Mechanism of pacemaking in IK1-downregulated myocytes

被引：55

作者：

Silva, J ^{[1
]}

Rudy, Y ^{[1
]}

机构：

[1] Case Western Reserve Univ, Cardiac Bioelect Res & Training Ctr, Cleveland, OH 44106 USA

来源：

CIRCULATION RESEARCH | 2003年 / 92卷 / 03期

关键词：

pacemaker; arrhythmias; ion channels; gene therapy;

D O I：

10.1161/01.RES.0000057996.20414.C6

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Biological pacemakers were recently created by genetic suppression of inward rectifier potassium current, I-K1,in guinea pig ventricular cells. We simulated these cells by adjusting I-K1 conductance in the Luo-Rudy model of the guinea pig ventricular myocyte. After 81% I-K1 suppression, the simulated cell reached steady state with pacemaker period of 594 ms. Pacemaking current is carried by the Na+-Ca2+ exchanger, I-NaCa, which depends on the intracellular calcium concentration [Ca2+](i). This [Ca2+](i) dependence suggests responsiveness (increase in rate) to beta-adrenergic stimulation (betaAS), as observed experimentally. Simulations of betaAS demonstrate such responsiveness, which depends on I-NaCa expression. However, a simultaneous betaAS-mediated increase in the slow delayed rectifier, I-Ks, limits betaAS sensitivity.

引用

页码：261 / 263

页数：3

共 10 条

[1] The sinoatrial node, a heterogeneous pacemaker structure [J].

Boyett, MR ;

Honjo, H ;

Kodama, I .

CARDIOVASCULAR RESEARCH, 2000, 47 (04) :658-687

[2] SYNCHRONOUS OCCURRENCE OF SPONTANEOUS LOCALIZED CALCIUM RELEASE FROM THE SARCOPLASMIC-RETICULUM GENERATES ACTION-POTENTIALS IN RAT CARDIAC VENTRICULAR MYOCYTES AT NORMAL RESTING MEMBRANE-POTENTIAL [J].

CAPOGROSSI, MC ;

HOUSER, SR ;

BAHINSKI, A ;

LAKATTA, EG .

CIRCULATION RESEARCH, 1987, 61 (04) :498-503

[3] T-type and tetrodotoxin-sensitive Ca2+ currents coexist in guinea pig ventricular myocytes and are both blocked by mibefradil [J].

Heubach, JF ;

Köhler, A ;

Wettwer, E ;

Ravens, U .

CIRCULATION RESEARCH, 2000, 86 (06) :628-635

[4] Ionic charge conservation and long-term steady state in the Luo-Rudy dynamic cell model [J].

Hund, TJ ;

Kucera, JP ;

Otani, NF ;

Rudy, Y .

BIOPHYSICAL JOURNAL, 2001, 81 (06) :3324-3331

[5] A DYNAMIC-MODEL OF THE CARDIAC VENTRICULAR ACTION-POTENTIAL .1. SIMULATIONS OF IONIC CURRENTS AND CONCENTRATION CHANGES [J].

LUO, CH ;

RUDY, Y .

CIRCULATION RESEARCH, 1994, 74 (06) :1071-1096

[6] Effects of Ca2+ channel antagonists on sinus node: Prolongation of late phase 4 depolarization by efonidipine [J].

Masumiya, H ;

Tanaka, H ;

Shigenobu, K .

EUROPEAN JOURNAL OF PHARMACOLOGY, 1997, 335 (01) :15-21

[7] Gene therapy -: Biological pacemaker created by gene transfer [J].

Miake, J ;

Marbán, E ;

Nuss, HB .

NATURE, 2002, 419 (6903) :132-133

[8] Localisation and functional significance of ryanodine receptors during β-adrenoceptor stimulation in the guinea-pig sino-atrial node [J].

Rigg, L ;

Heath, BM ;

Cui, Y ;

Terrar, DA .

CARDIOVASCULAR RESEARCH, 2000, 48 (02) :254-264

[9] EARLY AFTERDEPOLARIZATIONS IN CARDIAC MYOCYTES - MECHANISM AND RATE DEPENDENCE [J].

ZENG, JL ;

RUDY, Y .

BIOPHYSICAL JOURNAL, 1995, 68 (03) :949-964

[10] INaCa contributes to electrical heterogeneity within the canine ventricle [J].

Zygmunt, AC ;

Goodrow, RJ ;

Antzelevitch, C .

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2000, 278 (05) :H1671-H1678

← 1 →