Importance of Ca2+ influx by Na+/Ca2+ exchange under normal and sodium-loaded conditions in mammalian ventricles.
Na+/Ca2+ exchange (NCX) is a major Ca2+ extrusion system in cardiac myocytes, but can also mediate Ca2+ influx and trigger sarcoplasmic reticulum Ca2+ release. Under conditions such as digitalis toxicity or ischemia/reperfusion, increased [Na+]i may lead to a rise in [Ca2+]i through NCX, causing Ca2+ overload and triggered arrhythmias. Here we used an agent which selectively blocks Ca2+ influx by NCX, KB-R7943 (KBR), and assessed twitch contractions and Ca2+ transients in rat and guinea pig ventricular myocytes loaded with indo-1. KBR (5 microM) did not alter control steady-state twitch contractions or Ca2+ transients at 0.5 Hz in rat, but significantly decreased them in guinea pig myocytes. When cells were Na+-loaded by perfusion of strophanthidin (50 microM), the addition of KBR reduced diastolic [Ca2+]i and abolished spontaneous Ca2+ oscillations. In guinea pig papillary muscles exposed to substrate-free hypoxic medium for 60 min, KBR (10 microM applied 10 min before and during reoxygenation) reduced both the incidence and duration of reoxygenation-induced arrhythmias. KBR also enhanced the recovery of developed tension after reoxygenation. It is concluded that (1) the importance of Ca2+ influx via NCX for normal excitation-contraction coupling is species-dependent, and (2) Ca2+ influx via NCX may be critical in causing myocardial Ca2+ overload and triggered activities induced by cardiac glycoside or reoxygenation.
Satoh
Hiroshi
H
Division of Cardiology, Internal Medicine III, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Japan. satoh36@hama-med.ac.jp
Mukai
Masaaki
M
Urushida
Tsuyoshi
T
Katoh
Hideki
H
Terada
Hajime
H
Hayashi
Hideharu
H
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004563:Electrochemistry; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013327:Strophanthidin / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D019831:Sodium-Calcium Exchanger; D013327:Strophanthidin; D012964:Sodium; D013890:Thiourea; D010100:Oxygen; D002118:Calcium