The Novel Class III Antiarrhythmics NE-10064 and NE-10133 Inhibit Isk Channels Expressed in Xenopus Oocytes and Iks in Guinea Pig Cardiac Myocytes

HERG is a K+ channel with properties similar to the rapidly activating component (I(Kr)) of delayed rectifier K+ current, which is important for repolarization of human cardiac myocytes. In this study, we have characterized the single-channel properties of HERG expressed in Xenopus oocytes. Currents were measured in cell-attached patches with an extracellular K concentration of 120 mM. The single HERG channel conductance, determined at test potentials between -50 and -110 mV, was 12.1 +/- 0.6 pS. At positive test potentials (+40 to +80 mV), the probability of channel opening was low and slope conductance was 5.1 +/- 0.6 pS. The mean channel open times at -90 mV were 2.9 +/- 0.5 and 11.8 +/- 1.0 ms, and the mean channel closed times were 0.54 +/- 0.02 and 14.5 +/- 5.3 ms. Single HERG channels were blocked by MK-499, a class III antiarrhythmic agent that blocks I(Kr) in cardiac myocytes. The development of block was more rapid in inside-out patches than in cell-attached patches or in whole cell recordings, indicating that block occurs from the cytoplasmic side of the membrane. The single-channel properties of HERG are similar to I(Kr) channels of isolated cardiac myocytes, which provides further evidence that HERG proteins coassemble to form I(Kr) channels.

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Reduction of ischaemia-induced arrhythmias in the guinea-pig heart by lignocaine but not by class III antiarrhythmics

Journal of Molecular and Cellular Cardiology ◽

10.1016/0022-2828(90)91734-o ◽

1990 ◽

Vol 22 ◽

pp. S69

Keyword(s):

Guinea Pig ◽

Class Iii ◽

Guinea Pig Heart ◽

Class Iii Antiarrhythmics

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Blockade of human IsK channels expressed in Xenopus oocytes by the novel class III antiarrhythmic NE-10064

European Journal of Pharmacology ◽

10.1016/0014-2999(94)90632-7 ◽

1994 ◽

Vol 264 (1) ◽

pp. 33-37 ◽

Cited By ~ 19

Author(s):

Andreas E. Busch ◽

Tobias Herzer ◽

Toru Takumi ◽

Peter Krippeit-Drews ◽

Siefried Waldegger ◽

...

Keyword(s):

Xenopus Oocytes ◽

The Novel ◽

Class Iii

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Evidence for tachykinin NK-2 receptors in homogenates of guinea-pig lung, using the novel selective radioligand, [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4–10)

Regulatory Peptides ◽

10.1016/0167-0115(92)91039-3 ◽

1992 ◽

Vol 37 ◽

pp. S184 ◽

Cited By ~ 1

Author(s):

X.-P. Zeng ◽

S. Lavielle ◽

E. Burcher

Keyword(s):

Guinea Pig ◽

The Novel

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Inhibitory activity of the novel CB2 receptor agonist, GW833972A, on guinea-pig and human sensory nerve function in the airways

British Journal of Pharmacology ◽

10.1038/bjp.2008.298 ◽

2008 ◽

Vol 155 (4) ◽

pp. 547-557 ◽

Cited By ~ 34

Author(s):

M G Belvisi ◽

H J Patel ◽

V Freund-Michel ◽

D J Hele ◽

N Crispino ◽

...

Keyword(s):

Guinea Pig ◽

Inhibitory Activity ◽

Receptor Agonist ◽

Sensory Nerve ◽

The Novel ◽

Nerve Function ◽

Cb2 Receptor

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The kinetics of transport of lactate and pyruvate into isolated cardiac myocytes from guinea pig. Kinetic evidence for the presence of a carrier distinct from that in erythrocytes and hepatocytes

Biochemical Journal ◽

10.1042/bj2640409 ◽

1989 ◽

Vol 264 (2) ◽

pp. 409-418 ◽

Cited By ~ 64

Author(s):

R C Poole ◽

A P Halestrap ◽

S J Price ◽

A J Levi

Keyword(s):

Guinea Pig ◽

Cardiac Myocytes ◽

Ventricular Myocytes ◽

Silicone Oil ◽

Free Acid ◽

Competitive Inhibitor ◽

Isolated Cardiac Myocytes ◽

Lactate And Pyruvate ◽

Time Courses ◽

Kinetics Of

1. Time courses for the uptake of L-lactate, D-lactate and pyruvate into isolated cardiac ventricular myocytes from guinea pig were determined at 11 degrees C or 0 degrees C (for pyruvate) in a citrate-based buffer by using a silicone-oil-filtration technique. These conditions enabled initial rates of transport to be measured without interference from metabolism of the substrates. 2. At a concentration of 0.5 mM, transport of all these substrates was inhibited by approx. 90% by 5 mM-alpha-cyano-4-hydroxycinnamate; at 10 mM-L-lactate a considerable portion of transport could not be inhibited. 3. Initial rates of L-lactate and pyruvate uptake in the presence of 5 mM-alpha-cyano-4-hydroxycinnamate were linearly related to the concentration of the monocarboxylate and probably represented diffusion of the free acid. The inhibitor-sensitive component of uptake obeyed Michaelis-Menten kinetics, with Km values for L-lactate and pyruvate of 2.3 and 0.066 mM respectively. 4. Pyruvate and D-lactate inhibited the transport of L-lactate, with Ki values (competitive) of 0.077 and 6.6 mM respectively; the Ki for pyruvate was very similar to its Km for transport. The Ki for alpha-cyano-4-hydroxycinnamate as a non-competitive inhibitor was 0.042 mM. 5. These results indicate that L-lactate, D-lactate and pyruvate share a common carrier in guinea-pig cardiac myocytes; the low stereoselectivity for L-lactate over D-lactate and the high affinity for pyruvate distinguish it from the carrier in erythrocytes and hepatocytes. The metabolic roles for this novel carrier in heart are discussed.

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