Mechanism of Pacemaking in I(K1)-downregulated Myocytes

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2003 Feb 22

PMID 12595336

Citations 25

Authors

Jonathan Silva

Yoram Rudy

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

R-on-T and the initiation of reentry revisited: Integrating old and new concepts.

Qu Z, Liu M, Olcese R, Karagueuzian H, Garfinkel A, Chen P Heart Rhythm. 2022; 19(8):1369-1383.

PMID: 35364332 PMC: 11334931. DOI: 10.1016/j.hrthm.2022.03.1224.

Patch-Clamp Recordings of Action Potentials From Human Atrial Myocytes: Optimization Through Dynamic Clamp.

Verkerk A, Marchal G, Zegers J, Kawasaki M, Driessen A, Remme C Front Pharmacol. 2021; 12:649414.

PMID: 33912059 PMC: 8072333. DOI: 10.3389/fphar.2021.649414.

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study.

Li Y, Wang K, Li Q, Hancox J, Zhang H PLoS Comput Biol. 2021; 17(3):e1008177.

PMID: 33690622 PMC: 7984617. DOI: 10.1371/journal.pcbi.1008177.

Biological pacemaker: from biological experiments to computational simulation.

Li Y, Wang K, Li Q, Zhang H J Zhejiang Univ Sci B. 2020; 21(7):524-536.

PMID: 32633107 PMC: 7383327. DOI: 10.1631/jzus.B1900632.

A Simulation Study on the Pacing and Driving of the Biological Pacemaker.

Zhang Y, Zhang L, Wang Y, Wang K Biomed Res Int. 2020; 2020:4803172.

PMID: 32596315 PMC: 7273435. DOI: 10.1155/2020/4803172.

References

Zygmunt A, Goodrow R, Antzelevitch C . I(NaCa) contributes to electrical heterogeneity within the canine ventricle. Am J Physiol Heart Circ Physiol. 2000; 278(5):H1671-8. DOI: 10.1152/ajpheart.2000.278.5.H1671. View

Capogrossi M, Houser S, Bahinski A, Lakatta E . Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential. Circ Res. 1987; 61(4):498-503. DOI: 10.1161/01.res.61.4.498. View

Miake J, Marban E, Nuss H . Biological pacemaker created by gene transfer. Nature. 2002; 419(6903):132-3. DOI: 10.1038/419132b. View

Masumiya H, Tanaka H, Shigenobu K . Effects of Ca2+ channel antagonists on sinus node: prolongation of late phase 4 depolarization by efonidipine. Eur J Pharmacol. 1997; 335(1):15-21. DOI: 10.1016/s0014-2999(97)01150-3. View

Heubach J, Kohler A, Wettwer E, Ravens U . T-Type and tetrodotoxin-sensitive Ca(2+) currents coexist in guinea pig ventricular myocytes and are both blocked by mibefradil. Circ Res. 2000; 86(6):628-35. DOI: 10.1161/01.res.86.6.628. View