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[(\(CEUA/B/UNICAMP,)-288.8(Brazi)-9(l,)-275.4(No.)-283(4429-1\).)]TJ
1.0137 -1.1116 TD
[(Hypothyroidism)-564.9(was)-563.8(induced)-563.1(in)-555.3(Sprague)-562.8(Dawley)-563.7(rats)]TJ
-1.0137 -1.1116 TD
[(\(200)-171.4(g\).)-195.7(Primary)-200.1(hypothyroidism)-201.1(was)-201(induced)-200.2(by)-198(the)-194.7(addition)]TJ
25.5097 67.9242 TD
[(of)-572.4(0.02%)-573.3(propylthiouracil)-573.5(\(PTU;)-577.7(SigmaAldrich\))-578.7(to)-572.5(the)]TJ
0 -1.1174 TD
[(drinking)-348.9(water)-348.6(for)-348.8(six)-348.8(weeks,)-351.8(which)-347.5(is)-347.7(a)-353.6(widely)-348.7(used,)-348.6(well)]TJ
0 -1.1116 TD
[(characterized)-287.6(animal)-281.1(model)-284.5(of)-284.4(primary)-280.9(hypothyroidism.)-285.2(For)]TJ
T*
[(induction)-218.8(of)-215.3(central)-224.5(hypothyroidism,)-216.1(animals)-218.7(were)-220.7(treated)-224.5(by)]TJ
T*
[(daily)-271.9(gavage)-280.8(with)-276.2(bexarotene)-275(\(BXT\))-279.3(for)-273.9(six)-273.9(weeks)-279.2(at)-274.2(a)-273(dose)]TJ
0 -1.1174 TD
[(of)-307.4(50)-163.5(mg/kg,)-309.8(which)-312.9(was)-310.4(the)-304.1(lowest)-314(tested)-308.5(dose)-310.6(that)-311.1(induced)]TJ
0 -1.1116 TD
[(hypothyroidism)-362.4(in)-365.2(100%)-362.6(of)-359.3(the)-361.7(animals)-368.4(in)-359.4(preliminary)-367.3(ex-)]TJ
T*
[(periments.)-328(Previous)-332.3(tests)-329.1(also)-328(showed)-325.2(an)-331.7(absence)-328.9(of)-324.7(differ-)]TJ
0 -1.1174 TD
[(ences)-475.3(between)-478.7(rats)-477.8(receiving)-480.2(daily)-473.5(gavage)-476.6(with)-477.8(dimethyl)]TJ
0 -1.1116 TD
[(sulfoxide,)-268(which)-272.6(was)-270.1(used)-270.3(to)-267.3(dissolve)-269(BXT,)-269(and)-269.4(non-treated)]TJ
T*
(controls.)Tj
1.0137 -1.1174 TD
[(Animals)-229.9(were)-226.4(weighed)-229.9(weekly,)-232.2(and)-229.1(body)-229(temperature)-231.3(was)]TJ
-1.0137 -1.1116 TD
[(taken)-353.5(as)-360.3(that)-357.2(measured)-358.9(from)-356.9(the)-355.9(outer)-352.3(ear)-356.9(with)-356.9(an)-360.5(infrared)]TJ
T*
[(thermometer.)-183(Blood)-185.2(samples)-183.8(were)-180.4(collected)-187.7(from)-184.1(the)-177.4(tail)-184.5(vein)]TJ
T*
[(under)-219.7(light)-219(anesthesia)-228.6(\(with)-219.7(isouorane\),)-224.9(and)-223.3(hormone)-217.4(levels)]TJ
0 -1.1174 TD
[(were)-422.3(determined)-424.9(with)-420.2(T4)-423.9(and)-419.2(TSH)-425.7(enzyme-linked)-423.6(immu-)]TJ
0 -1.1116 TD
[(nosorbent)-477.5(assay)-479.7(kits)-471(\(Diametra)-482.2(and)-476.8(Demeditec)-483.5(Diagnosis)]TJ
T*
[(Gmbh,)-418.9(respectively\))-422.3(following)-420.1(the)-419.3(manufacturers)-424.3(instruc-)]TJ
0 -1.1174 TD
[(tions.)-331.5(After)-341.7(six)-331.5(weeks,)-340.3(the)-332.9(animals)-339.6(were)-335.9(killed)-336.5(by)-336.3(heart)-336.2(re-)]TJ
0 -1.1116 TD
[(moval)-451.5(under)-450.1(deep)-456(anesthesia)-453.3(with)-454.8(ketamine)-451.5(and)-453.7(xylazine)]TJ
T*
[(\(50)-164.5(mg/kg)-415.8(and)-419.2(1.5)-166.9(mg/kg,)-419.2(respectively,)-418.9(administered)-421.3(intra-)]TJ
0 -1.1174 TD
[(peritoneally)-426.1([i.p.]\).)-430.5(The)-426.1(thyroid)-428.4(glands)-422.4(were)-428(removed)-431.7(and)]TJ
0 -1.1116 TD
[(immersed)-457(in)-457.3(4%)-458.3(paraformaldehyde.)-460.1(After)-462.6(xation,)-455.9(30)]TJ
/F7 1 Tf
22.9582 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
(m)Tj
-23.5111 -1.1116 TD
[(sections)-281.7(were)-284(stained)-280.8(with)-282(hematoxylin)-286.8(and)-280.9(eosin.)]TJ
/F11 1 Tf
8.9663 0 0 8.9663 310.8472 445.6629 Tm
[(In)-330.4(vivo)]TJ
/F1 1 Tf
3.2689 0 TD
[(electrophysiological)-338.2(experiments)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 429.2219 Tm
[(ECG)-271.4(recording)-277.3(was)-270.1(carried)-276.2(out)-274.1(in)-273(conscious)-271.2(animals)-276.3(with)]TJ
-1.0137 -1.1116 TD
[(permanent)-187.5(surgical)-195.5(steel)-186.4(electrodes)-194.3(inserted)-189.7(under)-190.9(anesthesia,)]TJ
0 -1.1174 TD
[(positioned)-196.7(in)-198.2(the)-200.4(DII)-194.2(lead,)-200.4(and)-200.3(connected)-199(by)-198(exible)-200.2(cables)-200.1(to)]TJ
0 -1.1116 TD
[(a)-411.2(differential)-414.6(amplier)-415.6(MP35)-408.3(\(Biopac)-414.3(Systems,)-416.3(Inc.\).)-409.8(The)]TJ
T*
[(signal)-192.1(was)-189.5(ltered)-194.4(at)-193.6(100)-164.6(Hz)-194.3(and)-188.8(digitized)-197.1(at)-187.8(1)-168.1(kHz)-195.4(using)-189.8(BSL)]TJ
0 -1.1174 TD
[(Pro)-429.3(v3.7)-433(\(Biopac)-437.4(Systems,)-439.3(Inc.\).)-432.8(The)-431.9(measurements)-440.5(were)]TJ
0 -1.1116 TD
[(performed)-359(blinded)-360.5(to)-359.4(the)-355.9(experimental)-365(groups.)-361.2(The)-357(QT)-361.4(in-)]TJ
T*
[(terval)-216.5(was)-224(measured)-220.7(from)-218.7(the)-217.7(beginning)-218.7(of)-215.3(the)-223.5(QRS)-218.2(complex)]TJ
0 -1.1174 TD
[(to)-261.5(the)-258(end)-263.6(of)-261.4(the)-258(T)-261.5(wave)-266.8(and)-257.9(was)-264.3(corrected)-262.3(for)-262.4(the)-263.8(heart)-261.4(rate)]TJ
0 -1.1116 TD
[(using)-281.9(the)-281.1(Bazzet)-283.1(formula,)-284.3(QTc)]TJ
/F6 1 Tf
12.631 0 TD
(=)Tj
/F4 1 Tf
.72 0 TD
(QT/)Tj
/F12 1 Tf
1.6127 0 TD
(O)Tj
/F4 1 Tf
.6336 0 TD
(R-R.)Tj
-14.5836 -1.1116 TD
[(At)-389.1(the)-390.5(end)-390.4(of)-393.8(the)-390.5(six-week)-397.8(experimental)-393.8(period,)-391.4(the)-396.2(ar-)]TJ
-1.0137 -1.1116 TD
[(rhythmia)-478(vulnerability)-478(test)-477.9(was)-477.4(performed)-479.9(in)-474.6(control)-481.4(and)]TJ
0 -1.1174 TD
[(hypothyroid)-190.9(rats)-189.8(under)-190.9(isourane)-196.3(anesthesia.)-197.5(A)-186.3(baseline)-196.7(ECG)]TJ
0 -1.1116 TD
[(was)-316.2(recorded)-323.3(for)-320(three)-319(minutes,)-324.6(and)-315.5(then)-322.5(rats)-316.5(were)-324.4(injected)]TJ
T*
[(with)-512.4(caffeine)-514.6(\(120)-171.4(mg/kg)-508(i.p.\))-517.1(and)-511.3(dobutamine)-515.9(\(50)]TJ
/F7 1 Tf
21.956 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
(g/kg)Tj
-22.5089 -1.1174 TD
[(administered)-225.5(intravenously\).)-222.9(The)-218.8(ECG)-225.3(was)-224(then)-218.8(recorded)-225.3(for)]TJ
0 -1.1116 TD
[(10)-232.6(minutes,)-244(and)-234.9(the)-240.7(incidence)-239.5(of)-238.3(arrhythmias)-240.3(was)-235.5(quantied.)]TJ
/F11 1 Tf
8.9663 0 0 8.9663 310.8472 226.4315 Tm
[(Ventricular)-333(myocyte)-335(isolation)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 209.9905 Tm
[(Cardiac)-283(myocytes)-288.8(were)-289.8(isolated)-282(in)-284.6(a)-284.5(Langendorff)-292(appara-)]TJ
-1.0137 -1.1116 TD
[(tus,)-283.1(as)-285.4(previously)-288.7(described)-289.8(\(10,11\).)-284.1(The)-287.9(hearts)-291.1(were)-284(moun-)]TJ
0 -1.1174 TD
[(ted)-620.9(through)-618.3(the)-620.9(aorta)-624.2(on)-618.5(a)-618.5(Langendorff)-626.1(apparatus)-623.8(and)]TJ
0 -1.1116 TD
.0128 Tc
[(pe)-6.7(rf)-5.5(use)-6.7(d)-322.4(re)-6.7(tr)-5.5(og)-5.6(rad)-5.6(e)-1(l)-5.7(y)-322.4(wi)-5.7(th)-322.4(T)-6.8(yro)-5.6(de)-323.5(s)-5.4(o).2(l)-5.7(u).2(t)-5.7(i).1(o)-5.6(n)-322.4(con)-5.6(t).1(a)-6.7(i).1(n)-5.6(i).1(ng)-328.1(\(in)]TJ
T*
.0149 Tc
[(mmol/L\):)-458.6(N)1.4(a)-4.6(C)1.3(l)-452.9(1)-3.5(18,)-455.1(K)1.4(Cl)-458.6(5.4,)-455.1(NaH)-4.3(C)1.3(O)]TJ
7.3823 0 0 6.5614 476.7306 164.5228 Tm
0 Tc
(3)Tj
9.843 0 0 9.843 485.0078 166.1669 Tm
.0184 Tc
[(24)5.8(,)-451.6(M)-.9(g)5.8(C)4.8(l)]TJ
7.3823 0 0 6.5614 525.8267 164.5228 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 529.6818 166.1669 Tm
.0132 Tc
[(1.02)-5.2(,)]TJ
-22.2325 -1.1116 TD
.0136 Tc
[(Ca)-5.9(Cl)]TJ
7.3823 0 0 6.5614 331.7101 153.5811 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 340.044 155.2252 Tm
.0166 Tc
[(1.8)4(,)-453.4(NaH)]TJ
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0 Tc
(2)Tj
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.0182 Tc
(PO)Tj
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0 Tc
(4)Tj
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.0126 Tc
[(0)-5.8(.)-2.3(42)-5.8(,)-457.4(d)0(e)-6.9(x)0(tr)-5.7(os)-5.6(e)-456.2(1)-5.8(2,)-457.4(a)-6.9(n)0(d)-460.8(t)-.1(a)-6.9(u)0(r)-5.7(i)-.1(ne)-462(20)-5.8(,)]TJ
-9.4517 -1.1174 TD
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[(bubbled)-204.8(with)-201.4(95%)-206(O)]TJ
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(2)Tj
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[(and)-206.1(5%)-204.8(CO)]TJ
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(2)Tj
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[(,)-199.3(p)0(H)-204.7(7.4,)-204.9(at)-205.1(37)]TJ
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[(C,)-207.2(followed)]TJ
-19.606 -1.1116 TD
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(2)Tj
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[(to)-336.4(which)]TJ
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[(collagenase)-559.4(type)-552.9(II)-555.1(\(0.5)-168(mg/mL\))-551.8(and)-557.4(protease)-553.6(type)-558.6(XIV)]TJ
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[(\(0.03)-163.3(mg/mL\))-258(were)-261(added)-255.5(later.)-259.2(Hearts)-263.1(were)-255.2(nally)-261.3(perfused)]TJ
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[(with)-270.5(KB)-274.8(solution)-268.2(\(in)-274.1(mmol/L\):)-272(taurine)-275.2(10,)-270.6(glutamic)-271.9(acid)-271.8(70,)]TJ
T*
[(creatine)-319(0.5,)-320.1(succinic)-323.4(acid)-317.9(5,)-321.3(dextrose)-316.3(10,)-322.4(KH)]TJ
7.3823 0 0 6.5614 495.0424 87.8173 Tm
(2)Tj
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(PO)Tj
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(4)Tj
9.843 0 0 9.843 518.1164 89.4614 Tm
[(10,)-316.7(KCl)]TJ
-21.0575 -1.1174 TD
[(20,)-380(HEPES)]TJ
7.3823 0 0 6.5614 356.9385 82.885 Tm
(-)Tj
9.843 0 0 9.843 359.3763 78.463 Tm
(K)Tj
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7.3823 0 0 6.5614 366.4629 82.885 Tm
(+)Tj
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9.843 0 0 9.843 374.2865 78.463 Tm
[(10,)-380(EGTA)]TJ
7.3823 0 0 6.5614 416.6361 82.885 Tm
(-)Tj
9.843 0 0 9.843 419.0739 78.463 Tm
(K)Tj
/F6 1 Tf
7.3823 0 0 6.5614 426.1605 82.885 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 433.9841 78.463 Tm
[(0.2,)-383.4(pH)-377.4(adjusted)-385.6(to)-382.5(7.4)-380(with)]TJ
-12.5101 -1.1116 TD
[(KOH.)-205.2(Then,)-206(the)-206.2(ventricular)-211.8(cardiomyocytes)-205.7(were)-209.2(dissociated)]TJ
T*
[(by)-307.5(mechanical)-312.1(agitation.)-309.9(When)-313.1(isolated)-310.8(for)-308.5(cardiac)-312(calcium)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 59.7543 749.7069 Tm
[(TSH)-335.2(AND)-337.2(CARDIAC)-336.6(ARRHYTHMIA)]TJ
53.0113 0 TD
(935)Tj
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[(handling)-413.4(experiments,)-412(EGTA)-411.7(was)-408.3(not)-412.4(included)-408.8(in)-411.3(the)-407.8(KB)]TJ
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[(In)-336.7(vitro)]TJ
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[(electrophysiology)-339.8(patch-clamp)-335.2(experiments)]TJ
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[(All)-211.8(experiments)-218.5(were)-214.9(performed)-215(at)-216.6(room)-212.9(temperature)-214(\(20)]TJ
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[(C\).)-185.2(Following)-183.8(the)-183.1(patch)-180.8(rupture,)-185.2(the)-183.1(whole-cell)-182.8(membrane)]TJ
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[(capacitance)-394.9(was)-385.3(measured)-387.7(by)-388.1(integration)-389.3(of)-382.3(the)-390.5(capacitive)]TJ
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[(transients)-474.1(elicited)-479.3(by)-468.7(voltage)-471.1(steps)-478.7(from)]TJ
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[(Series)-227.5(resistance)-228.6(was)-224(compensated)-225.3(80%)-223.2(in)-221.2(order)-225.5(to)-221.2(minimize)]TJ
T*
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[(Ionic)-294.7(currents)-299(were)-295.6(recorded)-300.2(using)-293.4(the)-292.6(whole-cell)-303.7(cong-)]TJ
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[(uration)-677.2(with)-679.4(an)-677.2(Axopatch)-680.3(200B)-679.3(patch-clamp)-680.6(amplier)]TJ
T*
[(\()-81.7(Molecular)-342.8(Devices\).)-339.1(Recording)-335.9(pipettes)-339.6(pulled)-336.3(from)-333.9(boro-)]TJ
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[(silicate)-479.2(tubes)-473.1(\(Sutter)-475.4(Instruments\))-476.2(had)-471(a)-474.6(tip)-475.9(resistance)-476.3(of)]TJ
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[(13)-170.3(M)]TJ
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[(when)-363.5(lled)-369.6(with)-368.4(the)-361.7(internal)-368.6(solution.)-369.5(The)-368.5(pipette)]TJ
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[(solution)-250.9(used)-253(for)-250.9(I)]TJ
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(to)Tj
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[(and)-252.1(I)]TJ
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(Ca-L)Tj
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[(recording)-254.2(was)-252.8(\(in)-245.3(mmol/L\):)-254.7(L-)]TJ
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[(aspartic)-219.7(acid)-220(\(potassium)-220.6(salt\))-219.8(80,)-218.7(KH)]TJ
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(2)Tj
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(PO)Tj
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[(10,)-218.7(MgSO)]TJ
7.3823 0 0 6.5614 269.3479 542.6644 Tm
(4)Tj
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[(1,)-217.6(KCl)]TJ
-21.6565 -1.1174 TD
[(50,)-310.9(HEPES)]TJ
7.3823 0 0 6.5614 107.433 537.6755 Tm
(-)Tj
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(K)Tj
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[(5,)-309.8(ATP)]TJ
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(-)Tj
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(Na)Tj
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(2)Tj
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[(3,)-309.8(EGTA)]TJ
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(K)Tj
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[(10,)-305.1(pH)-314.1(adjusted)-310.7(to)]TJ
-16.7723 -1.1116 TD
[(7.2)-345.5(with)-345.4(KOH.)-343.4(For)-348.7(the)-344.4(current)-344.2(carried)-351.1(by)-342(NCX)-345.9(\(I)]TJ
7.3823 0 0 6.5614 264.359 520.7243 Tm
(NCX)Tj
9.843 0 0 9.843 279.8928 522.3683 Tm
[(\),)-344.3(the)]TJ
-22.1345 -1.1116 TD
[(internal)-316.8(solution)-320(was:)-317.4(CsCl)-317.4(115,)-317.8(NaCl)-318.6(10,)-316.7(TEA-Cl)-316.3(10,)-316.7(Mg-)]TJ
0 -1.1174 TD
[(ATP)-183.8(5,)-188.8(MgCl)]TJ
7.3823 0 0 6.5614 114.5763 498.7841 Tm
(2)Tj
9.843 0 0 9.843 120.0755 500.4282 Tm
[(0.5,)-187.6(HEPES)-187(10,)-184.2(pH)-181.6(adjusted)-189.8(to)-186.6(7.2)-184.2(with)-184.1(CsOH.)]TJ
-4.8842 -1.1116 TD
[(For)-227.7(I)]TJ
7.3823 0 0 6.5614 91.1622 487.8424 Tm
(to)Tj
9.843 0 0 9.843 99.1559 489.4865 Tm
[(recording,)-234.6(the)-229.2(bath)-230.3(solution)-227.9(was)-229.8(\(in)-233.8(mmol/L\):)-225.9(NaCl)]TJ
-3.7726 -1.1116 TD
[(86,)-385.8(MgCl)]TJ
7.3823 0 0 6.5614 101.0834 476.9007 Tm
(2)Tj
9.843 0 0 9.843 108.5669 478.5447 Tm
[(1,)-384.7(HEPES)]TJ
7.3823 0 0 6.5614 149.7826 482.9101 Tm
(-)Tj
9.843 0 0 9.843 152.2771 478.5447 Tm
(Na)Tj
/F6 1 Tf
7.3823 0 0 6.5614 163.7291 482.9101 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 171.6094 478.5447 Tm
[(10,)-385.8(KCl)-385.5(4,)-390.4(CaCl)]TJ
7.3823 0 0 6.5614 239.4141 476.9007 Tm
(2)Tj
9.843 0 0 9.843 246.8976 478.5447 Tm
[(0.5,)-383.4(CoCl)]TJ
7.3823 0 0 6.5614 286.2425 476.9007 Tm
(2)Tj
9.843 0 0 9.843 293.7259 478.5447 Tm
(2,)Tj
-23.5399 -1.1174 TD
[(dextrose)-258.7(11,)-253.3(TEA-Cl)-258.7(50,)-259.1(pH)-256.5(adjusted)-253.1(to)-255.8(7.4)-259.1(with)-253.2(NaOH.)-259.3(For)]TJ
0 -1.1116 TD
(I)Tj
7.3823 0 0 6.5614 65.3102 454.9605 Tm
(Ca)Tj
9.843 0 0 9.843 73.5307 456.6046 Tm
[(-L,)-329.3(the)-327.1(solution)-331.6(composition)-331.5(was)-327.7(\(in)-325.9(mmol/L\):)-335.4(NaCl)-330.1(86,)]TJ
-1.1692 -1.1116 TD
(MgCl)Tj
7.3823 0 0 6.5614 84.9826 444.0188 Tm
(2)Tj
9.843 0 0 9.843 92.0126 445.6629 Tm
[(1,)-338.6(HEPES)]TJ
7.3823 0 0 6.5614 132.7748 450.0282 Tm
(-)Tj
9.843 0 0 9.843 135.2126 445.6629 Tm
(Na)Tj
/F6 1 Tf
7.3823 0 0 6.5614 146.7212 450.0282 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 154.0913 445.6629 Tm
[(10,)-339.7(KCl)-333.6(4,)-338.6(CaCl)]TJ
7.3823 0 0 6.5614 220.422 444.0188 Tm
(2)Tj
9.843 0 0 9.843 224.107 445.6629 Tm
[(1.8,)-337.4(TEA-Cl)-339.3(50,)-339.7(4-)]TJ
-16.467 -1.1116 TD
[(aminoprirydine)-549.2(4,)-540.2(dextrose)-540.9(11,)-541.3(pH)-544.5(adjusted)-546.9(to)-538(7.4)-541.3(with)]TJ
0 -1.1174 TD
[(NaOH.)-547.3(Voltage)-541.1(pulses)-543.2(\(500)-171.4(ms)-538.9(long\))-541.3(to)-543.7(a)-543.7(test)-541.3(potential)]TJ
0 -1.1116 TD
[(ranging)-412.2(from)]TJ
/F6 1 Tf
5.8288 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(30)-405.4(to)]TJ
/F6 1 Tf
2.5976 0 TD
(+)Tj
/F4 1 Tf
.5529 0 TD
[(50)-163.5(mV,)-410.9(starting)-413.3(from)-408.7(a)-405.4(holding)-411.2(po-)]TJ
-9.5323 -1.1116 TD
[(tential)-321.6(of)]TJ
/F6 1 Tf
3.9915 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(60)-163.5(mV,)-318.8(were)-324.4(applied)-315.6(at)-320.3(a)-319(frequency)-318.6(of)-318.9(0.1)-166.9(Hz)-321(to)]TJ
-4.5444 -1.1174 TD
[(ensure)-314(the)-315.6(full)-309.9(channel)-316.6(recovery)-317.5(from)-310.8(inactivation,)-320.3(whereas)]TJ
0 -1.1116 TD
[(for)-193.3(I)]TJ
7.3823 0 0 6.5614 78.6897 378.255 Tm
(Ca)Tj
9.843 0 0 9.843 86.9102 379.8991 Tm
[(-L)-199.2(recording,)-194.3(the)-194.7(500)-164.6(ms)-193.3(test)-195.7(pulses)-197.6(were)-197.6(preceded)-197.7(by)-192.3(a)]TJ
-2.5285 -1.1116 TD
[(40)-169.2(ms)-279.7(pre-pulse)-282.8(to)]TJ
/F6 1 Tf
7.6834 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(40)-169.2(mV.)]TJ
-7.2227 -1.1174 TD
[(For)-210.5(recording)-208.1(I)]TJ
7.3823 0 0 6.5614 130.8472 356.3149 Tm
(NCX)Tj
9.843 0 0 9.843 146.3811 357.959 Tm
[(,)-210.8(the)-211.9(external)-208.4(solution)-210.6(was)-212.5(\(in)-205(mmol/L\):)]TJ
-8.5704 -1.1116 TD
[(CsCl)-208(10,)-213(NaCl)-209.2(130,)-208.3(MgCl)]TJ
7.3823 0 0 6.5614 163.2188 345.3731 Tm
(2)Tj
9.843 0 0 9.843 168.9448 347.0172 Tm
[(0.5,)-210.7(CaCl)]TJ
7.3823 0 0 6.5614 206.0787 345.3731 Tm
(2)Tj
9.843 0 0 9.843 211.8047 347.0172 Tm
[(1,)-211.9(HEPES)-210(10,)-207.2(dextrose)]TJ
-15.2171 -1.1116 TD
[(10,)-236(pH)-233.5(adjusted)-235.8(to)-238.5(7.4)-230.3(with)-235.9(NaOH.)-242(The)-230.3(current)-240.5(was)-235.5(recorded)]TJ
0 -1.1174 TD
[(during)-219.8(application)-223.5(of)-221(a)-215.4(ramp)-219.9(from)]TJ
/F6 1 Tf
13.6851 0 TD
(+)Tj
/F4 1 Tf
.5529 0 TD
[(80)-221.1(to)]TJ
/F6 1 Tf
2.2175 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(140)-170.3(mV)-217.4(following)]TJ
-17.0084 -1.1116 TD
[(a)-186.6(150)-170.3(ms)-187.5(step)-184.1(to)]TJ
/F6 1 Tf
6.4221 0 TD
(+)Tj
/F4 1 Tf
.5529 0 TD
[(80)-169.2(mV,)-186.3(from)-184.1(a)-186.6(holding)-192.3(potential)-185.6(of)]TJ
/F6 1 Tf
13.8463 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(90)-169.2(mV,)]TJ
-21.3743 -1.1116 TD
[(after)-226.8(sequential)-233.6(pre-pulses)-226.1(to)]TJ
/F6 1 Tf
11.7152 0 TD
(-)Tj
/F4 1 Tf
.5529 0 TD
[(45)-226.8(and)-229.1(0)-162.4(m)0(V)-228.9(t)0(o)-227(inactivate)-229.3(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 297.0708 307.559 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 62.022 292.2519 Tm
[(and)-315.5(Ca)]TJ
7.3823 0 0 6.5614 90.3685 296.6172 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 101.2535 292.2519 Tm
[(channels,)-315.2(respectivel)-11.2(y.)-315.6(The)-316.7(protocol)-315.5(was)-316.2(repeated)]TJ
-3.9857 -1.1174 TD
[(in)-353.7(the)-355.9(presence)-364.6(of)-353.5(10)-169.2(mM)-355.7(NiCl)]TJ
7.3823 0 0 6.5614 189.1275 279.6094 Tm
(2)Tj
9.843 0 0 9.843 196.3275 281.2535 Tm
[(to)-353.7(inhibit)-359.6(NCX.)-355.1(I)]TJ
7.3823 0 0 6.5614 266.7968 279.6094 Tm
(NCX)Tj
9.843 0 0 9.843 285.8456 281.2535 Tm
(was)Tj
-22.7393 -1.1116 TD
[(considered)-337(as)-337.2(the)-332.9(difference)-338.2(of)-336.2(the)-332.9(currents)-333.6(recorded)-340.5(in)-330.6(the)]TJ
T*
[(absence)-282.9(and)-280.9(presence)-289.7(of)-278.6(Ni)]TJ
7.3823 0 0 6.5614 171.2125 263.7354 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 178.9795 259.37 Tm
(.)Tj
-10.8686 -1.1174 TD
[(The)-195.7(voltage-clamp)-199.1(experimental)-198(protocols)-195.4(were)-191.9(controlled)]TJ
-1.0137 -1.1116 TD
[(with)-333.8(the)-327.1()50.8(Clampex)43()-329.4(program,)-330.3(and)-332.8(current)-332.6(recordings)-330(were)]TJ
T*
[(analyzed)-370.7(with)-374.2(the)-367.5()50.8(Clampt)44.2()-363.9(program)-372.9(of)-370.8(the)-367.5(pClamp10.2)]TJ
0 -1.1174 TD
[(software)-616.6(\()-87.5(Molecular)-619.3(Devices\).)-615.5(Current)-620.5(amplitudes)-613.8(were)]TJ
0 -1.1116 TD
[(normalized)-286.7(to)-278.8(cell)-283.5(capacitance)-285.5(and)-280.9(expressed)-283.7(as)-285.4(pA/pF.)]TJ
/F11 1 Tf
8.9663 0 0 8.9663 62.022 182.6078 Tm
[(Measurement)-332.1(of)-336.7([Ca)]TJ
6.7246 0 0 5.9768 144 186.5763 Tm
(2)Tj
/F6 1 Tf
.5564 0 TD
(+)Tj
/F11 1 Tf
8.9663 0 0 8.9663 151.4834 182.6078 Tm
(])Tj
6.7246 0 0 5.9768 153.9779 181.0771 Tm
(i)Tj
/F4 1 Tf
9.843 0 0 9.843 72 166.1669 Tm
[(After)-318.6(24)-319(hours)-316.3(of)-318.9(incubation)-319(at)-314.5(4)]TJ
/F6 1 Tf
13.5353 0 TD
()Tj
/F4 1 Tf
.3974 0 TD
[(C)-318.9(with)-316.6(EGTA-free)-321.6(KB)]TJ
-14.9464 -1.1116 TD
[(solution)-354.6(with)-356.9(or)-347.7(without)-354.6(30)-353.5(mIU/L)-354.5(TSH,)-354.2([Ca)]TJ
7.3823 0 0 6.5614 245.9905 159.5905 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 253.7574 155.2252 Tm
(])Tj
7.3823 0 0 6.5614 257.0456 153.5811 Tm
(i)Tj
9.843 0 0 9.843 262.6015 155.2252 Tm
[(was)-356.5(mea-)]TJ
-20.3778 -1.1174 TD
[(sured)-403.9(in)-405.5(rat)-402(myocytes)-404(loaded)-406.5(with)-403(indo-1)-404.1(AM)-401.4(\()-81.7(Molecular)]TJ
0 -1.1116 TD
[(Probes\))-308(for)-302.7(15)-307.5(minutes)-303.9(followed)-310.6(by)-301.7(30)-301.7(minutes)-309.7(of)-301.7(washout.)]TJ
T*
[(Cells)-560.7(were)-566.3(perfused)-558.1(at)-562.2(2224)]TJ
/F6 1 Tf
12.9248 0 TD
()Tj
/F4 1 Tf
.3974 0 TD
[(C)-560.8(with)-558.5(Tyrodes)-563.8(solution)]TJ
-13.3222 -1.1174 TD
[(containing)-249.9(1)-168.1(mmol/L)-246.7(CaCl)]TJ
7.3823 0 0 6.5614 167.3574 109.7007 Tm
(2)Tj
9.843 0 0 9.843 171.0425 111.3448 Tm
[(.)-245.3(The)-247.6(uorescence)-253.7(emission)-247.2(ratio)]TJ
-11.0759 -1.1116 TD
[(at)-245.4(410)-239.5(and)-240.6(485)-170.3(nm)-239.6(under)-242.8(360)-170.3(nm)-239.6(excitation)-245.4(was)-247.1(converted)-243.9(to)]TJ
T*
([Ca)Tj
7.3823 0 0 6.5614 76.3086 93.8268 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 84.0755 89.4614 Tm
(])Tj
7.3823 0 0 6.5614 87.3637 87.8173 Tm
(I)Tj
9.843 0 0 9.843 89.8015 89.4614 Tm
[(,)-418.1(a)0(s)-417.9(described)-422.2(elsewhere)-418.5(\(11\).)-416.7(Ca)]TJ
7.3823 0 0 6.5614 228.1322 93.8268 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 240.0377 89.4614 Tm
[(transients)-416.5(were)]TJ
-18.0855 -1.1174 TD
[(recorded)-553.6(after)-555.1(interruption)-556.2(of)-555.1(1)-162.4(H)0(z)-557.2(electrical)-558.7(stimulation)]TJ
0 -1.1116 TD
[(followed)-247.2(by)-244.1(switching)-248.3(perfusion)-247.1(to)-250(normal)-245.2(or)-244.1(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 254.7779 71.8866 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 258.8598 67.5212 Tm
.2453 Tc
[(,C)245.3(a)]TJ
7.3823 0 0 6.5614 274.6771 71.8866 Tm
0 Tc
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 282.444 67.5212 Tm
(-free)Tj
-22.3937 -1.1116 TD
[(Tyrode)-492.8(solution)-498.6(containing)-491.8(10)-169.2(mmol/L)-494.3(caffeine.)-495(The)-495.2(rate)]TJ
25.504 67.9242 TD
[(constant)-276.2(of)-272.9([Ca)]TJ
7.3823 0 0 6.5614 373.8329 729.5242 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 381.5999 725.1588 Tm
(])Tj
7.3823 0 0 6.5614 384.8881 723.5148 Tm
(i)Tj
9.843 0 0 9.843 389.6503 725.1588 Tm
[(decline)-270.6(\(K\))-274.8(was)-275.8(determined)-275.2(by)-272.9(nonlinear)]TJ
-7.7814 -1.1174 TD
[(curve)-192.1(t.)-184.1(Sustained)-190.7(activation)-187.8(of)-186.5(sarcoplasmic)-191.7(reticulum)-192.4(\(SR\))]TJ
0 -1.1116 TD
(Ca)Tj
7.3823 0 0 6.5614 324.0566 707.5841 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 335.6786 703.2188 Tm
[(release)-398.2(channels)-398.1(by)-388.1(caffeine)-399.4(prevents)-396.9(net)-390.5(Ca)]TJ
7.3823 0 0 6.5614 519.1369 707.5841 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 530.7589 703.2188 Tm
(accu-)Tj
-22.1173 -1.1116 TD
[(mulation)-432.1(in)-428.5(the)-430.8(organelle,)-431.8(so)-428.2(that)-426.3(most)-431.8(of)-428.4([Ca)]TJ
7.3823 0 0 6.5614 506.2109 696.6423 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 514.0345 692.277 Tm
(])Tj
7.3823 0 0 6.5614 517.266 690.6329 Tm
(i)Tj
9.843 0 0 9.843 523.5589 692.277 Tm
(decline)Tj
-21.3858 -1.1116 TD
[(should)-323.3(be)-320.1(carried)-328(by)-319(the)-321.4(NCX,)-326.3(if)-319.1(the)-321.4(external)-323.6(solution)-325.8(con-)]TJ
0 -1.1174 TD
[(tains)-340.8(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 346.507 674.7021 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 350.5889 670.3369 Tm
[(,)-331.7(whereas)-340.2(the)-332.9(exchanger)-337.1(is)-336.2(thermodynamically)-337.4(in-)]TJ
-3.8129 -1.1116 TD
[(hibited)-262.7(in)-255.8(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 364.7621 663.7605 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 368.844 659.3951 Tm
[(-free)-261.2(medium.)-255.7(Thus,)-256.5(the)-258(ratio)-260.3(of)-255.6(K)-255.4(determined)]TJ
-5.6676 -1.1116 TD
[(in)-255.8(the)-252.3(presence)-255.1(and)-257.9(absence)-254.1(of)-249.8(extracellular)-262.5(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 499.5211 652.8187 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 506.0975 648.4534 Tm
[(can)-253.3(be)-256.8(used)]TJ
-19.6118 -1.1174 TD
[(as)-227.8(an)-228(index)-225.7(of)-226.8(the)-223.5(NCX)-225(activity)-230.5(in)-227(the)-223.5(Ca)]TJ
7.3823 0 0 6.5614 474.0093 641.877 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 483.9873 637.455 Tm
[(efux)-225.3(mode)-225.7(\(12\).)]TJ
-16.3518 -1.1116 TD
[(The)-357(effect)-361.5(of)]TJ
/F7 1 Tf
5.7539 0 TD
(b)Tj
/F4 1 Tf
.5529 0 TD
[(-adrenergic)-362.4(stimulation)-354.8(at)-360.6(inducing)-355.8(spon-)]TJ
-7.3206 -1.1116 TD
[(taneo)-8(us)-382.1(activity)-380.3(was)-385.3(assessed)-385.9(by)-382.3(determination)-388.2(of)-382.3(concen-)]TJ
0 -1.1174 TD
[(trationeffect)-222.1(curves)-216.1(to)-209.7(isoproterenol)-218.4(\(ISO\),)-211.1(in)-215.4(which)-215(the)-211.9(rate)]TJ
0 -1.1116 TD
[(of)-290.1(spontaneous)-290.7(Ca)]TJ
7.3823 0 0 6.5614 386.6456 597.9967 Tm
(2)Tj
/F6 1 Tf
.4992 0 TD
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 397.2471 593.6313 Tm
[(transients)-289.8(was)-287.4(measured)-289.8(after)-290.1(interrup-)]TJ
-8.5532 -1.1116 TD
[(tion)-281.1(of)-284.4(electrical)-282.3(stimulation)-9.2(.)]TJ
/F11 1 Tf
8.9663 0 0 8.9663 313.0582 555.1935 Tm
[(Quantitative)-339(real-time)-332.8(polymerase)-338(chain)-332.2(reaction)]TJ
/F4 1 Tf
9.843 0 0 9.843 323.0361 538.7526 Tm
[(This)-310.8(study)-310.7(conforms)-310.5(to)-307.6(the)-309.9(principles)-313(outlined)-309.9(in)-307.6(the)-309.9(De-)]TJ
-1.0137 -1.1116 TD
[(claration)-319(of)-307.4(Helsinki)-316.3(and)-309.7(was)-310.4(approved)-310.6(by)-313.2(the)-309.9(Ethics)-314.3(Com-)]TJ
T*
[(mittee)-327.3(of)-324.7(the)-327.1(Instituto)-327(Nacional)-330.2(de)-320.1(Cardiologia)-332.6(\(CEP-0358/)]TJ
0 -1.1174 TD
[(07-11-)-6.5(2011\).)-216.3(Human)-221.9(right)-224.6(atrial)-222.4(samples)-224.1(were)-220.7(obtained)-224.5(from)]TJ
0 -1.1116 TD
[(patients)-518.2(in)-509.2(sinus)-517.9(rhythm)-509(who)-511(underwent)-520.1(cardiac)-513.6(surgery)]TJ
T*
(\()Tj
/F5 1 Tf
.3341 0 TD
(n)Tj
/F6 1 Tf
.6681 0 TD
(=)Tj
/F4 1 Tf
.72 0 TD
[(8\).)-316.6(Clinical)-323.7(data)-317.9(of)-313.2(the)-321.4(patients)-322.4(are)-316.6(included)-316.7(in)-319.1(Supple-)]TJ
-1.7222 -1.1174 TD
[(mentary)-287.8(Table)-279.9(S1.)]TJ
1.0137 -1.1116 TD
[(Ju)26.8(s)16.4(t)-266.2(a)15(f)16.2(te)25.3(r)-266(e)15(x)16.2(c)15(is)26.7(i)16.1(o)16.2(n,)-252.2(e)15(a)15(c)0(h)-251(s)0(a)25.6(m)15(p)16.2(l)16(e)-267.2(w)0(a)24.6(s)-265.9(c)15(u)16.2(t)-266.2(i)16.1(n)-266(p)16.2(ie)25.3(c)15(e)15(s)-265.9(t)16.1(h)16.2(at)-256.9(w)15.3(e)15(r)16.2(e)]TJ
-1.0137 -1.1116 TD
-.016 Tc
[(i)-16(n)10.5(cub)-16(a)9.4(ted)-166.8(for)-166.8(24)-161.1(ho)-16(u)10.6(r).2(s)-166.7(a)-1(t)-161.2(4)]TJ
/F6 1 Tf
10.0046 0 TD
0 Tc
()Tj
/F4 1 Tf
.3801 0 TD
-.0158 Tc
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T*
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T*
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[(ke)13.9(ep)19.7(in)20.7(g)-237.2(t)0(h)20.7(e)-238.4(AP)-233.3(pa)19.7(ra)19.7(me)18.4(te)19.6(rs)-226.6(\(p)15.1(ea)18.5(k)-237.2(v)0(o)20.8(l)0(t)20.6(a)0(g)19.7(e)0(,)-230.3(m)0(a)18.4(x)0(i)20.7(m)0(u)19.6(m)-238.5(up)15.1(st)20.9(ro)20.9(ke)]TJ
0 -1.1116 TD
[(ve)13.9(lo)20.7(ci)19.5(ty)20.7(,)-233.8(r)0(e)19.7(s)0(t)20.9(i)0(n)15(g)-231.5(me)18.4(mb)19.6(ra)19.7(ne)-222.2(po)15.1(te)19.6(nt)20.7(ia)19.6(l,)-223.5(AP)-221.8(du)15.1(ra)19.7(ti)20.6(on)-221.1(at)-228.1(50)20.8(%)-232.5(a)0(n)19.7(d)]TJ
T*
-.0203 Tc
[(9)-20.3(0)-5.2(%)-604.2(r)-20.3(ep)-20.3(ol)-20.3(ar)-20.3(iz)-20.3(at)-20.3(i)-5.5(o)-20.3(n,)-599.7(a)-20.3(n)-6.4(d)-603.1(t)-20.3(ri)-20.3(an)-20.3(gu)-20.3(la)-20.3(t)-6.5(i)-20.3(on)-20.3(\))-592.7(w)-20.3(it)-20.3(hi)-20.3(n)-598.6(t)-20.3(he)-604.3(n)-20.3(o).5(r)-20.3(m)-.7(a)-20.3(l)]TJ
0 -1.1174 TD
0 Tc
[(ra)14(ng)20.8(e.)-213(Th)19.6(e)-221.1(m)0(a)18.4(i)0(n)-215.4(i)0(o)20.7(n)0(i)20.7(c)-226.9(co)19.7(nd)20.8(uc)19.7(ta)19.6(nc)19.7(es)-216.3(co)19.7(ns)21(id)15(er)19.7(ed)-210.7(we)18.8(re)14(:)-220.1(f)0(a)19.7(s)0(t)-215.2(a)0(n)19.7(d)]TJ
0 -1.1116 TD
[(la)13.8(te)-326(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 88.4976 558.1416 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 95.9244 553.7762 Tm
[(cu)19.7(rr)20.9(en)19.7(ts)-330.4(\(G)]TJ
7.3823 0 0 6.5614 140.5417 552.1321 Tm
(Na)Tj
9.843 0 0 9.843 152.3905 553.7762 Tm
[(an)19.7(d)-340.9(G)]TJ
7.3823 0 0 6.5614 176.7684 552.1321 Tm
[(Na)20.7(L)]TJ
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7.3823 0 0 6.5614 254.2676 552.1321 Tm
0 Tc
(to)Tj
9.843 0 0 9.843 263.2818 553.7762 Tm
(\(G)Tj
7.3823 0 0 6.5614 273.4298 552.1321 Tm
(to)Tj
9.843 0 0 9.843 279.0424 553.7762 Tm
[(\),)-327(I)]TJ
7.3823 0 0 6.5614 291.1747 552.1321 Tm
(Kr)Tj
9.843 0 0 9.843 59.7543 542.8345 Tm
[(an)13.9(d)-208.4(I)]TJ
7.3823 0 0 6.5614 79.1433 541.1904 Tm
(Ks)Tj
9.843 0 0 9.843 89.2913 542.8345 Tm
(\(G)Tj
7.3823 0 0 6.5614 99.4393 541.1904 Tm
(Kr)Tj
9.843 0 0 9.843 109.2472 542.8345 Tm
[(an)19.7(d)-214.2(G)]TJ
7.3823 0 0 6.5614 132.3779 541.1904 Tm
(Ks)Tj
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[(\),)-200.3(in)15(wa)18.8(rd)-203.8(re)19.7(ct)19.6(i)20.9(ed)-205(K)]TJ
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(+)Tj
/F4 1 Tf
9.843 0 0 9.843 224.107 542.8345 Tm
[(cu)19.7(rr)20.9(en)19.7(t)-214.3(\()0(G)]TJ
7.3823 0 0 6.5614 263.7354 541.1904 Tm
(K1)Tj
9.843 0 0 9.843 272.5794 542.8345 Tm
[(\),)-206.1(I)]TJ
7.3823 0 0 6.5614 283.5212 541.1904 Tm
[(NC)24.7(X)]TJ
9.843 0 0 9.843 59.7543 531.8361 Tm
(\(G)Tj
7.3823 0 0 6.5614 69.959 530.2487 Tm
[(NC)24.7(X)]TJ
9.843 0 0 9.843 85.2094 531.8361 Tm
[(\),)-281(Na)]TJ
/F6 1 Tf
7.3823 0 0 6.5614 104.9952 536.2581 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 109.0204 531.8361 Tm
(/K)Tj
/F6 1 Tf
7.3823 0 0 6.5614 118.6582 536.2581 Tm
(+)Tj
/F4 1 Tf
9.843 0 0 9.843 125.6315 531.8361 Tm
[(pu)20.8(mp)-285.7(\(G)]TJ
7.3823 0 0 6.5614 160.8377 530.2487 Tm
[(Na)20.7(K)]TJ
9.843 0 0 9.843 174.5007 531.8361 Tm
[(\),)-281(an)19.7(d)-294.8(I)]TJ
7.3823 0 0 6.5614 203.1306 530.2487 Tm
[(Ca)22.5(-L)]TJ
9.843 0 0 9.843 220.9889 531.8361 Tm
(\(G)Tj
7.3823 0 0 6.5614 231.1369 530.2487 Tm
[(Ca)22.5(-L)]TJ
9.843 0 0 9.843 245.9905 531.8361 Tm
[(\).)-286.7(Al)19.8(l)-295(s)0(i)20.9(m)0(u)19.6(l)0(a)19.6(-)]TJ
-18.9206 -1.1116 TD
[(ti)14.8(on)20.8(s)-427.1(p)0(r)20.9(e)0(s)14.1(e)0(n)19.7(t)0(e)19.6(d)-427.3(in)-417(th)15(is)-416.8(st)20.9(ud)20.8(y)-433.1(w)0(e)18.8(r)0(e)-418(c)0(o)19.7(n)0(d)20.8(u)0(c)19.7(t)0(e)13.8(d)-427.3(us)21(in)20.7(g)-427.3(V)0(i)14.1(r)0(t)20.7(u)0(a)19.7(l)]TJ
T*
[(As)14.4(sa)19.9(y)-220(\()]TJ
/F6 1 Tf
2.9432 0 TD
()Tj
/F4 1 Tf
1.0079 0 TD
[(20)20.8(16)15.1(,)-216.5(U)0(n)20(i)0(v)20.7(e)0(r)13.9(s)0(i)20.9(t)0(y)-209.7(o)0(f)-209.5(O)0(x)20(f)0(o)20.9(r)0(d)20.9(;)-220.1(v.)18.5(1.)18.5(3.)24.3(64)15.1(0)-214.2(2)0(0)15.1(1)0(4)20.8(;)-220.1(Ox)20(fo)20.9(rd)]TJ
-3.9512 -1.1116 TD
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/F5 1 Tf
21.069 0 TD
[(in)-313.3(si)15.1(li)20.6(co)]TJ
/F4 1 Tf
-21.069 -1.1174 TD
[(dr)15.1(ug)-255.6(as)14.1(sa)19.9(ys)21(,)-268.4(k)0(i)15(n)0(d)20.8(l)0(y)-261.5(p)0(r)20.9(o)0(v)20.8(i)0(d)20.7(e)0(d)-262.5(b)0(y)-261.4(B)0(.)-259(R)0(o)19.8(d)0(r)20.9()]TJ
16.012 .0403 TD
()Tj
.2937 -.0403 TD
[(gu)20.8(ez)18.5(.)]TJ
-15.292 -1.1116 TD
[(In)-416.9(or)20.9(de)19.7(r)-421.5(t)0(o)-417(r)0(e)19.7(p)0(r)20.9(o)0(d)20.8(u)0(c)19.7(e)-428.5(th)20.7(e)-422.7(h)0(y)20.8(p)0(o)20.8(t)0(h)15(y)0(r)20.9(o)0(i)20.7(d)-421.6(ph)15.1(en)19.7(ot)20.7(yp)20.8(e)-422.7(i)0(n)-417(t)0(h)20.7(i)0(s)]TJ
-1.0137 -1.1116 TD
[(po)15.1(pu)20.8(la)19.6(ti)20.6(on)-261.4(of)-261.4(55)20.8(0)-271.8(A)0(P)-262.1(m)0(o)19.6(d)0(e)19.7(l)0(s)20.9(,)-274.1(io)20.7(ni)20.7(c)-273(c)0(o)19.7(n)0(d)20.8(u)0(c)13.9(t)0(a)19.6(n)0(c)19.7(e)0(s)-262.4(w)0(e)18.8(r)0(e)-262.5(m)0(o)19.6(d)0(-)]TJ
0 -1.1174 TD
[(i)15.1(ed)-158.9(ac)18.5(co)19.7(rd)20.9(in)15(g)-168.1(t)0(o)-157.8(t)0(h)20.7(e)-175(ex)19.7(pe)19.7(ri)20.7(me)18.4(nt)20.7(al)-164.8(n)21(di)20.7(ng)20.8(s)-173.7(i)0(n)-157.8(b)0(o)20.8(t)0(h)-163.6(a)-169.3(pa)19.7(st)-163.4(st)20.9(ud)20.8(y)]TJ
0 -1.1116 TD
[(\(1)15.1(0\))-261.4(an)19.7(d)-271.8(t)0(h)20.7(e)-273(pr)20.9(es)19.9(en)19.7(t)-271.9(s)0(t)15.1(u)0(d)20.8(y)0(.)-258(T)0(o)-262.6(s)0(i)20.9(m)0(u)19.6(l)0(a)13.8(t)0(e)-262.7(t)0(h)20.7(e)-273(ch)19.7(an)19.7(ge)-262.5(in)-261.5(I)]TJ
7.3823 0 0 6.5614 273.6566 442.5447 Tm
[(Ca)22.5(-L)]TJ
9.843 0 0 9.843 291.2881 444.1889 Tm
(in)Tj
-23.5226 -1.1116 TD
[(bo)15.1(th)-244.2(ty)20.7(pe)19.7(s)-260.1(o)0(f)-244.1(h)0(y)15.1(p)0(o)20.8(t)0(h)20.7(y)0(r)20.9(o)0(i)20.7(d)0(i)14.9(s)0(m)19.8(,)-256.9(G)]TJ
7.3823 0 0 6.5614 186.1795 431.603 Tm
[(Ca)22.5(-L)]TJ
9.843 0 0 9.843 203.6409 433.2471 Tm
[(wa)18.8(s)-260.1(a)0(u)19.7(g)0(m)19.6(e)0(n)19.7(t)0(e)19.5(d)-260.3(by)-244.1(55)15.1(%)15.1(.)]TJ
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[(To)-423.9(si)20.9(mu)19.6(la)13.8(te)-418.2(th)15(e)-428.5(c)0(h)19.7(a)0(n)13.9(g)0(e)19.7(s)-432.9(as)19.9(so)21(ci)19.5(at)19.5(ed)-423.8(wi)19.8(th)-422.8(pr)20.9(im)19.5(ar)14(y)-427.3(h)0(y)15.1(p)0(o)20.8(t)0(h)20.7(y)0(-)]TJ
0 -1.1116 TD
[(ro)15.1(id)20.7(is)20.9(m,)-195.8(G)]TJ
7.3823 0 0 6.5614 100.6866 409.6629 Tm
(to)Tj
9.843 0 0 9.843 108.3401 411.307 Tm
[(an)19.7(d)-202.7(G)]TJ
7.3823 0 0 6.5614 131.3574 409.6629 Tm
(K1)Tj
9.843 0 0 9.843 142.2992 411.307 Tm
[(we)18.8(re)-193.4(re)19.7(du)15.1(ce)18.5(d)-202.7(t)0(o)-192.4(5)0(0)20.8(%)-203.7(of)-192.2(co)19.7(nt)14.9(ro)20.9(l,)-194.7(wh)20(er)19.7(ea)18.5(s)]TJ
-8.3861 -1.1116 TD
(G)Tj
7.3823 0 0 6.5614 66.7275 398.7212 Tm
(Ks)Tj
9.843 0 0 9.843 77.726 400.3652 Tm
[(an)19.7(d)-300.6(G)]TJ
7.3823 0 0 6.5614 101.707 398.7212 Tm
[(NC)24.7(X)]TJ
9.843 0 0 9.843 119.9622 400.3652 Tm
[(we)18.8(re)-291.3(re)19.7(du)20.8(ce)18.5(d)-294.8(t)0(o)-290.3(6)0(0)20.8(%)-295.9(an)19.7(d)-300.6(7)0(0)20.8(%)-295.9(of)-284.4(co)19.7(nt)15(ro)20.9(l,)-286.9(re)19.7(-)]TJ
-6.1168 -1.1174 TD
[(sp)15.3(ec)18.5(ti)20.6(ve)19.7(ly)20.7(.)-205(I)0(n)-198(t)0(h)20.7(e)-203.8(si)20.9(mu)19.6(la)19.6(ti)14.8(on)20.8(s,)-194.4(tr)20.7(ai)19.5(ns)-197.8(of)-192.2(50)20.8(0)-208.4(A)0(P)-193(w)0(e)18.8(r)0(e)-193.4(e)0(v)13.9(o)0(k)20.8(e)0(d)-193.4(a)0(t)]TJ
0 -1.1116 TD
[(1)-156.6(H)0(z)13(,)-239.6(an)19.7(d)-237.2(t)0(h)20.7(e)-244.2(la)19.6(st)-232.5(AP)-227.5(tr)15(ac)18.5(e)-238.4(i)0(n)-232.7(e)0(a)18.5(c)0(h)-228(s)0(i)15.1(m)0(u)19.6(l)0(a)19.6(t)0(i)20.6(o)0(n)-232.6(w)0(a)18.8(s)-237(pr)15.1(es)19.9(en)19.7(te)19.6(d.)]TJ
26.5234 35.2264 TD
[(Simulations)-325.7(of)-324.7(the)-327.1(impact)-333(of)-324.7(the)-327.1(ion)-326(current)-326.9(changes)-333.6(ob-)]TJ
-1.0137 -1.1174 TD
[(served)-653.8(in)-658.9(hypothyroidism)-656.1(were)-658.4(also)-656.3(performed)-658.5(on)-653(the)]TJ
0 -1.1116 TD
[(NygrenFirekClarkLindbladClarkGiles)-504.7(model)-486.1(\(15\))-493.9(of)]TJ
T*
[(human)-439.9(atrial)-447(AP.)-444.1(The)-443.4(simulations)-446.6(presented)-445.3(in)-445.8(this)-442.2(study)]TJ
T*
[(were)-462.6(conducted)-468.6(with)-460.6(permission)-468.3(using)-466.2(The)-460.7(Virtual)-465.1(Heart)]TJ
0 -1.1174 TD
[(Web)-219.8(page)-225.6(by)-221.1(Flavio)-221(Fenton)-220.9(\(1618\),)-224.2(and)-217.6(are)-224.5(described)-226.4(in)-221.2(the)]TJ
0 -1.1116 TD
[(Supplementary)-284.1(Methods.)]TJ
/F11 1 Tf
8.9663 0 0 8.9663 310.8472 636.718 Tm
[(Statistical)-336.1(analysis)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 620.277 Tm
[(Data)-272.7(are)-276.3(presented)-278.3(as)-279.6(means)]TJ
/F6 1 Tf
11.6288 0 TD
()Tj
/F4 1 Tf
.7142 0 TD
[(standard)-281.7(error)-277.3(of)-272.9(the)-275.3(mean.)]TJ
-13.3568 -1.1116 TD
[(Data)-503.1(were)-508.7(compared)-503.1(with)-506.6(Students)]TJ
/F5 1 Tf
15.8737 0 TD
(t)Tj
/F4 1 Tf
.2822 0 TD
[(-test)-507.8(or)-503.3(analysis)-506.3(of)]TJ
-16.156 -1.1116 TD
[(variance)-405.2(followed)-408.5(by)-405.4(Bonferronis)]TJ
/F5 1 Tf
14.6988 0 TD
(t)Tj
/F4 1 Tf
.2822 0 TD
[(-test.)-407.6(Arrhythmia)-406.1(inci-)]TJ
-14.981 -1.1174 TD
[(dence)-268.2(was)-264.3(evaluated)-268.2(with)-264.7(a)-267.2(contingency)-263.5(table)-267.3(and)-269.4(Pearsons)]TJ
0 -1.1116 TD
[(chi-square)-383(test.)-383.4(A)]TJ
/F5 1 Tf
7.6834 0 TD
(p)Tj
/F4 1 Tf
.5011 0 TD
[(-value)-383.4(of)]TJ
/F6 1 Tf
4.1009 0 TD
(<)Tj
/F4 1 Tf
.5529 0 TD
[(0.05)-381.1(was)-385.3(considered)-383(as)-383.3(sta-)]TJ
-12.8384 -1.1116 TD
[(tistically)-284.6(signicant.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 542.8345 Tm
(Results)Tj
/F11 1 Tf
0 -1.8336 TD
[(Animal)-331.1(models)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 509.9526 Tm
[(Although)-367.1(PTU)-373.8(treatment)-372.1(is)-370.8(a)-370.9(widely)-371.8(used)-368.2(procedure)-376.2(for)]TJ
-1.0137 -1.1116 TD
[(induction)-328.3(of)-324.7(primary)-327(hypothyroidism,)-325.5(to)-324.9(the)-327.1(best)-328(of)-324.7(the)-327.1(au-)]TJ
0 -1.1174 TD
[(thors)-329(knowledge,)-333.5(an)-331.7(animal)-333(model)-330.6(of)-330.5(central)-334(hypothyroid-)]TJ
0 -1.1116 TD
[(ism)-344.3(had)-338.5(not)-343.3(yet)-344.4(been)-346.6(developed.)-345.3(The)-345.5(anticancer)-345.4(drug)-344.2(BXT)]TJ
T*
[(exerts)-193.1(a)-192.3(direct)-193.5(inhibitory)-190.1(effect)-194.5(on)-192.3(the)-194.7(TSH-producing)-190.3(cells)-198(of)]TJ
0 -1.1174 TD
[(the)-286.8(pituitary)-288(gland)-289(\(19,20\).)-284.1(Advantage)-290.9(was)-287.4(taken)-284.4(of)-290.1(this)-286.7(un-)]TJ
0 -1.1116 TD
[(wanted)-436.2(side)-437.5(effect)-442.1(to)-434.3(create)-443.3(a)-434.2(central)-443.4(hypothyroidism)-437.3(ex-)]TJ
T*
[(perimental)-281(model,)-282.2(which)-284.1(was)-281.6(tested)-285.5(in)-278.8(this)-280.9(study.)]TJ
1.0137 -1.1174 TD
[(Bo)19.8(th)-290.3(PT)19.8(U)-301.5(a)0(n)19.7(d)-300.6(BX)18.9(T)-301.8(t)0(r)20.7(e)0(a)12.8(t)0(m)19.5(e)0(n)19.7(t)0(s)-290.1(r)0(e)19.7(d)0(u)20.8(c)0(e)18.5(d)-306.4(bl)20.7(oo)20.8(d)-300.6(T)0(4)-291.4(c)0(o)19.7(n)0(c)19.7(e)0(n)19.7(-)]TJ
-1.0137 -1.1116 TD
[(tr)20.7(at)19.5(io)20.7(n)-306.4(w)0(i)19.8(t)0(h)20.7(i)0(n)-296.1(o)0(n)20.8(e)-301.8(we)13(ek)19.7(,)-302.9(a)0(t)19.5(t)0(a)19.6(i)0(n)20.7(i)0(n)20.7(g)-306.4(al)19.6(mo)19.6(st)-295.9(un)20.8(de)19.7(te)19.6(ct)19.6(ab)19.7(le)-297.2(le)19.6(ve)19.7(ls)]TJ
T*
[(af)19.7(te)19.5(r)-335.1(t)0(w)19.8(o)-340.9(we)18.8(ek)19.7(s)-335(\()0(F)21(i)0(g)15(.)-331.7(1A)20(\).)-327(Si)20.9(nc)13.9(e)-336.3(P)0(T)19.8(U)-336(di)20.7(re)19.7(ct)19.6(ly)-330.6(in)20.7(du)20.8(ce)18.5(s)-335(m)0(a)18.4(l)0(-)]TJ
0 -1.1174 TD
[(fu)20.9(nc)19.7(ti)20.6(on)-152(of)-146.2(th)20.7(e)-157.8(t)0(h)20.7(y)0(r)15.1(o)0(i)20.7(d)-156.6(gl)20.7(an)19.7(d,)-148.5(bl)20.7(oo)20.8(d)-162.4(T)0(S)19.8(H)-157.5(co)19.7(nc)19.7(en)19.7(tr)15(at)19.5(io)20.7(n)-156.6(s)0(h)21(o)0(w)20(e)0(d)]TJ
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