Ca2+-dependent reduction of IK1 in rat ventricular cells: a novel paradigm for arrhythmia in heart failure?

Abstract

OBJECTIVES:

We investigated the inward rectifier potassium current (I(K1)), which can be blocked by intracellular Ca(2+), in heart failure (HF).

METHODS:

We used the whole-cell patch-clamp technique to record I(K1) from single rat ventricular myocytes in voltage-clamp conditions. Fluorescence measurements of diastolic Ca(2+) were performed with Indo-1 AM. HF was examined 8 weeks after myocardial infarction (coronary artery ligation).

RESULTS:

I(K1) was reduced and diastolic Ca(2+) was increased in HF cells. The reduction of I(K1) was attenuated when EGTA was elevated from 0.5 to 10 mM in the patch pipette and prevented with high BAPTA (20 mM). Ryanodine (100 nM) and FK506 (10 microM), both of which promote spontaneous SR Ca(2+) release from ryanodine receptor (RyR2) during diastole, reproduced the effect of HF on I(K1) in normal cells but had no effect in HF cells. The effects of ryanodine and FK506 were not additive and were prevented by BAPTA. Rapamycin (10 microM), which removes FKBP binding proteins from RyR2 with no effect on calcineurin, mimicked the effect of FK506 on I(K1). Cyclosporine A (10 microM), which inhibits calcineurin via cyclophilins, had no effect. In both HF cells and normal cells treated by FK506, the protein kinase C (PKC) inhibitor staurosporine totally restored the inward component of I(K1), but only partially restored its outward component at potentials corresponding to the late repolarizing phase of the action potential (-80 to -40 mV).

CONCLUSIONS:

I(K1) is reduced by elevated diastolic Ca(2+)in HF, which involves in parallel PKC-dependent and PKC-independent mechanisms. This regulation provides a novel paradigm for Ca(2+)-dependent modulation of membrane potential in HF. Since enhanced RyR2-mediated Ca(2+)release also reduces I(K1), this paradigm might be relevant for arrhythmias related to acquired or inherited RyR2 dysfunction.

• Authors: Jérémy Fauconnier, Alain Lacampagne, Jean-Michel Rauzier, Guy Vassort, Sylvain Richard
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 68 Issue 2 Pg. 204-12 (Nov 01 2005) ISSN: 0008-6363 [Print] England
• PMID: 16083867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Potassium Channels, Inwardly Rectifying
• Ryanodine Receptor Calcium Release Channel
• Ryanodine
• Egtazic Acid
• Protein Kinase C
• Staurosporine
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Calcium
• Sirolimus
• Tacrolimus

Topics

• Action Potentials
• Animals
• Arrhythmias, Cardiac (metabolism)
• Calcium (metabolism)
• Depression, Chemical
• Egtazic Acid (analogs & derivatives)
• Heart Failure (metabolism)
• Immunosuppressive Agents
• Male
• Myocardial Infarction (metabolism)
• Myocardium (metabolism)
• Patch-Clamp Techniques
• Potassium Channels, Inwardly Rectifying (metabolism)
• Protein Kinase C (antagonists & inhibitors)
• Rats
• Rats, Wistar
• Ryanodine (pharmacology)
• Ryanodine Receptor Calcium Release Channel (drug effects, metabolism)
• Sirolimus (pharmacology)
• Staurosporine (pharmacology)
• Tacrolimus (pharmacology)