Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle

Kirkup, Anthony J.; Edwards, Gillian; Green, Michelle E.; Miller, Marilyn; Walker, S D; Weston, A.H.

doi:10.1016/s0014-2999(96)00713-3

Cited by 29 publications

(29 citation statements)

References 39 publications

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“…Yarar et al [43], using two other blockers of I Cl-Ca, also reported an inhibition of frequency in myometrium but a decrease in contraction amplitude, although [Ca 2+ ] i was not measured. Similar findings have been reported for some vascular smooth muscles [20,44]. When the uterus was depolarised with high-K + solution, neither inhibitor was effective.…”

Section: Functional Effectssupporting

confidence: 87%

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Electrophysiological characterization and functional importance of calcium-activated chloride channel in rat uterine myocytes

Jones

Shmygol

Kupittayanant

et al. 2004

Pfl�gers Archiv European Journal of Physiology

109

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In order to better understand the mechanisms underlying excitation of the uterus, we have elucidated the characteristics and functional importance of Ca(2+)-activated Cl(-) currents ( I(Cl-Ca)) in pregnant rat myometrium. In 101/320 freshly isolated myocytes, there was a slowly inactivating tail current (162+/-48 pA) upon repolarization following depolarising steps. This current has a reversal potential close to that for chloride, and was shifted when [Cl(-)] was altered. It was activated by Ca(2+) (but not Ba(2+)) entry through L-type Ca(2+) channels, enhanced by the Ca(2+) channel agonist Bay K8644 (2 microM), and inhibited by the Cl(-) channel blockers, niflumic acid (10 microM) and anthracene-9-carboxylic acid (9-AC, 100 microM). We therefore conclude that the pregnant rat myometrium contains Ca(2+)-activated Cl(-) channels producing inward current in ~30% of its cells. When these channels were inhibited by niflumic acid or 9-AC in intact tissues, the frequency of spontaneous contractions, was significantly reduced. Niflumic acid was also shown to inhibit oxytocin-induced contractions and Ca(2+) transients. Neither 9-AC nor niflumic acid had any effect on high-K-invoked contractions. Taken together these data suggest that Ca(2+)-activated Cl(-) channels are activated by Ca(2+) entry and play a functionally important role in myometrium, probably by contributing to membrane potential and firing frequency (pacemakers) in these cells.

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Section: Functional Effectssupporting

confidence: 87%

“…Niflumic acid inhibits I Cl-Ca by open channel blockade [8,15,20,24,28] and is the most potent blocker of I Cl-Ca in smooth muscle. In rat portal vein it has been reported that niflumic acid is more potent in inhibition of I Cl-Ca induced by Ca 2+ influx, compared to that induced by agonist-stimulated SR Ca 2+ release [28].…”

Section: Ca 2+ Entry Stimulates CL Camentioning

confidence: 99%

Electrophysiological characterization and functional importance of calcium-activated chloride channel in rat uterine myocytes

Jones

Shmygol

Kupittayanant

et al. 2004

Pfl�gers Archiv European Journal of Physiology

109

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“…A reduced contractility to noradrenaline of rat aorta has previously been reported in the presence of niflumic acid where the authors interpreted this effect as inhibition of I Cl(Ca) reducing membrane depolarization and voltage-dependent Ca 2+ influx [162]. This received experimental support from other studies where contractile responses to agonist stimulation were suppressed by inhibitors of the I Cl(Ca) [111,141,142,143,144]. Although the I Cl(Ca) inhibitors have significant non-selectivity, the use of several inhibitors of different origin with differing off-target effects could minimize misinterpretation of the experimental results.…”

Section: Overlapping Pharmacological Properties Of the Icl(ca) And Otmentioning

confidence: 63%

“…A role of Cl – efflux for agonist-induced contraction has been shown in several types of smooth muscles and the role of I Cl(Ca) has been emphasized [96,111,141,142,143,144]. The major problem with these studies is a lack of direct demonstration for an involvement of specific CaCCs in the contractile response.…”

Section: The Caccs Are Involved In Some Excitation-contraction Couplimentioning

confidence: 99%

“…The I Cl(Ca) in isolated VSMCs has been shown in response to agonist stimulation in the whole-cell and single-channel voltage-clamp mode [103,141,143,145]. Stimulation of the G-protein-coupled receptor increases [Ca 2+ ] i by stimulating membrane Ca 2+ channels or Ca 2+ release either via IP 3 signaling or via Ca 2+ -induced Ca 2+ release (fig.…”

Section: The Caccs Are Involved In Some Excitation-contraction Couplimentioning

confidence: 99%

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Transport and Function of Chloride in Vascular Smooth Muscles

et al. 2012

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This review summarizes the current knowledge of Cl^– transport in vascular smooth muscle cells (VSMCs). VSMCs accumulate Cl^– intracellularly using two secondary-active transport mechanisms. The Cl^– equilibrium potential is more positive than the resting membrane potential enabling Cl^– to be a depolarizing ion upon activation of a Cl^– conductance. Cl^– currents are involved in different vascular responses suggesting a number of different Cl^– channels. All known Cl^– channel families, with the exception of the GABA-/glycine-receptor family, have been identified in VSMCs. At least one member of the voltage-activated ClC family – ClC-3 – has been suggested to be involved in myogenic constriction, in cell proliferation and to have an anti-apoptotic action. The cystic fibrosis transmembrane conductance regulator is also demonstrated in VSMCs. The molecular identity of the major anion conductance in VSMCs – a Ca²⁺-activated Cl^– current – is uncertain. Several candidates have been suggested with bestrophin and TMEM16 protein families the current favorites. Specific pharmacological tools are lacking for Cl^– channels but recent molecular biology developments have made selective gene manipulations possible. A continuing quest within the vascular research field is to explicitly demonstrate the coupling between a putative channel protein and an endogenous Cl^– current and the importance of these for specific functions.

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Recent advances in potassium channel modulation

Edwards

Weston

1997

Progress in Drug Research/Fortschritte Der Arzneimittelforschung/Progrès Des Recherches Pharmaceutiques

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Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle

Cited by 29 publications

References 39 publications

Electrophysiological characterization and functional importance of calcium-activated chloride channel in rat uterine myocytes

Electrophysiological characterization and functional importance of calcium-activated chloride channel in rat uterine myocytes

Transport and Function of Chloride in Vascular Smooth Muscles

Recent advances in potassium channel modulation

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