title: KB-R7943 block of Ca(2+) influx via Na(+)/Ca(2+) exchange does not alter twitches or glycoside inotropy but prevents Ca(2+) overload in rat ventricular myocytes.
abstract: BACKGROUND
  The Na(+)/Ca(2+) exchange (NCX) extrudes Ca(2+) from cardiac myocytes, but it can also mediate Ca(2+) influx, load the sarcoplasmic reticulum with Ca(2+), and trigger Ca(2+) release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular [Na(+)] ([Na(+)](i)) may raise levels of intracellular [Ca(2+)] ([Ca(2+)](i)) via NCX, leading to cell injury and arrhythmia.
  
  
  RESULTS
  We used KB-R7943 (KBR) to selectively block Ca(2+) influx via NCX to study the role of NCX-mediated Ca(2+) influx in intact rat ventricular myocytes. Removing extracellular Na(+) caused [Ca(2+)](i) to rise, due to Ca(2+) influx via NCX, and this was blocked by 90% with 5 micromol/L KBR. However, KBR did not alter [Ca(2+)](i) decline due to NCX. Thus, we used 5 micromol/L KBR to selectively block Ca(2+) entry but not efflux via NCX. Under control conditions, 5 micromol/L KBR did not alter steady-state twitches, Ca(2+) transients, Ca(2+) load in the sarcoplasmic reticulum, or rest potentiation, but it did prolong the late low plateau of the rat action potential. When Na(+)/K(+) ATPase was inhibited by strophanthidin, KBR reduced diastolic [Ca(2+)](i) and abolished the spontaneous Ca(2+) oscillations, but it did not prevent inotropy.
  
  
  CONCLUSIONS
  In rat ventricular myocytes, Ca(2+) influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca(2+) efflux alone (as [Na(+)](i) rises) may be sufficient to cause glycoside inotropy. In contrast, Ca(2+) overload and spontaneous activity at high [Na(+)](i) was blocked by KBR, suggesting that net Ca(2+) influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca(2+) overload.
authors.affiliation: Third Department of Internal Medicine, and Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. satoh36@hama-med.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Satoh
authors.forename: K S
authors.initials: KS
authors.lastname: Ginsburg
authors.forename: K
authors.initials: K
authors.lastname: Qing
authors.forename: H
authors.initials: H
authors.lastname: Terada
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: D M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006027:Glycosides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D006027:Glycosides; D019831:Sodium-Calcium Exchanger; D013890:Thiourea; D002118:Calcium