐10−6 m) produced concentration‐related inhibition of the spontaneous contractive activity and glibenclamide (3 × 10−7‐3 × 10−6 m) prevented this inhibitory action in a concentration‐dependent manner. In both rat aortic rings and portal veins, cromakalim (10−5 m) stimulated 86Rb efflux. Prior exposure to glibenclamide (10−7‐10−6 m) produced a concentration‐related inhibition of this response. In conscious rats, cromakalim, 0.075 mg kg−1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg−1). In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg−1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg−1, given by the intravenous route. The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP‐sensitive K+ channel of the pancreatic β‐cell.