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Victoria K. Snowdon, Neil J. Lachlan, Anna M. Hoy, Patrick W. F. Hadoke, Scott I. Semple, Dilip Patel, Will Mungall, Timothy J. Kendall, Adrian Thomson, Ross J. Lennen, Maurits A. Jansen, Carmel M. Moran, Antonella Pellicoro, Prakash Ramachandran, Isaac Shaw, Rebecca L. Aucott, Thomas Severin, Rajnish Saini, Judy Pak, Denise Yates, Neelesh Dongre, Jeremy S. Duffield, David J. Webb, John P. Iredale, Peter C. Hayes, Jonathan A. Fallowfield
Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial
www.plosmedicine.org
www.plosmedicine.org
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199.9998 560.0001 l
f*
0.83 0.64 0.02 0 k
222.463 484.8945 m
227.1685 484.8945 l
h
f*
536.7685 471.9118 m
541.5307 471.9118 l
h
f*
337.7197 445.9465 m
342.4819 445.9465 l
h
f*
318.9543 419.9244 m
323.7165 419.9244 l
h
f*
370.2614 367.937 m
375.0236 367.937 l
h
f*
377.2913 367.937 m
382.0535 367.937 l
h
f*
221.7827 328.9323 m
226.5449 328.9323 l
h
f*
288.7937 302.9102 m
293.5559 302.9102 l
h
f*
295.8236 302.9102 m
300.5858 302.9102 l
h
f*
203.4142 263.9055 m
212.9386 263.9055 l
h
f*
461.2535 237.9402 m
470.778 237.9402 l
h
f*
369.411 198.9354 m
378.9354 198.9354 l
h
f*
336.8693 146.948 m
346.3937 146.948 l
h
f*
541.8709 81.9213 m
551.3953 81.9213 l
h
f*
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(1)Tj
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(].)Tj
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(AKI)Tj
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(20%)Tj
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(].)Tj
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(cirrhosis)Tj
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(who)Tj
1.9389 0 Td
(die)Tj
1.4343 0 Td
([)Tj
0.83 0.64 0.02 0 k
(3)Tj
0 g
(].)Tj
1.6044 0 Td
(HRS)Tj
2.0863 0 Td
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0.8447 0 Td
(a)Tj
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(functional,)Tj
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(and)Tj
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(reversible,)Tj
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(\(PHT\))Tj
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(resistance)Tj
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(\(RVR\))Tj
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([)Tj
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(5)Tj
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(,)Tj
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(6)Tj
0 g
(].)Tj
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(bacterial)Tj
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(translocation,)Tj
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(].)Tj
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(volunteers)Tj
4.3823 0 Td
([)Tj
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(,)Tj
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(9)Tj
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(].)Tj
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(AKI)Tj
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(10)Tj
0 g
(].)Tj
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0.8504 0 Td
(only)Tj
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(4)Tj
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(wk,)Tj
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(the)Tj
1.4684 0 Td
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1.3889 0 Td
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(pharmacological)Tj
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([)Tj
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(11)Tj
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(].)Tj
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(that)Tj
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1.0261 0 Td
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(a)Tj
0.6577 0 Td
(diagnosis)Tj
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(HRS,)Tj
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(a)Tj
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-33.9475 -1.2983 Td
(impact)Tj
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(on)Tj
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(survival,)Tj
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1.7802 0 Td
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(these)Tj
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(clinical)Tj
3.0784 0 Td
(outcomes)Tj
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([)Tj
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(12)Tj
0 g
(].)Tj
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1.7858 0 Td
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(pharmacological)Tj
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2.0807 0 Td
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(1)Tj
0.6917 0 Td
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0.8447 0 Td
(terlipressin)Tj
4.6714 0 Td
(\(a)Tj
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(splanchnic)Tj
4.5184 0 Td
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1.7234 0 Td
(systemic)Tj
3.6227 0 Td
(vasoconstrictor\).)Tj
6.9165 0 Td
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(a)Tj
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-35.104 -1.2983 Td
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7.7272 0 Td
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(only)Tj
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(terlipressin,)Tj
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(and)Tj
1.7291 0 Td
(the)Tj
1.474 0 Td
(drug)Tj
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(permanently)Tj
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(20.4%)Tj
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-35.2627 -1.2983 Td
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(\(mainly)Tj
3.3279 0 Td
(ischemic\))Tj
4.0762 0 Td
(events)Tj
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([)Tj
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(13)Tj
0 g
(].)Tj
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(\(12:12)Tj
2.6872 0 Td
(h)Tj
0.7483 0 Td
(light-dark)Tj
4.201 0 Td
(cycle,)Tj
2.4207 0 Td
(temperature)Tj
-29.6728 -1.2982 Td
(23)Tj
/F15 1 Tf
1.1678 0 Td
[()]TJ
/F6 1 Tf
0.788 0 Td
(2C\),)Tj
2.3131 0 Td
(three)Tj
2.2564 0 Td
(rats)Tj
1.6837 0 Td
(per)Tj
1.5307 0 Td
(cage,)Tj
2.1884 0 Td
(and)Tj
1.7234 0 Td
(were)Tj
2.1203 0 Td
(acclimatized)Tj
5.1931 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4627 0 Td
(room)Tj
2.4264 0 Td
(for)Tj
1.3776 0 Td
(1)Tj
0.6973 0 Td
(wk)Tj
1.3947 0 Td
(before)Tj
2.7382 0 Td
(the)Tj
1.4684 0 Td
(beginning)Tj
-33.5563 -1.3039 Td
(of)Tj
1.0147 0 Td
(the)Tj
1.4684 0 Td
(experiments.)Tj
5.3631 0 Td
(Cirrhosis)Tj
3.9175 0 Td
(and)Tj
1.7291 0 Td
(PHT)Tj
2.16 0 Td
(were)Tj
2.1203 0 Td
(induced)Tj
3.4696 0 Td
(in)Tj
1.0318 0 Td
(8-wk)Tj
2.228 0 Td
(\(250300)Tj
3.9344 0 Td
(g\))Tj
1.0205 0 Td
(male)Tj
2.143 0 Td
(wild-type)Tj
-31.6004 -1.2983 Td
(Sprague-Dawley)Tj
6.7634 0 Td
(rats)Tj
1.6837 0 Td
(by)Tj
1.1792 0 Td
(intraperitoneal)Tj
6.1795 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 373.7763 544.4787 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 379.559 546.1228 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(\(Sigma-Aldrich\))Tj
6.7577 0 Td
(treatment)Tj
4.1386 0 Td
(for)Tj
1.3833 0 Td
(up)Tj
1.2642 0 Td
(to)Tj
1.0261 0 Td
(16)Tj
1.1736 0 Td
(wk)Tj
1.4003 0 Td
(or)Tj
1.0998 0 Td
(by)Tj
-36.1981 -1.2982 Td
(BDL)Tj
2.075 0 Td
(for)Tj
1.3833 0 Td
(up)Tj
1.2642 0 Td
(to)Tj
1.0261 0 Td
(4)Tj
0.6974 0 Td
(wk,)Tj
1.627 0 Td
(as)Tj
1.0148 0 Td
(described)Tj
4.0479 0 Td
(previously)Tj
4.354 0 Td
([)Tj
0.83 0.64 0.02 0 k
(17)Tj
0 g
(].)Tj
2.0748 0 Td
(Cage-mates)Tj
4.8926 0 Td
(were)Tj
2.126 0 Td
(randomly)Tj
4.1272 0 Td
(allocated)Tj
3.7587 0 Td
(to)Tj
1.0261 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 570.7275 531.4393 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 520.1007 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(versus)Tj
2.7155 0 Td
(olive)Tj
2.1203 0 Td
(oil)Tj
1.2416 0 Td
(\(OO\))Tj
2.3924 0 Td
(vehicle)Tj
2.9877 0 Td
(treatment)Tj
4.1329 0 Td
(or)Tj
1.0998 0 Td
(to)Tj
1.0262 0 Td
(BDL)Tj
2.0749 0 Td
(versus)Tj
2.7156 0 Td
(sham)Tj
2.3641 0 Td
(procedure)Tj
4.3143 0 Td
(\(where)Tj
2.9877 0 Td
(the)Tj
1.474 0 Td
(common)Tj
-33.647 -1.2982 Td
(bile)Tj
1.661 0 Td
(duct)Tj
2.0013 0 Td
(was)Tj
1.6951 0 Td
(exposed)Tj
3.4469 0 Td
(but)Tj
1.5534 0 Td
(not)Tj
1.5704 0 Td
(ligated\).)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 479.8488 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Sustained)Tj
4.611 0 Td
(\(72)Tj
1.6488 0 Td
(h\))Tj
1.0961 0 Td
(serelaxin)Tj
4.167 0 Td
(hemodynamic)Tj
6.3733 0 Td
(study)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 462.8409 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Both)Tj
2.1259 0 Td
(16-wk)Tj
2.6929 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 263.9622 461.1968 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 269.6314 462.8409 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0828 0 Td
[()]TJ
/F6 1 Tf
0.805 0 Td
(16\))Tj
1.5024 0 Td
(and)Tj
1.7234 0 Td
(3-wk)Tj
2.2224 0 Td
(post-BDL)Tj
4.0988 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0829 0 Td
[()]TJ
/F6 1 Tf
0.7993 0 Td
(14\))Tj
1.5081 0 Td
(rats)Tj
1.6781 0 Td
(were)Tj
2.1146 0 Td
(randomized)Tj
5.0513 0 Td
(to)Tj
1.0205 0 Td
(receive)Tj
2.999 0 Td
(contin-)Tj
-34.6504 -1.2982 Td
(uous)Tj
2.1373 0 Td
(treatment)Tj
4.1272 0 Td
(for)Tj
1.3832 0 Td
(72)Tj
1.1622 0 Td
(h)Tj
0.7427 0 Td
(with)Tj
1.9899 0 Td
(serelaxin)Tj
3.7587 0 Td
(\(4)Tj
/F15 1 Tf
1.0262 0 Td
[()]TJ
/F6 1 Tf
(g/h\))Tj
2.3867 0 Td
(or)Tj
1.0885 0 Td
(vehicle)Tj
2.982 0 Td
(via)Tj
1.372 0 Td
(subcutaneous)Tj
5.6579 0 Td
(\(s.c.\))Tj
2.1317 0 Td
(osmotic)Tj
3.3958 0 Td
(mini-)Tj
-35.342 -1.3039 Td
(pumps)Tj
2.9594 0 Td
(\(2ML1)Tj
2.9423 0 Td
(Alzet,)Tj
2.5114 0 Td
(Durect\).)Tj
3.5659 0 Td
(Groups)Tj
3.2202 0 Td
(of)Tj
1.0148 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 377.9149 435.1748 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 383.6409 436.8188 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(rats)Tj
1.6837 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0885 0 Td
[()]TJ
/F6 1 Tf
0.8107 0 Td
(12\))Tj
1.5137 0 Td
(were)Tj
2.1203 0 Td
(also)Tj
1.7688 0 Td
(randomized)Tj
5.057 0 Td
(to)Tj
1.0261 0 Td
(serelaxin)Tj
-33.4315 -1.2982 Td
(or)Tj
1.0942 0 Td
(vehicle)Tj
2.9877 0 Td
(plus)Tj
1.8708 0 Td
(coadministration)Tj
7.1036 0 Td
(of)Tj
1.0148 0 Td
(L-N)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 356.9952 428.2582 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(G)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 362.3244 423.8362 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(-nitroarginine)Tj
5.8903 0 Td
(methyl)Tj
2.9877 0 Td
(ester)Tj
2.0976 0 Td
(\(L-NAME\))Tj
4.6715 0 Td
(\(Sigma-)Tj
-31.8781 -1.2982 Td
(Aldrich\))Tj
3.6056 0 Td
(250)Tj
1.6498 0 Td
(mg/ml)Tj
2.897 0 Td
(in)Tj
1.0374 0 Td
(drinking)Tj
3.7134 0 Td
(water,)Tj
2.6532 0 Td
(starting)Tj
3.2654 0 Td
(24)Tj
1.1735 0 Td
(h)Tj
0.7484 0 Td
(before)Tj
2.7382 0 Td
(osmotic)Tj
3.4016 0 Td
(minipump)Tj
4.507 0 Td
(insertion)Tj
3.8098 0 Td
(and)Tj
-35.2003 -1.3039 Td
(continuing)Tj
4.6204 0 Td
(for)Tj
1.389 0 Td
(the)Tj
1.4683 0 Td
(72-h)Tj
2.0466 0 Td
(study)Tj
2.3924 0 Td
(period.)Tj
3.0558 0 Td
(After)Tj
2.2846 0 Td
(72)Tj
1.1735 0 Td
(h,)Tj
0.9751 0 Td
(rats)Tj
1.6838 0 Td
(had)Tj
1.7064 0 Td
(hemodynamic)Tj
5.9754 0 Td
(and)Tj
1.7292 0 Td
(renal)Tj
2.245 0 Td
(functional)Tj
-32.7455 -1.2983 Td
(measurements)Tj
6.0321 0 Td
(performed)Tj
4.4673 0 Td
(under)Tj
2.6192 0 Td
(terminal)Tj
3.6283 0 Td
(isoflurane)Tj
4.1952 0 Td
(anesthesia,)Tj
4.5241 0 Td
(as)Tj
1.0148 0 Td
(detailed)Tj
3.3675 0 Td
(below.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 357.5622 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Acute)Tj
2.7543 0 Td
(serelaxin)Tj
4.1622 0 Td
(hemodynamic)Tj
6.378 0 Td
(study)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 340.5543 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Serelaxin)Tj
3.8721 0 Td
(was)Tj
1.7007 0 Td
(supplied)Tj
3.6057 0 Td
(under)Tj
2.6192 0 Td
(material)Tj
3.5149 0 Td
(transfer)Tj
3.3165 0 Td
(agreement)Tj
4.4277 0 Td
(by)Tj
1.1849 0 Td
(Corthera)Tj
3.8154 0 Td
(\(a)Tj
0.9921 0 Td
(Novartis)Tj
3.651 0 Td
(affiliate)Tj
-32.7002 -1.2982 Td
(company\).)Tj
4.49 0 Td
(Groups)Tj
3.2201 0 Td
(of)Tj
1.0148 0 Td
(OO)Tj
1.7121 0 Td
(control)Tj
3.1238 0 Td
(rats)Tj
1.6838 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0885 0 Td
[()]TJ
/F6 1 Tf
0.8107 0 Td
(12\))Tj
1.508 0 Td
(or)Tj
1.0998 0 Td
(16-wk)Tj
2.7043 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 440.2771 325.8708 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 446.0598 327.5716 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(rats)Tj
1.6837 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0885 0 Td
[()]TJ
/F6 1 Tf
0.8051 0 Td
(14\))Tj
1.5136 0 Td
(were)Tj
2.1203 0 Td
(randomized)Tj
-31.8157 -1.3039 Td
(to)Tj
1.0261 0 Td
(injection)Tj
3.7587 0 Td
(of)Tj
1.0148 0 Td
(serelaxin)Tj
3.7587 0 Td
(\(4)Tj
/F15 1 Tf
1.0375 0 Td
[()]TJ
/F6 1 Tf
(g)Tj
1.1906 0 Td
(in)Tj
1.0374 0 Td
(200)Tj
/F15 1 Tf
1.6441 0 Td
[()]TJ
/F6 1 Tf
(l)Tj
0.9751 0 Td
(intravenous)Tj
4.9606 0 Td
([i.v.]\))Tj
2.4151 0 Td
(or)Tj
1.0942 0 Td
(an)Tj
1.2075 0 Td
(equivalent)Tj
4.3483 0 Td
(volume)Tj
3.1974 0 Td
(of)Tj
1.0148 0 Td
(vehicle,)Tj
-33.6809 -1.2982 Td
(and)Tj
1.7291 0 Td
(anesthetized)Tj
5.1647 0 Td
(for)Tj
1.389 0 Td
(continuous)Tj
4.7338 0 Td
(hemodynamic)Tj
5.9754 0 Td
(monitoring)Tj
4.8189 0 Td
(over)Tj
1.9784 0 Td
(60)Tj
1.1679 0 Td
(min.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 274.2803 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Acute)Tj
2.7543 0 Td
(nitrovasodilator)Tj
6.9071 0 Td
(hemodynamic)Tj
6.378 0 Td
(study)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 257.2724 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Groups)Tj
3.2201 0 Td
(of)Tj
1.0148 0 Td
(16-wk)Tj
2.6985 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 285.1086 255.6283 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 290.8346 257.2724 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(rats)Tj
1.6894 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0828 0 Td
[()]TJ
/F6 1 Tf
0.8107 0 Td
(6\))Tj
1.0375 0 Td
(were)Tj
2.1203 0 Td
(anesthetized)Tj
5.1704 0 Td
(and)Tj
1.7291 0 Td
(treated)Tj
2.9933 0 Td
(with)Tj
2.0013 0 Td
(a)Tj
0.652 0 Td
(range)Tj
2.4661 0 Td
(of)Tj
1.0148 0 Td
(doses)Tj
2.3981 0 Td
(of)Tj
-34.2479 -1.2982 Td
(sodium)Tj
3.2315 0 Td
(nitroprusside)Tj
5.5672 0 Td
(\(SNP;)Tj
2.5567 0 Td
(0.09,)Tj
2.0976 0 Td
(0.9,)Tj
1.6215 0 Td
(and)Tj
1.7291 0 Td
(9)Tj
/F15 1 Tf
0.6973 0 Td
[()]TJ
/F6 1 Tf
(g)Tj
1.1905 0 Td
(in)Tj
1.0375 0 Td
(200)Tj
/F15 1 Tf
1.6441 0 Td
[()]TJ
/F6 1 Tf
(l)Tj
0.9751 0 Td
(i.v.;)Tj
1.6157 0 Td
(Sigma-Aldrich\))Tj
6.4233 0 Td
(or)Tj
1.0942 0 Td
(an)Tj
1.2019 0 Td
(equivalent)Tj
-32.6832 -1.2983 Td
(volume)Tj
3.1975 0 Td
(of)Tj
1.0148 0 Td
(vehicle.)Tj
3.2144 0 Td
(Continuous)Tj
4.9719 0 Td
(hemodynamic)Tj
5.9754 0 Td
(monitoring)Tj
4.8188 0 Td
(was)Tj
1.7008 0 Td
(undertaken)Tj
4.8189 0 Td
(for)Tj
1.3833 0 Td
(10)Tj
1.1735 0 Td
(min)Tj
1.8539 0 Td
(after)Tj
-34.1232 -1.3039 Td
(each)Tj
2.0296 0 Td
(dose,)Tj
2.262 0 Td
(as)Tj
1.0148 0 Td
(described)Tj
4.0534 0 Td
(above.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 190.9984 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Hemodynamic)Tj
6.5433 0 Td
(measurements)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 173.9905 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Hemodynamic)Tj
6.2135 0 Td
(monitoring)Tj
4.8188 0 Td
(was)Tj
1.7008 0 Td
(performed)Tj
4.4674 0 Td
(using)Tj
2.3867 0 Td
(aseptic)Tj
2.948 0 Td
(technique)Tj
4.1669 0 Td
(in)Tj
1.0318 0 Td
(rats)Tj
1.6895 0 Td
(anesthetized)Tj
5.1647 0 Td
(with)Tj
-34.5881 -1.2982 Td
(Inactin)Tj
3.0784 0 Td
(\(Sigma-Aldrich\))Tj
6.7577 0 Td
(0.1)Tj
1.4003 0 Td
(ml/100)Tj
3.0387 0 Td
(g)Tj
0.686 0 Td
(\(125)Tj
1.9899 0 Td
(mg/ml\))Tj
3.2372 0 Td
(unless)Tj
2.6929 0 Td
(otherwise)Tj
4.0818 0 Td
(specified.)Tj
3.9458 0 Td
(Briefly,)Tj
3.0728 0 Td
(a)Tj
0.6519 0 Td
(trache-)Tj
-34.6334 -1.2983 Td
(ostomy)Tj
3.1577 0 Td
(was)Tj
1.6951 0 Td
(created,)Tj
3.3392 0 Td
(the)Tj
1.4627 0 Td
(right)Tj
2.143 0 Td
(internal)Tj
3.3505 0 Td
(jugular)Tj
3.0387 0 Td
(vein)Tj
1.9106 0 Td
(cannulated)Tj
4.6261 0 Td
(with)Tj
1.9899 0 Td
(PE50)Tj
2.2904 0 Td
(tubing)Tj
2.8289 0 Td
(\(Smiths)Tj
3.2995 0 Td
(Medi-)Tj
-35.1323 -1.3039 Td
(cal\),)Tj
1.8878 0 Td
(and)Tj
1.7291 0 Td
(0.9%)Tj
2.1544 0 Td
(NaCl)Tj
2.3017 0 Td
(instilled)Tj
3.4072 0 Td
(at)Tj
0.9468 0 Td
(0.05)Tj
1.8765 0 Td
(ml/100)Tj
3.0387 0 Td
(g/min)Tj
2.6532 0 Td
(throughout)Tj
4.7792 0 Td
(surgery)Tj
3.1918 0 Td
(and)Tj
1.7291 0 Td
(then)Tj
2.0183 0 Td
(0.03)Tj
1.8765 0 Td
(ml/100)Tj
3.0387 0 Td
(g/)Tj
-36.629 -1.2983 Td
(min)Tj
1.8538 0 Td
(during)Tj
2.9253 0 Td
(stabilization/mon)Tj
7.0583 0 Td
(itoring.)Tj
3.1691 0 Td
(Rats)Tj
1.9332 0 Td
(received)Tj
3.5376 0 Td
(5%)Tj
1.4513 0 Td
(inulin-FITC)Tj
5.1194 0 Td
(\(Sigma-Aldrich\))Tj
6.7577 0 Td
(in)Tj
1.0375 0 Td
(0.9%)Tj
-34.8432 -1.2982 Td
(NaCl)Tj
2.296 0 Td
(for)Tj
1.389 0 Td
(GFR)Tj
2.0863 0 Td
(measurement.)Tj
5.896 0 Td
(Body)Tj
2.2904 0 Td
(temperature)Tj
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1 J
0 w
7.4999 0 0 6.6659 402.0661 711.8362 cm
BT
/F15 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
/F6 1 Tf
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 412.1007 707.4141 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(M;)Tj
1.3379 0 Td
(Sigma-Aldrich\),)Tj
6.6444 0 Td
(the)Tj
1.474 0 Td
(cyclooxygenase)Tj
-30.6649 -1.3039 Td
(\(COX\))Tj
2.9593 0 Td
(inhibitor)Tj
3.7814 0 Td
(indomethacin)Tj
5.8167 0 Td
(\(1)Tj
/F15 1 Tf
1.0318 0 Td
[()]TJ
/F6 1 Tf
0.7937 0 Td
(10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 353.3102 698.8535 cm
BT
/F15 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
/F6 1 Tf
(5)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 363.3448 694.3748 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(M;)Tj
1.3379 0 Td
(Sigma-Aldrich\),)Tj
6.6444 0 Td
(or)Tj
1.0998 0 Td
(the)Tj
1.4683 0 Td
(endothelium-derived)Tj
-26.8835 -1.2982 Td
(hyperpolarizing)Tj
6.548 0 Td
(factor)Tj
2.5455 0 Td
(inhibitors)Tj
4.1386 0 Td
(apamin)Tj
3.2427 0 Td
(\(1)Tj
/F15 1 Tf
1.0375 0 Td
[()]TJ
/F6 1 Tf
0.788 0 Td
(10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 392.5417 685.8708 cm
BT
/F15 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
/F6 1 Tf
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 402.5196 681.3921 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(M;)Tj
1.3379 0 Td
(Sigma-Aldrich\))Tj
6.4233 0 Td
(and)Tj
1.7291 0 Td
(charybdotoxin)Tj
-29.7408 -1.2982 Td
(\(1)Tj
/F15 1 Tf
1.0318 0 Td
[()]TJ
/F6 1 Tf
0.7937 0 Td
(10)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 227.7921 672.8314 cm
BT
/F15 1 Tf
1 TL
-0.0053 Tc
0 0 Td
[()]TJ
/F6 1 Tf
(5)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 237.77 668.4094 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(M;)Tj
1.3379 0 Td
(Sigma-Aldrich\))Tj
6.4233 0 Td
(before)Tj
2.7382 0 Td
(stimulation)Tj
4.7962 0 Td
(with)Tj
1.9956 0 Td
(ACh.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 642.274 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Kidney)Tj
3.2362 0 Td
(blood-oxygen-level-depend)Tj
11.8962 0 Td
(ent)Tj
1.5968 0 Td
(magnetic)Tj
4.2284 0 Td
(resonance)Tj
4.8331 0 Td
(imaging)Tj
-25.7907 -1.1669 Td
(studies)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 611.2629 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Groups)Tj
3.2201 0 Td
(of)Tj
1.0148 0 Td
(8-wk)Tj
2.2223 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0885 0 Td
[()]TJ
/F6 1 Tf
0.8107 0 Td
(16\))Tj
1.5137 0 Td
(and)Tj
1.7291 0 Td
(16-wk)Tj
2.7043 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 358.7527 609.6188 cm
BT
/F6 1 Tf
1 TL
-0.0053 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 362.3244 611.2629 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(-treated)Tj
3.3448 0 Td
(rats)Tj
1.6838 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0885 0 Td
[()]TJ
/F6 1 Tf
0.8107 0 Td
(12\))Tj
1.5137 0 Td
(were)Tj
2.1203 0 Td
(randomized)Tj
5.0626 0 Td
(to)Tj
1.0262 0 Td
(serelaxin)Tj
-0.01 Tc
-32.8816 -1.2982 Td
(\(4)Tj
/F15 1 Tf
1.0204 0 Td
[()]TJ
/F6 1 Tf
(g)Tj
1.1849 0 Td
(in)Tj
1.0205 0 Td
(200)Tj
/F15 1 Tf
1.6271 0 Td
[()]TJ
/F6 1 Tf
(l)Tj
0.9637 0 Td
(i.v.\))Tj
1.7008 0 Td
(or)Tj
1.0885 0 Td
(vehicle)Tj
2.9423 0 Td
(\(200)Tj
/F15 1 Tf
1.9673 0 Td
[()]TJ
/F6 1 Tf
(l\),)Tj
1.5137 0 Td
(and)Tj
1.712 0 Td
(kidney)Tj
2.9026 0 Td
(blood-oxygen-level-dependent)Tj
12.2967 0 Td
(MRI)Tj
2.0522 0 Td
(\(BOLD-)Tj
-33.9927 -1.3039 Td
(MRI\))Tj
2.3867 0 Td
(measurements)Tj
5.9641 0 Td
(\(T2)Tj
ET
Q
q
1 j
1 J
0 w
6.9998 0 0 6.9998 297.5811 588.8692 cm
BT
/F13 1 Tf
1 TL
0 0 Td
()Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 301.6062 585.2409 cm
BT
/F6 1 Tf
1 TL
-0.01 Tc
0 0 Td
(\))Tj
0.5555 0 Td
(were)Tj
2.0977 0 Td
(acquired)Tj
3.651 0 Td
(using)Tj
2.3584 0 Td
(a)Tj
0.6519 0 Td
(7.0)Tj
1.3777 0 Td
(Tesla)Tj
2.2677 0 Td
(preclinical)Tj
4.3199 0 Td
(MRI)Tj
2.058 0 Td
(scanner)Tj
3.2881 0 Td
(\(Agilent)Tj
-32.7852 -1.2982 Td
(Technologies\).)Tj
-0.004 Tc
1.1963 -1.2983 Td
(Animals)Tj
3.5829 0 Td
(were)Tj
2.1203 0 Td
(anesthetized)Tj
5.1703 0 Td
(with)Tj
1.9956 0 Td
(isoflurane,)Tj
4.422 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4683 0 Td
(tail)Tj
1.4684 0 Td
(vein)Tj
1.9105 0 Td
(was)Tj
1.7008 0 Td
(cannulated)Tj
4.6318 0 Td
(for)Tj
1.3833 0 Td
(serelaxin)Tj
3.7644 0 Td
(or)Tj
-36.544 -1.2982 Td
(vehicle)Tj
2.9877 0 Td
(injection.)Tj
3.9855 0 Td
(Core)Tj
2.1827 0 Td
(body)Tj
2.2166 0 Td
(temperature)Tj
5.1306 0 Td
(was)Tj
1.6952 0 Td
(maintained)Tj
4.7905 0 Td
(at)Tj
0.9524 0 Td
(37C,)Tj
2.4491 0 Td
(and)Tj
1.7348 0 Td
(respiratory)Tj
4.5921 0 Td
(rate)Tj
1.7518 0 Td
(was)Tj
-34.469 -1.304 Td
(recorded)Tj
3.7928 0 Td
(throughout)Tj
4.7792 0 Td
(the)Tj
1.4683 0 Td
(scanning)Tj
3.8153 0 Td
(protocol.)Tj
3.8268 0 Td
(A)Tj
0.9014 0 Td
(birdcage)Tj
3.6396 0 Td
(volume)Tj
3.1975 0 Td
(coil)Tj
1.6667 0 Td
(\(72-mm)Tj
3.498 0 Td
(diameter\))Tj
4.1272 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
-36.4419 -1.2982 Td
(four-channel)Tj
5.4142 0 Td
(phased)Tj
3.0104 0 Td
(array)Tj
2.2846 0 Td
(surface)Tj
3.05 0 Td
(coil)Tj
1.6668 0 Td
(\(Rapid)Tj
2.9253 0 Td
(Biomedical\))Tj
5.057 0 Td
(were)Tj
2.1203 0 Td
(used)Tj
2.0636 0 Td
(for)Tj
1.3833 0 Td
(radio)Tj
2.3301 0 Td
(frequency)Tj
-31.3056 -1.2983 Td
(transmission)Tj
5.3632 0 Td
(and)Tj
1.7291 0 Td
(signal)Tj
2.5455 0 Td
(reception,)Tj
4.2235 0 Td
(respectively.)Tj
5.108 0 Td
(BOLD-MRI)Tj
5.0286 0 Td
(image)Tj
2.6305 0 Td
(acquisition)Tj
4.6262 0 Td
(used)Tj
2.0579 0 Td
(a)Tj
0.6576 0 Td
(multie-)Tj
-33.9701 -1.3039 Td
(cho)Tj
1.6781 0 Td
(gradient-recalled)Tj
7.0016 0 Td
(echo)Tj
2.1032 0 Td
(pulse)Tj
2.296 0 Td
(sequence)Tj
3.8551 0 Td
(of)Tj
1.0148 0 Td
(ten)Tj
1.491 0 Td
(T2)Tj
ET
Q
q
1 j
1 J
0 w
6.9998 0 0 6.9998 405.2976 497.8771 cm
BT
/F13 1 Tf
1 TL
0 0 Td
()Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 411.4771 494.2488 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(weighted)Tj
3.838 0 Td
(images;)Tj
3.2145 0 Td
(TE)Tj
1.4003 0 Td
(=)Tj
0.7994 0 Td
(4,)Tj
0.9241 0 Td
(8,)Tj
0.9184 0 Td
(12,)Tj
1.4003 0 Td
(16,)Tj
1.3946 0 Td
(20,)Tj
-35.0359 -1.2982 Td
(24,)Tj
1.3947 0 Td
(28,)Tj
1.3946 0 Td
(32,)Tj
1.4003 0 Td
(36,)Tj
1.3946 0 Td
(and)Tj
1.7292 0 Td
(40)Tj
1.1735 0 Td
(ms;)Tj
1.6271 0 Td
(TR)Tj
1.4513 0 Td
(=)Tj
0.7994 0 Td
(100)Tj
1.6497 0 Td
(ms;)Tj
1.6214 0 Td
(and)Tj
1.7348 0 Td
(flip)Tj
1.5364 0 Td
(angle)Tj
2.3356 0 Td
(of)Tj
1.0148 0 Td
(30.)Tj
1.7915 0 Td
(An)Tj
1.4513 0 Td
(axial)Tj
2.0693 0 Td
(slice)Tj
1.9389 0 Td
(through)Tj
3.4469 0 Td
(the)Tj
1.4683 0 Td
(center)Tj
-34.4236 -1.2983 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(right)Tj
2.1486 0 Td
(kidney)Tj
2.9367 0 Td
(was)Tj
1.7008 0 Td
(selected)Tj
3.3505 0 Td
(with)Tj
1.9956 0 Td
(50)Tj
/F15 1 Tf
1.1678 0 Td
[()]TJ
/F6 1 Tf
0.7937 0 Td
(40)Tj
1.1679 0 Td
(mm)Tj
1.8595 0 Td
(field)Tj
1.9728 0 Td
(of)Tj
1.0148 0 Td
(view)Tj
2.0523 0 Td
(containing)Tj
4.524 0 Td
(a)Tj
0.6577 0 Td
(192)Tj
/F15 1 Tf
1.6441 0 Td
[()]TJ
/F6 1 Tf
0.788 0 Td
(128)Tj
1.6497 0 Td
(acquisi-)Tj
-33.9077 -1.3039 Td
(tion)Tj
1.8312 0 Td
(matrix)Tj
2.8743 0 Td
(\(in-plane)Tj
3.8891 0 Td
(resolution)Tj
4.269 0 Td
(=)Tj
0.7937 0 Td
(0.26)Tj
/F15 1 Tf
1.8708 0 Td
[()]TJ
/F6 1 Tf
0.7824 0 Td
(0.31)Tj
1.8652 0 Td
(mm\).)Tj
2.4207 0 Td
(Selecting)Tj
3.7813 0 Td
(a)Tj
0.652 0 Td
(single)Tj
2.5228 0 Td
(axial)Tj
2.0636 0 Td
(slice)Tj
1.9332 0 Td
(aligned)Tj
3.1238 0 Td
(parallel)Tj
-34.6731 -1.2983 Td
(with)Tj
1.9956 0 Td
(the)Tj
1.4683 0 Td
(renal)Tj
2.2451 0 Td
(artery,)Tj
2.8006 0 Td
(identified)Tj
4.0592 0 Td
(by)Tj
1.1792 0 Td
(rapid)Tj
2.3357 0 Td
(scout)Tj
2.3414 0 Td
(scanning)Tj
3.8153 0 Td
(\(fast)Tj
1.9389 0 Td
(gradient)Tj
3.5546 0 Td
(echo,)Tj
2.3301 0 Td
(three)Tj
2.262 0 Td
(slices)Tj
2.3017 0 Td
(in)Tj
1.0375 0 Td
(cor-)Tj
-35.6652 -1.2982 Td
(onal)Tj
1.9559 0 Td
(orientation\),)Tj
5.2554 0 Td
(ensured)Tj
3.4016 0 Td
(that)Tj
1.7801 0 Td
(the)Tj
1.4684 0 Td
(slice)Tj
1.9445 0 Td
(position)Tj
3.4923 0 Td
(encompassed)Tj
5.5671 0 Td
(the)Tj
1.4683 0 Td
(most)Tj
2.2054 0 Td
(representative)Tj
5.8336 0 Td
(section)Tj
-34.3726 -1.3039 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(kidney)Tj
2.9366 0 Td
(regions.)Tj
3.3902 0 Td
(Slice)Tj
2.058 0 Td
(thickness)Tj
3.9231 0 Td
(was)Tj
1.7008 0 Td
(2)Tj
0.6973 0 Td
(mm,)Tj
2.0863 0 Td
(with)Tj
1.9955 0 Td
(14)Tj
1.1678 0 Td
(signal)Tj
2.5455 0 Td
(averages.)Tj
3.8098 0 Td
(The)Tj
1.7858 0 Td
(scan)Tj
1.9842 0 Td
(time)Tj
2.0296 0 Td
(was)Tj
1.7008 0 Td
(3)Tj
-36.2945 -1.2983 Td
(min)Tj
1.8539 0 Td
(for)Tj
1.3889 0 Td
(each)Tj
2.024 0 Td
(BOLD-MRI)Tj
5.0286 0 Td
(scan.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 377.1212 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(High-resolution)Tj
6.8504 0 Td
(ultrasound)Tj
4.8284 0 Td
(studies)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 360.1133 cm
BT
/F6 1 Tf
1 TL
-0.02 Tc
0 0 Td
(Groups)Tj
3.1237 0 Td
(of)Tj
0.9808 0 Td
(16-wk)Tj
2.6249 0 Td
(CCl)Tj
ET
Q
q
1 j
1 J
0 w
7.4999 0 0 6.6659 282.5574 358.4692 cm
BT
/F6 1 Tf
1 TL
-0.0266 Tc
0 0 Td
(4)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 288.1133 360.1133 cm
BT
/F6 1 Tf
1 TL
-0.02 Tc
0 0 Td
(rats)Tj
1.6214 0 Td
(\()Tj
/F16 1 Tf
[()]TJ
1.0601 0 Td
[()]TJ
/F6 1 Tf
0.7937 0 Td
(16\))Tj
1.4627 0 Td
(were)Tj
2.0579 0 Td
(randomized)Tj
4.8982 0 Td
(to)Tj
0.9922 0 Td
(serelaxin)Tj
3.617 0 Td
(\(4)Tj
/F15 1 Tf
1.0034 0 Td
[()]TJ
/F6 1 Tf
(g)Tj
1.1622 0 Td
(in)Tj
1.0035 0 Td
(200)Tj
/F15 1 Tf
1.5987 0 Td
[()]TJ
/F6 1 Tf
(l)Tj
0.9411 0 Td
(i.v.\))Tj
1.6554 0 Td
(or)Tj
1.0658 0 Td
(vehicle)Tj
-33.7433 -1.2982 Td
(\(200)Tj
/F15 1 Tf
1.9219 0 Td
[()]TJ
/F6 1 Tf
(l\),)Tj
1.474 0 Td
(and)Tj
1.6838 0 Td
(RBF)Tj
1.8992 0 Td
(and)Tj
1.6837 0 Td
(cardiac)Tj
2.9876 0 Td
(output)Tj
2.8007 0 Td
(\(CO\))Tj
2.245 0 Td
(were)Tj
2.0579 0 Td
(assessed)Tj
3.3449 0 Td
(by)Tj
1.1508 0 Td
(ultrasound)Tj
4.4107 0 Td
(\(Vevo)Tj
2.5625 0 Td
(770,)Tj
1.8085 0 Td
(VisualSonics\).)Tj
-0.004 Tc
-30.835 -1.2983 Td
(Animals)Tj
3.583 0 Td
(were)Tj
2.1203 0 Td
(anesthetized)Tj
5.1703 0 Td
(with)Tj
1.9955 0 Td
(isoflurane,)Tj
4.4221 0 Td
(placed)Tj
2.7892 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.652 0 Td
(supine)Tj
2.8686 0 Td
(position)Tj
3.4923 0 Td
(on)Tj
1.2756 0 Td
(a)Tj
0.6519 0 Td
(heated)Tj
2.8573 0 Td
(table)Tj
-34.1118 -1.3039 Td
(\(VisualSonics,)Tj
5.8961 0 Td
(Fujifilm\),)Tj
3.9853 0 Td
(and)Tj
1.7292 0 Td
(cannulated)Tj
4.6374 0 Td
(via)Tj
1.372 0 Td
(tail)Tj
1.4683 0 Td
(vein)Tj
1.9105 0 Td
(for)Tj
1.389 0 Td
(injection)Tj
3.7587 0 Td
(of)Tj
1.0148 0 Td
(serelaxin)Tj
3.7587 0 Td
(or)Tj
1.0999 0 Td
(vehicle.)Tj
3.2145 0 Td
(Heart)Tj
-35.2344 -1.2983 Td
(rate)Tj
1.7462 0 Td
(was)Tj
1.7007 0 Td
(monitored)Tj
4.4901 0 Td
(continuously)Tj
5.4367 0 Td
(using)Tj
2.3868 0 Td
(an)Tj
1.2018 0 Td
(electrocardiogram,)Tj
7.7613 0 Td
(and)Tj
1.7291 0 Td
(core)Tj
1.9445 0 Td
(body)Tj
2.2167 0 Td
(temperature)Tj
5.1307 0 Td
(was)Tj
-35.7446 -1.2982 Td
(maintained)Tj
4.7849 0 Td
(at)Tj
0.9524 0 Td
(37C)Tj
2.228 0 Td
(using)Tj
2.3924 0 Td
(the)Tj
1.4683 0 Td
(heated)Tj
2.8516 0 Td
(table)Tj
2.1317 0 Td
(and)Tj
1.7291 0 Td
(a)Tj
0.6576 0 Td
(heat)Tj
1.8992 0 Td
(lamp)Tj
2.2394 0 Td
(as)Tj
1.0148 0 Td
(required.)Tj
3.8664 0 Td
(The)Tj
1.7802 0 Td
(chest)Tj
2.2563 0 Td
(and)Tj
1.7291 0 Td
(abdomi-)Tj
-33.9814 -1.2983 Td
(nal)Tj
1.4457 0 Td
(regions)Tj
3.1634 0 Td
(were)Tj
2.126 0 Td
(shaved)Tj
2.9479 0 Td
(and)Tj
1.7291 0 Td
(remaining)Tj
4.3654 0 Td
(hair)Tj
1.8198 0 Td
(removed)Tj
3.7474 0 Td
(with)Tj
1.9956 0 Td
(depilatory)Tj
4.2689 0 Td
(cream.)Tj
2.9197 0 Td
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