Selective Phenylalkylamine Block of I(Kr) over Other K(+) Currents in Guinea-pig Ventricular Myocytes

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2001 Jan 5

PMID 11139462

Citations 1

Authors

S E Jones

S Missan

P Zhabyeyev

T F McDONALD

Affiliations

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Abstract

Previous studies on verapamil and D600 have established that the Ca(2+)-channel blockers also inhibit delayed-rectifier K(+) currents in cardiac tissues and myocytes. However, estimated IC(50) values range over two to three orders of concentration, and it is unclear whether this reflects a high selectivity by one or both of the phenylalkylamines for particular K(+) channels. The purpose of the present study was to determine the concentration-dependent actions of verapamil and D600 on three defined cardiac K(+) currents. Guinea-pig ventricular myocytes in the conventional whole-cell configuration were bathed with normal Tyrode's or K(+)-free solution, and pulsed from -80 mV for measurement of the effects of 0.01 microM to 3 mM verapamil and D600 on the inwardly-rectifying K(+) current (I:(Kl)) and the two delayed-rectifier K(+) currents, rapidly-activating I:(Kr) and slowly-activating I:(Ks). The phenylalkylamines inhibited both inward- and outward-directed I:(Kl). The IC(50) values for outward I:(Kl) were approximately 220 microM. Verapamil and D600 were approximately equipotent inhibitors of the delayed-rectifier K(+) currents. They inhibited I:(Kr) with IC(50) near 3 microM, and I:(Ks) with IC(50) > or =280 microM. These results are discussed in relation to previous findings on K(+) currents and to the clinical actions of the drugs.

Citing Articles

Verapamil inhibits Kir2.3 channels by binding to the pore and interfering with PIP binding.

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PMID: 36445385 PMC: 10042922. DOI: 10.1007/s00210-022-02342-z.

References

Rampe D, Wible B, Brown A, Dage R . Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart. Mol Pharmacol. 1993; 44(6):1240-5. View

Jahnel U, Klemm P, Nawrath H . Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol. 1994; 349(1):87-94. DOI: 10.1007/BF00178211. View

Tatsuta H, Ueda S, Morishima S, Okada Y . Voltage- and time-dependent K+ channel currents in the basolateral membrane of villus enterocytes isolated from guinea pig small intestine. J Gen Physiol. 1994; 103(3):429-46. PMC: 2216846. DOI: 10.1085/jgp.103.3.429. View

Sanguinetti M, Jiang C, Curran M, Keating M . A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995; 81(2):299-307. DOI: 10.1016/0092-8674(95)90340-2. View

Ogura T, Shuba L, McDONALD T . Action potentials, ionic currents and cell water in guinea pig ventricular preparations exposed to dimethyl sulfoxide. J Pharmacol Exp Ther. 1995; 273(3):1273-86. View

Trudeau M, Warmke J, Ganetzky B, Robertson G . HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995; 269(5220):92-5. DOI: 10.1126/science.7604285. View

Ono K, Ito H . Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity. Am J Physiol. 1995; 269(2 Pt 2):H453-62. DOI: 10.1152/ajpheart.1995.269.2.H453. View

DeCoursey T . Mechanism of K+ channel block by verapamil and related compounds in rat alveolar epithelial cells. J Gen Physiol. 1995; 106(4):745-79. PMC: 2229280. DOI: 10.1085/jgp.106.4.745. View

Lukyanenko V, Katina I, Nasledov G, Terentyev D . Pharmacological analysis of voltage-dependent potassium currents in cultured skeletal myocytes of the frog Rana temporaria. Gen Physiol Biophys. 1995; 14(6):525-34. View

10.

Heath B, Terrar D . Separation of the components of the delayed rectifier potassium current using selective blockers of IKr and IKs in guinea-pig isolated ventricular myocytes. Exp Physiol. 1996; 81(4):587-603. DOI: 10.1113/expphysiol.1996.sp003961. View

11.

McDonald T, Yu Z, Ming Z, Palma E, MEYERS M, Wang K . A minK-HERG complex regulates the cardiac potassium current I(Kr). Nature. 1997; 388(6639):289-92. DOI: 10.1038/40882. View

12.

Stadnicka A, Bosnjak Z, Kampine J, Kwok W . Effects of sevoflurane on inward rectifier K+ current in guinea pig ventricular cardiomyocytes. Am J Physiol. 1997; 273(1 Pt 2):H324-32. DOI: 10.1152/ajpheart.1997.273.1.H324. View

13.

Zhang S, Sawanobori T, Hirano Y, Hiraoka M . Multiple modulations of action potential duration by different calcium channel blocking agents in guinea pig ventricular myocytes. J Cardiovasc Pharmacol. 1997; 30(4):489-96. DOI: 10.1097/00005344-199710000-00013. View

14.

Trequattrini C, Catacuzzeno L, Petris A, Franciolini F . Verapamil block of the delayed rectifier K current in chick embryo dorsal root ganglion neurons. Pflugers Arch. 1998; 435(4):503-10. DOI: 10.1007/s004240050545. View

15.

Takeuchi S, Ando M . Inwardly rectifying K+ currents in intermediate cells in the cochlea of gerbils: a possible contribution to the endocochlear potential. Neurosci Lett. 1998; 247(2-3):175-8. DOI: 10.1016/s0304-3940(98)00318-8. View

16.

Zhabyeyev P, Missan S, Jones S, McDONALD T . Low-affinity block of cardiac K(+) currents by nifedipine. Eur J Pharmacol. 2000; 401(2):137-43. DOI: 10.1016/s0014-2999(00)00413-1. View

17.

Cranefield P, Aronson R, Wit A . Effect of verapamil on the noraml action potential and on a calcium-dependent slow response of canine cardiac Purkinje fibers. Circ Res. 1974; 34(2):204-13. DOI: 10.1161/01.res.34.2.204. View

18.

Kass R, Tsien R . Multiple effects of calcium antagonists on plateau currents in cardiac Purkinje fibers. J Gen Physiol. 1975; 66(2):169-92. PMC: 2226200. DOI: 10.1085/jgp.66.2.169. View

19.

Bayer R, Kalusche D, Kaufmann R, Mannhold R . Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium. III. Effects of the optical isomers on transmembrane action potentials. Naunyn Schmiedebergs Arch Pharmacol. 1975; 290(1):81-97. DOI: 10.1007/BF00499991. View

20.

Kostyuk P, Krishtal O, Pidoplichko V . Effect of internal fluoride and phosphate on membrane currents during intracellular dialysis of nerve cells. Nature. 1975; 257(5528):691-3. DOI: 10.1038/257691a0. View