Effects of JTV-519, a novel anti-ischaemic drug, on the delayed rectifier K + current in guinea-pig ventricular myocytes

The effects of endothelin, a novel vasoconstrictive peptide, on the delayed rectifier K+ current (IK) were examined in single dialyzed cells from guinea pig ventricles. Either big endothelin or endothelin-1 enhanced IK at a dissociation constant of 2 nM with L-type Ca2+ current being unaffected. Under intracellular perfusion with pCa 7.6 solution, 3 nM big endothelin increased IK by 55 +/- 38.5%. Either pretreatment with 10 microM 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7) or a low Ca2+ [10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and minus CaCl2] internal solution diminished the enhancement. Preceding stimulation of protein kinase C (PKC) by 10-20 nM 12-O-tetradecanoylphorbol-13-acetate also reduced the degree of enhancement. When Na+ was eliminated from the solutions, endothelin increased IK distinctively in cells internally dialyzed with a low Ca2+ solution. This enhancement was not abolished by either pretreatment with H 7 or by removal of Ca2+ from the external perfusate but by increasing the internal EGTA concentration to 40 mM. Preincubation with ryanodine or internal perfusion with heparin also reduced the IK enhancement under Na(+)-free conditions. Intracellular application of 200 microM guanosine 5'-O-(3-thiotriphosphate) effectively attenuated the effect of endothelin. It is concluded that endothelin enhances IK via phospholipase C-mediated PKC activation and intracellular Ca2+ mobilization. GTP-binding protein is involved in these reactions.

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Propafenone Preferentially Blocks the Rapidly Activating Component of Delayed Rectifier K + Current in Guinea Pig Ventricular Myocytes

Circulation Research ◽

10.1161/01.res.76.2.223 ◽

1995 ◽

Vol 76 (2) ◽

pp. 223-235 ◽

Cited By ~ 34

Author(s):

Eva Delpón ◽

Carmen Valenzuela ◽

Onésima Pérez ◽

Oscar Casis ◽

Juan Tamargo

Keyword(s):

Guinea Pig ◽

Ventricular Myocytes ◽

Delayed Rectifier ◽

K Current

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Magnesium shifts voltage dependence of activation of delayed rectifier I(K) in guinea pig ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1292 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1292-H1301 ◽

Cited By ~ 5

Author(s):

B. A. Williams ◽

G. N. Beatch

Keyword(s):

Guinea Pig ◽

Ventricular Myocytes ◽

Inward Rectification ◽

Delayed Rectifier ◽

Maximal Effect ◽

Patch Clamp Technique ◽

Whole Cell Patch Clamp ◽

K Current ◽

Dose Dependent Decrease ◽

20 Nm

The sensitivity of the delayed rectifier K+ current (I(K)) to intracellular Mg2+ was investigated in guinea pig ventricular myocytes using the whole cell patch-clamp technique. An increase in free intracellular Mg2+ concentration ([Mg2+]i) led to a dose-dependent decrease in I(K) with a half-maximal effect of approximately 20 nM. Activation of I(K) was shifted toward more positive voltages on increasing [Mg2+]i, but little effect was observed on activation and deactivation kinetics. Isoproterenol increased I(K) and was partially reversible in both control and 100 nM [Mg2+]i. The antiarrhythmic drug dofetilide was used to separate I(K) into its two components, rapidly activating (I(Kr)) and slowly activating (I(Ks)). The magnitude of both components decreased to a similar extent with an increase in [Mg2+]i. As [Mg2+]i was reduced, however, the number of experiments in which the dofetilide-sensitive current I(Kr) displayed inward rectification was reduced. In contrast to results previously reported for frog myocytes, it is unlikely that Mg2+ effects on guinea pig I(K) are mediated by a protein phosphatase.

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