alcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes

21 Prolongation of the Ca transient and action potential (AP) durations are two characteristic changes in myocyte physiology in the 21 1 21 21 failing human heart. The hypothesis of this study is that Ca influx via reverse mode Na /Ca exchanger (NCX) or via L-type Ca 21 channels directly activates contraction in failing human myocytes while in normal myocytes this Ca is transported into the sarcoplasmic 21 reticulum (SR) to regulate SR Ca stores. Methods: Myocytes were isolated from failing human (n56), nonfailing human (n53) and normal feline hearts (n59) and whole cell current and voltage clamp techniques were used to evoke and increase the duration of APs (0.5 26 26 26 Hz, 37 8C). Cyclopiazonic acid (CPA 10 M), nifedipine (NIF;10 M) and KB-R 7943 (KB-R; 3310 M) were used to reduce SR 21 21 21 1 Ca uptake, Ca influx via the L-type Ca current and reverse mode NCX, respectively. [Na ] was changed by dialyzing myocytes i 1 with 0, 10 and 20 mM Na pipette solutions. Results: Prolongation of the AP duration caused an immediate prolongation of contraction 21 and Ca transient durations in failing myocytes. The first beat after the prolonged AP was potentiated by 2165 and 2765% in nonfailing human and normal feline myocytes, respectively (P,0.05), but there was no significant effect in failing human myocytes (1564% vs. steady state). CPA blunted the potentiation of the first beat after AP prolongation in normal feline and nonfailing human myocytes, mimicking the failing phenotype. NIF reduced steady state contraction in feline myocytes but the potentiation of the first beat after AP prolongation was unaltered (2163% vs. base, P,0.05). KB-R reduced basal contractility and abolished the potentiation of the first beat 1 21 after AP prolongation (261% vs. steady state). Increasing [Na ] shortened AP, Ca transient and contraction durations and increased i 1 21 steady state and post AP prolongation contractions. Dialysis with 0 Na eliminated these effects. Conclusions: Ca enters both normal and failing cardiac myocytes during the late portion of the AP plateau via reverse mode NCX. In (normal) myocytes with good SR 21 21 21 function, this Ca influx helps maintain and regulate SR Ca load. In (failing) human myocytes with poor SR function this Ca influx 21 directly contributes to contraction. These studies suggest that the Ca transient of the failing human ventricular myocytes has a higher 21 than normal reliance on Ca influx via the reverse mode of the NCX during the terminal phases of the AP.  2003 Published by Elsevier Science B.V. on behalf of European Society of Cardiology.