Potent block of volume‐activated chloride currents in endothelial cells by the uncharged form of quinine and quinidine

Voets, Thomas; Droogmans, Guillaume; Nilius, Bernd

doi:10.1111/j.1476-5381.1996.tb15616.x

Cited by 28 publications

(24 citation statements)

References 17 publications

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“…In both cases, Hill coefficients were Ϸ2 (1.81 for Cx36, 1.92 for Cx50), indicating that binding of two molecules of quinine was required to block gap junction channels. The EC 50 values for the effect of quinine are comparable to those found for block of potassium (22,23) and volume-activated chloride channels (24) and are within the range of plasma concentrations achieved during antimalarial therapy (18-71 M: ref. 25).…”

Section: Resultssupporting

confidence: 71%

Quinine blocks specific gap junction channel subtypes

Srinivas

Hopperstad

Spray

2001

Proc. Natl. Acad. Sci. U.S.A.

194

165

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We demonstrate that the antimalarial drug quinine specifically reduces currents through gap junctions formed by some connexins (Cx) in transfected mammalian cells, but does not affect other gap junction types. Quinine blocked Cx36 and Cx50 junctional currents in a reversible and concentration-dependent manner with half maximal blocking concentrations of 32 and 73 M, respectively; Hill coefficients for block by quinine were about 2 for both connexins. In contrast, quinine did not substantially block gap junction channels formed by Cx26, Cx32, Cx40, and Cx43, and only moderately affected Cx45 junctions. To determine the location of the binding site of quinine (pKa ‫؍‬ 8.7), we investigated the effect of quinine at various external and internal pH values and the effect of a permanently charged quaternary derivative of quinine. Our results indicate that the binding site for quinine is intracellular, possibly within the pore. Single-channel studies indicated that exposure to quinine induced slow transitions between open and fully closed states that decreased open probability of the channel. Quinine thus offers a potentially useful method to block certain types of gap junction channels, including those between neurons that are formed by Cx36. Moreover, quinine derivatives that are excluded from other types of membrane channels may provide molecules with connexin-specific as well as connexin-selective blocking activity.

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Section: Resultssupporting

confidence: 71%

Quinine blocks specific gap junction channel subtypes

Srinivas

Hopperstad

Spray

2001

Proc. Natl. Acad. Sci. U.S.A.

194

165

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“…Increasing the portion of uncharged molecules from 2 to 20% by a change of the external pH from 7.3 to 8.3 did not change the effects of quinidine and quinine on I Ca or I to . For comparison, a similar extracellular alkalinization has been shown to increase the potency of tertiary local anesthetics affecting Na + channels [23] and the effects of tertiary 4-aminopyridine on I to [25] and, in addition, of quinidine and quinine acting on volume-activated Cl -currents in bovine pulmonary arterial cells [26]. In the latter study, the results indicate that the blockade is mediated by the uncharged form of both drugs.…”

Section: Discussionsupporting

confidence: 54%

Effects of Quinine and Quinidine on the Transient Outward and on the L-Type Ca<sup>2+</sup> Current in Rat Ventricular Cardiomyocytes

Wegener

Nawrath³

2002

Pharmacology

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The effects of the enantiomers quinine and quinidine on the transient outward current (I_to) and on the L-type Ca²⁺ current (I_Ca) were investigated in rat ventricular cardiomyocytes using the patch-clamp technique. At a stimulation frequency of 2 Hz, both quinine and quinidine depressed the magnitude of I_to and I_Ca; the half-maximal effects on I_to were achieved at 11 and 15 µmol/l, respectively, and those on I_Ca at 14 and 10 µmol/l, respectively. At 0.2 Hz, both drugs depressed the magnitude of I_to, but not that of I_Ca. A change in extracellular pH from 7.3 to 8.3 did not significantly influence the effects of the drugs (which are protonated to 98% at pH 7.3) on I_to or I_Ca. It is concluded that neither the different chemical structure nor the amount of protonation of quinine and quinidine controls their effects on I_to or I_Ca.

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“…There is a huge variety of compounds that inhibit VRAC with moderate affinity (EC 50 between 1 and 1000 µM) and specificity. Among these compounds are not only several classical Cl -channel blockers, such as DIDS, SITS, NPA, 9-AC, NPPB and niflumic acid, but also several "surprising" substances, such as the P-glycoprotein inhibitors tamoxifen, 1,9-dideoxyforskolin, verapamil [17], quinine and quinidine [24], antiallergic drugs from the chromone family [25], the inositol-tetrakisphophates Ins(3,4,5,6)P 4 and Ins(1,4,5,6)P 4 [26], the anti-hypertensive Ca 2+ -antagonist mibefradil [27], and the widely used antidepressant drug fluoxetine, supposed to be a selective serotonin (5-hydroxytryptamine) re-uptake inhibitor [28]. Most of the voltage-independent blockers are relatively hydrophobic aromatic compounds, which can easily permeate the cell membrane.…”

Section: Pharmacologymentioning

confidence: 99%

The Endothelial Volume-Regulated Anion Channel, VRAC

Nilius

Eggermont

Droogmans³

2000

Cell Physiol Biochem

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We discuss in this short review properties of a volume-regulated anion channel that we have described in vascular endothelial cells. This channel, VRAC (volume-regulated anion channel) is outwardly rectifying with single channel conductances between 10-20pS for inward currents and 40-50pS for outward currents. VRAC is permeable for a wide range of anions, amino acids and organic osmolytes. The estimated pore diameter is approximately 1.1nm. VRAC is gated by a probably complex mechanism in which changes in ionic strength, tyrosine phosphorylation, the cytoskeletal organiser RhoA and possibly caveolin are essentially involved. The molecular candidate for this channel is still elusive. The functional impact of VRAC as a possible mechano-sensor in endothelium and as a regulatory component in the cell cycle, endothelial cell proliferation and possible angiogenesis will be discussed.

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Potent block of volume‐activated chloride currents in endothelial cells by the uncharged form of quinine and quinidine

Cited by 28 publications

References 17 publications

Quinine blocks specific gap junction channel subtypes

Quinine blocks specific gap junction channel subtypes

Effects of Quinine and Quinidine on the Transient Outward and on the L-Type Ca<sup>2+</sup> Current in Rat Ventricular Cardiomyocytes

The Endothelial Volume-Regulated Anion Channel, VRAC

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