Effects of rubidium on responses to potassium channel openers in rat isolated aorta

Greenwood, Iain A.; Weston, A.H.

doi:10.1111/j.1476-5381.1993.tb13709.x

Cited by 32 publications

(13 citation statements)

References 26 publications

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“…However, we could not demonstrate any antagonism of aprikalim vasorelaxant effects by 30 or 100 µM minoxidil sulphate in aortic rings contracted with 40 mM KCl (unpublished observations). Finally, some differences in the mechanisms of vasorelaxation utilised by minoxidil and other K + channel openers have been documented (Bray and Quast 1992;Greenwood and Weston 1993).…”

Section: Discussionmentioning

confidence: 99%

Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings

Magnon

Calderone

Floch

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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We examined the effects of various KCl concentrations on the actions of some vasodilators belonging to different pharmacological classes in rat aortic rings. In some experiments, tissues were precontracted with noradrenaline after blocking voltage-dependent channels to assess the effects of depolarisation unaccompanied by the entry of extracellular Ca2+ into the cytosol. Concentration/response curves for the vasorelaxant effect of calcium entry blockers (e.g. diltiazem), K+ channel openers (e.g. aprikalim), nitrate derivatives (e.g. nitroglycerin), a beta2-adrenergic agonist (salbutamol) and papaverine were obtained by using endothelium-denuded rat aortic rings precontracted with KC1 (20-60 mM) to determine the potencies and efficacies of the drugs. The efficacies and potencies of calcium entry inhibitors were virtually independent of the [KCl]. A reduction in the potency (up to 18-fold) of papaverine occurred without changes in efficacy when the [KCl] was raised from 20 to 60 mM. The decline in potency was even greater for nitrate-like compounds. The potency of K+ channel openers in aortic rings precontracted with 30 mM KCI decreased by three- to sixfold compared with those precontracted with 20 mM KCl. With the exception of pinacidil, the efficacy of these agents already started to decline in preparations precontracted with 25 mM KCI and was virtually zero in preparations precontracted with 60 mM KCI. In contrast to other K+ channel openers, the vasorelaxant action of pinacidil was relatively resistant to glibenclamide. Salbutamol produced only a slight relaxation even in preparations precontracted with 20 mM KCl. In nitrendipine-pretreated, noradrenaline-precontracted aortic rings, the vasorelaxant effects of aprikalim, but not those of linsidomine or papaverine, declined when the [KCl] of the bathing medium was increased. In conclusion, the vasorelaxant potency and efficacy of calcium entry blockers is independent of the [KCI] used to precontract rat aortic rings, and thus, of the degree of membrane depolarisation. In contrast, increasing the [KCl] strongly reduces the potency and the efficacy of K+ channel openers not only in this preparation but also in noradrenaline-precontracted rings in which the entry of extracellular Ca2+ was prevented with nitrendipine. This indicates that, with the exception of pinacidil, the vasorelaxant activity of K+ channel openers depends on the degree of membrane depolarisation. Finally, the vasorelaxant potency and efficacy of nitrate-like compounds and papaverine are independent of depolarisation per se but they are markedly affected by the influx of Ca2+ accompanying elevated [KCI]. Thus, the degree of vessel depolarisation should be taken into consideration when attempting to compare potencies and efficacies among vasorelaxant agents.

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Section: Discussionmentioning

confidence: 99%

Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings

Magnon

Calderone

Floch

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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“…The fact that glibenclamide, the standard inhibitor of the KAT P channel openers, inhibits the K + channel opening and the vasorelaxant effects of cromakalim with the same inhibition constant (Quast and Cook 1989) seemingly confirms this hypothesis. However, more recent work using the K + channel blockers tedisamil Quast 1991a, 1992a) and Rb + (Foster et al 1992;Greenwood and Weston 1993) or stimulation of protein kinase C (Linde et al 1995) shows that the vast majority of K + channels activated by the openers can be blocked without preventing vasorelaxation; however, some rightward shift and steepening of the relaxation-concentration curve for the opener are observed (for review see Quast 1993). Here we show that Ba 2 + is to be added to the list of compounds which preferentially block the K + channel activating effect of the openers.…”

Section: Introductionmentioning

confidence: 99%

Ba2+ differentially inhibits the Rb+ efflux promoting and the vasorelaxant effects of levcromakalim and minoxidil sulfate in rat isolated aorta

Quast

Baumlin

Löffler

1995

Naunyn-Schmiedeberg's Arch Pharmacol

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The K+ channel openers activate ATP-sensitive K+ channels (KATP) in vascular smooth muscle and induce relaxation. In this study, the relationship between these two effects was examined in rings of rat aorta using levcromakalim and minoxidil sulfate as the openers and Ba2+ as the K+ channel blocker; K+ channel opening was assessed by determining the rate constant of 86Rb+ efflux from the preparation. Ba2+ inhibited the 86Rb+ efflux stimulated by levcromakalim in a noncompetitive manner with an IC50 value of 29 microM and a Hill-coefficient of 1.2. At concentrations >300 microM, Ba2+ increased the tension of rat aortic rings concentration-dependently. Levcromakalim relaxed contractions to Ba2+ (0.5 and 1 mM) with potencies similar to those determined against KCl (25 mM) or noradrenaline as spasmogens (EC50 values 15-40 nM). The vasorelaxant effect against Ba2+ was inhibited by the KATP channel blockers, glibenclamide and tedisamil, and abolished in depolarizing medium (55 mM KCl). At 3 mM Ba2+, levcromakalim was still able to transiently induce complete relaxation; however, within 1 h oscillations in tension developed, leading to a stable level of only 15% relaxation. A similar level of relaxation was achieved against 10 mM Ba2+ whereas the combination of 0.5 mM Ba2+ and 3 microM tedisamil blocked the relaxant effect of levcromakalim completely. With minoxidil sulfate as the KATP channel opener the results of the 86Rb+ efflux and tension experiments were similar to those obtained with levcromakalim. It is concluded that Ba2+ is more potent in inhibiting the K+ channel opening than the vasorelaxant effects of the openers. On the basis of the 86Rb+ efflux experiments it is estimated that at least 97% of the channels opened by the activators can be blocked without major effects on vasorelaxation suggesting a dissociation between the two effects. However, if the block is pushed to extremes (> or = 99.95%) the vasorelaxant effect of the openers is also abolished suggesting a link between both effects. This paradoxon remains to be solved.

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“…It is proposed that levcromakalim opens K+-channels and hyperpolarizes the plasma membrane, an action thought to deactivate voltage-dependent Ca2"-channels and inhibit spasm (Weston & Edwards, 1992 (Greenwood & Weston, 1993;Quast, 1993 …”

Section: Effects Of Levcromakalimmentioning

confidence: 99%

Cellular localization of the inhibitory action of relaxin against uterine spasm

Hughes

Hollingsworth

1995

British J Pharmacology

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1 The aim of this study was to determine whether the site of action of relaxin as a relaxant of rat myometrium is at the cell membrane or at an intracellular site. Therefore, the potency of relaxin was determined against spasms reliant predominantly upon either extracellular Ca2+ or intracellular Ca2". Uterine spasms dependent upon extracellular Ca2" were elicited by (i) oxytocin (0.2 nM) (ii) Bay K 8644(1 yM) in 10 mm K+-rich PSS and (iii) KCl (80 mM). Uterine spasm dependent upon intracellular Ca2+ was elicited by oxytocin (20 nM) in the presence of nifedipine (500 nM). The effects of relaxin against these spasmogens were compared with those of levcromakalim, nifedipine and salbutamol. 2 Relaxin (0.2-6.3 nM), levcromakalim (25-800 nM), salbutamol (1-63 nM) and nifedipine (1-250 nM) caused concentration-dependent inhibition of the spasm evoked by oxytocin (0.2 nM) and relaxin was the most potent relaxant. 3 Relaxin and nifedipine were slightly less potent against the spasm induced by Bay K 8644 (1 uM) than against spasm induced by oxytocin (0.2 nM) (15 fold and 13 fold respectively). Levcromakalim and salbutamol were equipotent against the spasm evoked by Bay K 8644 (1 uM) and that evoked by oxytocin (0.2 nM). 4 Relaxin induced only 47 + 7% inhibition of the KCl (80 mM)-evoked spasm at a concentration of 0.8 JM. Levcromakalim was much less potent (427 fold) against the spasm evoked by KCl (80 mM) than against the spasm evoked by oxytocin (0.2 nM). The potency of salbutamol against the spasm evoked by KCl (80 mM) was modestly reduced (14 fold) compared to that against the spasm evoked by oxytocin (0.2 nM). The potency of nifedipine against the KCl (80 mM)-evoked spasm was not different from that against the oxytocin (0.2 nM)-evoked spasm. 5 The potencies of relaxin and levcromakalim against the spasm evoked by oxytocin (20 nM) + nifedipine (500 nM) were greatly reduced (74 fold and 234 fold respectively) compared to their potencies against the spasm evoked by oxytocin (0.2 nM). The potency of salbutamol against these two spasmogens was not different. 6 Relaxin was much less potent against the spasm dependent upon intracellular Ca21 (that induced by oxytocin (20 nM) + nifedipine (500 nM)) than against the spasms dependent upon extracellular Ca2 , those induced by oxytocin (0.2 nM) and Bay K 8644 (1 gM). In this regard, relaxin resembled levcromakalim and nifedipine rather than salbutamol. Therefore, the major site of action of relaxin appears to be located at the plasma membrane rather than at an intracellular level. The observation that relaxin was less effective against the KCl (80 mM)-induced spasm than against the oxytocin (0.2 nM)-evoked spasm may indicate that relaxin has a minor action involving K + -channel opening. 7 High concentrations of relaxin (up to 1 gM) induced significant inhibition of the spasm dependent upon intracellular Ca2+. Thus at high concentrations relaxin also appears to have an additional intracellular action.

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Effects of rubidium on responses to potassium channel openers in rat isolated aorta

Cited by 32 publications

References 26 publications

Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings

Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings

Ba2+ differentially inhibits the Rb+ efflux promoting and the vasorelaxant effects of levcromakalim and minoxidil sulfate in rat isolated aorta

Cellular localization of the inhibitory action of relaxin against uterine spasm

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