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MwGNiiK R6UN.nr( IN Mem(l\E 7. 143-ISS (1988)<br />
Acute Volume Loading Studied in Cat Myocardium with 31P Nuclear<br />
, Magnetic Resonance•<br />
MARY OSBAKKEN . MARIE YOUNG. JUDY HUDDELL. JEFFERYROSTER.<br />
MANFRED PRAMMER, AND BRITTON CHA\IC[<br />
Drtnnmaus nl.inerrAma and Brmkemrun/&orArnn, l'anwaor!fPrnnsytrome .<br />
PAiladtlphm. Penmlitnnsa 19100<br />
Rettitrzd Aupul $. 1987; rerited Nonembn 19.1997<br />
Tu nudy the nfrets of acute tolume irodine on myorardW meubotic and mcchanid<br />
funnion- se.m ens ..rt .ernrne loadrd vla anauorrmsis of the aDdomioal aom r9 Iht<br />
.tnap+a(AVShunIL hleuboliceRecauxnnalumr .d oiN"PnudarmaTneurnaonanre<br />
(NMR) . MecMniral funnion -arrr .lumN•im 1mn rate x I.ywac nbod peasuepadmi<br />
(HR x SOP) . Shunts rete opened (or 1-2 h durin8 .hich timt pnuNhorreanne (PCr) .<br />
Wenosinr rripbosphan (ATP1 . Inor,amc phosplutt (P,L and HR x SOP a,rae monitomt .<br />
Hirh~erg,v phosphate enerteues asdeeennined bf P,flY'rand P(WATP onmrerr com .<br />
re6tcd with HR X SBP.Openin8 of ine AV aaunu wm arsocialed .ith an inrrcue (four<br />
ntsl or a dernase (thrce nn1 ao HR x SBP . P,/PCr ratim increased and PCNATP rnins<br />
demeased in r.n ..ilb an innesu in HR x SOP. In nt. .itb a dernuse in HR x SBP .<br />
P,/PCr and PCr/ATP genenlp- drd nm clranet siani6o .ntly. In summary . amu rMume<br />
leadilra could be aROrlnled elih aE illnraR or derleaM in m)'neardial MICIaa1 xVrk ar<br />
evaluated bf HR X SOP. acroc .rdid<br />
meehanial Ioadin8 can bt naluated .ita "P Nh1R technlpun and may pra.ide insiaht<br />
into in Wro meutnlic eontml mrrhenums.
144 oSaAKKEV FT .V ..<br />
are these changes^ It is postdlated that tin understanding of thest mechanisms in<br />
animal models mav lead to a better understanding of similar processes in a clinical<br />
setting.<br />
)n the following studies. s'P nuclear magoetic resonance (NMR)was used togenemte<br />
data concerning phosphate rrdetabo)ism (IK'r . phosphocreatine: ATP. adenosine ariphosphata<br />
P„ inorganic phosphate). Ratios of P,/PZ-r and PCr/A'iP were used to<br />
estimate phosphorvlation potential (PP) ahd adenosine diphosphate (ADP) coneentration,<br />
both potential regulators ofoxidatna phosphorylation (24) . The P,/PCr ratio<br />
would be a better estimator of oxidative pho-cphoq-(ation based on the equation<br />
PP' J~ADPT]P) . l P~l x KcK jCrj ' [I)<br />
where KcK is the equilibrium constant ol' creatine kinase . H' is the hydrogen ion<br />
concentration. and Cr is cteatine (2f. =t) . Howe.rr• at times it is impoisible to interpret<br />
information concerning the P. peaks because of its contamination by 2 .3-diphosphoglycerie<br />
aeid (2J-DPG) . Therefore . the second ratio. PCr/ATP, can be used to provide<br />
similar. if not as sensitive. informaion concerning bioenergetic control mechanisms .<br />
Aafrnal Preparoriwr<br />
METHdDS<br />
Nine cats were anesthetized with nembutal (20-30 mg/kg. ip) and intubated for<br />
respiratory maintenance. (Onl% data from seven cats are presented because the shunts<br />
were found to be paniallp Ihrombosed in ~tw•o cats at the end of the experiment .)<br />
Anesthesia was maintained b% intravenous nembuWl (10-20 nrg/kg, iv) . Intravenous<br />
and intraarterial lines were placed for fluid and dmg administmtion, and blood preswte<br />
and arterial blood gas monitoring . nespatisrly. Median stcrnotomy was done to expose<br />
the hean for surface coil placement . A pericardial cradle was created for support and<br />
movement of the hran within the magnetic frcld (to help position the hean in the<br />
sensitive volume of the magnet) . A Iwo-turn . 1-cm-diameter surface coil, tuned to<br />
33 .8 MHz for phosphnrus and 8$A MHz for protons• wasattaehed to the left rentricle<br />
with cyanoaccrylate. Creation of an abdominal aorta to vena cava shunt was done<br />
using 3-mm (id) pol.rthylene tubing which was inserted between the two vessels (/? .<br />
7f). This shunt w-as kept closed wirh a plastic roller clamp until volume overload was<br />
required . Each animal was maintained under stable physiological conditions by monitoring<br />
and maintaining anerial Wood gases within physiologic range and by mainte•<br />
nance of volume and blood pressure status with fluid administration as required .<br />
X.t fR JYudres<br />
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Cats were placed in a plexigla$s holder and introduced into a 2 .1-T . 23-em-bore.<br />
Oxford magnet . The surface coil used for transmission and reception of radiofrequency<br />
signal was tuned to 35.8 MHi (phosphorus) and 88 .4 MHz (protons). The animalsurface<br />
coil-magnet combination was made as homogeneous as possible with the magnet<br />
shim coils (shimming was dorfe using proton signals . 'H NMR). Pulse width (P W)<br />
optimization was performed for each animal-coil interface . For this procedure, a<br />
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VOLUME LOADING EiTECrS ON THE HEART USING "P NMR 145<br />
series of pulses of diH'erent dumsion'(15-50 us) was applied and spectra were acquired<br />
with a delay time of 4 s. The pulse width which provided the best signal/noise for PCr<br />
and ATP was used for radiofiepuency stimulation for each expnimmt . Opttlmat pulses<br />
were between 35 and 30 µs .<br />
The schematic repraenlation of pla,ccment of the 1-cm-diameter surface cail on<br />
the heart is shown in Frg 1 . Practically a)1 the NMR signal cantributing to the spectrum<br />
was generated from the indicated sensitive region . which extends from the heae sullhtt<br />
by 4 mm into the myocardium and is roughly ellipsoidally shaped with a diameter<br />
varying from 12 to 13 mm . These data were generated by integrating over the threedimensional<br />
modulation profile of a suPface coil, BI x sie(ryBJ . 8ased on this infor<br />
mation, we do not expect an appreciabfe amount of contamination of the muscle<br />
spectrum from blood within the ventricle.<br />
t1P NMR spectra were obtained using respiratory and electrocardiographic gating .<br />
To do this , the following procedure was used . The respirator was outfened with a<br />
switch which was turned on at end expiration . Respiratory informarion along with<br />
ECG signal was fed into a uiggering lrox . (built in our lab) . The first QRS. on the ECG,<br />
observed by the sensing device in the triggering box. after end expimtion was used to<br />
trigger the mdiofrequertcy pulse for NMR spectra acquisition . Each spectrum consisted<br />
of 100 seans obtained with a delay tiine of 4 s(based on preset respiration rate main•<br />
tained by the ventilator) and an NMR acquisition time of 200 ms per wan, for a total<br />
time per spectrum of approximarely 6 min .<br />
Since the TI's for PCr. d-ATP, and P, are approximately 4. 1 .5 . and 1 . S s. respectively<br />
(26), saturation e&cts wnuid result from using a delay time of 4 s . However. using<br />
longer delay times would make data collection times inordinately long . Therefore.<br />
MY[e aqe<br />
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C~CM Yt~Yn r, NrO .~<br />
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F•lo . 1 . Cwn•stcuond diatram of tulfatt eui7 placement an the heart weh a pmale urUhe eendti .
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146 oSBAKKEN ET AL .<br />
sereral sets of experiments were performed to determine the etfects of saturation .<br />
Delay times (TR time) of 4, 8 . 12 . 16. and 20 s were used . No change in signal/noise<br />
occurred for ATP or P, with a TR time of 4 s or greater . The PCr siplal increased<br />
progressively up to a TR time of 16 s(16% incpease from a 4 f TR time), with no<br />
funher increase in PCr signal with longer TR times . Since only one p:ak, the PCr<br />
peak, would experience saturation effecu and because we were osing taYeo data and<br />
not pertonning absolute quantification, we chose not to apply a correction /atctor for<br />
saturation to our data .<br />
The Pmblinn uf glotd ?.3J)ipposphughar~dre<br />
Samples otblood from three cats were taken and placed immediately in NMR tubes<br />
and studied at room remperature with 1aP NMR using a 12 .4-T magnet to determine<br />
the quantity of 2 .3-diphosphoglrceric acid in the btood which might contaminate the<br />
heart spectm under in rnn co:n3itions . Spectra wers obtained using melhylene diphosphonic<br />
acid (Meth Phos) as a standard. as wasdodie in trro. Inaddition. NaH2P0s<br />
was used as a P, reference . and 2 .3-DPG. PCr. and ATP were added sequentially to<br />
the blood to determine the relation or the chemical shi/t of blood peaks to those of<br />
known standards (Fig. 2). There was no evidence of 2•3•DPG in the blood spectra.<br />
B n. S~sbo•n<br />
.n. .+w<br />
C n~em n~.r N1<br />
froneem btt•^t . K' e// ~<br />
rw.r t .e¢ota<br />
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Fq. 2. B1ood fm
VOLUME LOADI.'G EFfEC13ON THE HEARt USING "P NMR 147<br />
This inditates Nat 2 .3-DPG is present in too small a qudntity to cause a problem with<br />
contamination of in vira hean spectm. There were twro blood peaks (peak 1 . peak 2)<br />
in the s'P NMR spectra of cat blood . Peak one had a chemical shift consistent with<br />
dtat of P, . Peak two had a chemical shift consistent with that of a phosphodiester .<br />
Thus.any increase in the P, peak ofin viraspectm would most likeiy be that generated<br />
fmnt intracellular metabolism .<br />
Pln:ciologira/ lmrnrntirnr<br />
~ After control spectra were acquired . volume o.Yrload (high output state) was produced<br />
by opening the previously constructed abdominal aorta-vena cava shunts . a'P<br />
spectra were obtained sequentially at 6-min intervals o .er I to 2 h or acute volume<br />
loading. Upon opening of the AVS . all cats had the typical increase in pulse pressure<br />
which is a good indication that the shunt has been opened .<br />
N.71R Data Anahsis<br />
Each free induction decay (FlD) was Fourier tmnsformed and filtered with 10 Hz<br />
line bmadening Spectra .verc phased and curve fi0ed(Lorcnt8an) using a least-squarex<br />
fit algorithm. Areas under each peak were integrated . Each spcctrvm contained the<br />
following peaks from left to right : inorganic phosphate . phosphocrcatine. and adenosine<br />
triphosphate (ATP: T . a . tT). Figs. 3 and 4. Ratios of P,/PCr and PCr/ATP were used<br />
to estimate the slatc ofoaidati•r phosphopiation . The chemical shift of P, with respect<br />
to PCr was used to determine the pH of myocardial cells during physiological intervention<br />
.<br />
To determine the reproducibility of"P NhfR data, the following was done . Under<br />
• contrd conditions (no physiological intervention) . five sets of spectra were obtained<br />
at the beginning of each esperfinent and at the end of each experiment for each cat .<br />
P,IPCr and PCr/ATP data were averaged and the standard deviation was determined .<br />
TTere was ±6% variability for P,/PCr ratios from acquisition of one slxctnnn m the<br />
next and t 108% variability for PCr/ATP ratios. Thus, there is mme random variability<br />
in "P NMR data which must be acknowledged when responses to physiological in•<br />
tervention areevalualed . A change in the P~/PCr mtio of greater than 61, and a ch ange<br />
in the PCr/ATP ratio of greater than i0't, must ocrur for a responsc to be considered<br />
due to physiological intervention and not due to random variability .<br />
Bioenergetir data as determined by P,/PCr and PCr/ATP ratios were corrclated<br />
with mechanical function as determined by hean m1e x systolic blood pressureprodun<br />
lHR x SBP is an estimate of oxygcn consumption (27)) with a linear regression algorithm<br />
. In addition, in order to follow changes in the above-mentioned parameters<br />
• with time and intervention (i .e . . to observe the effects of continuous modulation of<br />
feedback control ofchanges in wark load on metabolism and vice versa). percentage<br />
changes of P,/PCr, PCr/ATP. and HR x SBP from control were plotted with respect<br />
• to time and intervention .<br />
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RESULTS<br />
Although all animals were prepared and treated in a similar manner concerning<br />
maintenance of stable physiological conditions (maintenance of arterial blood gases .<br />
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149 OSBAKKEN ET AL<br />
a,,,. ena<br />
w M e<br />
^ . t : hta . .ric'<br />
flG . 3 . tompaile gaure of syeetri from a ar who ItapaMed to arule ancnrl-•enoYf Shumina rAVSr<br />
aith an increase in HR x SBP. Note that openina af ine AVS wat avonned ith an inneam in the as.<br />
under the P, pesk and a dennne in the uea under the Pt7 penk- flownr of the shanl %w associated %ith<br />
the relurn of P, and PCG peaks to neal avnuol lerclx Vme that the ehe/ni Wshia di8nenre bnuten p and<br />
PCe wu connant indicating Ihat PH did nol change durins •nlume loading Melhyienr diphovyhonic acid<br />
tMeah Phmr was used as a standard todelemmne that Ihe mqmerie Re1d/Bs1 rHnained tonstam Ihrouthout<br />
the eapenment P, inorganic Phosphure PCr . phosphocrtatinr: and ATT, adenodne tnphotphte .<br />
blood pressure. and volume status in physiological mngesl . metabolic and HR x SBP<br />
responses to acute volume loading nere .ariaMe for the different cats . Cats 1 . 3. 5 .<br />
and 6 had an increase and cats 2 . 4 . and 7 had a decrease in HR x SBP during acute<br />
volume loading. This may he due to intrinsicdiFerences in baseline physical condition<br />
or due to variable refle% responses secondary to imposition of volume load . Because<br />
these phenomena are not uncommon in clinical situations, ur think it is valid to<br />
preamt our data as such .<br />
Acute volume loading was not associated with a change in intmcdlular pH . as the<br />
chemical shiB betazen the P, and PC7peaks did not change during orafter completion<br />
of acute volume loading (as can be seen in representali .r spectra in Figs. 3 and 4) .<br />
After exlensive analysis . we determined that data woubd be most meoningfull,v rcporud<br />
by using a graphic presentmion ofpercentage chanibe from control ofinetabolic<br />
and mechanical fbncrional pammeurs. and a graphic presentation of the correla•<br />
tion analysis of raw data and percentage change Itom control data parameters<br />
(Fgs. 5-10).<br />
There were t.vo general tppes of HR x SBP responses resulting from imposition of<br />
the acute volume load of an AV shunt on the hean : krut cats (1, 3. 5. and 6) had an<br />
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VOLUh1E LOADIVG ER.r(TS ON THE HEART USING "P NMR 149<br />
~ . Rn A . n1b'<br />
~\.. .. ../w' V 1I~`M^b<br />
Fla. 4 . Comlwute 6purc of spmn fmro a aaw .tno mpondrC to .rnle anesial-.xnous sEuntinr IA VS/<br />
nilh a dntease in HR x SBP . Nole aat ,q'reirl opening of thr,huni aau asaonaed uith a $111111 innease<br />
in P, and slighl derreasP ; PC, peaL. . Mowtn. ahhourh sAen am 0unwnons In both peakt dnh<br />
minimal ehanm in both I . .aks ottVnM airouthnm rhe semmndnofmaimrnm•e ohhe nnmd-anour<br />
shunt . Spergra obtained aRer Hmure of ine shunt sho.d rhar P, irc¢ned and PCr d[deased slighti) . The<br />
legrnd u the Rme as that for Fig . I .<br />
increase in HR x SBP. and three cats (1, . 4_ 7) had a decrease in HR x SBP . Reprcsenmtice<br />
spectra throughout snlume loading for croswith ahe t ..-o di/ferent typrs of<br />
HR x SBP responses are presented in Figs . 3 and 4.IVotc that in cat 6 (Fig. 31• the P,<br />
peak increased and PCr peak decreased during volume load . while in cat 7(Fig 4) .<br />
there were minimal changes in these parameters. As can be seen from group dam for<br />
all cats presented in Fig . 5 . the bioenergetic responses to volume loading teqd to<br />
correspond to changes in mechanical work estimated by HR x SBP. Although not all<br />
of the P,/PCr or PCr/ATP responses w•ere gmater or less than 6 and 1011 . mspectisrly,<br />
which was considered necessan' for a response to he considered due to a ph)siologir<br />
intervention (determined via error analysis) . them wxreclear trends. When HR x SBP<br />
increased. P,/PCr increased and PCr/ATP decreased . When HR X SBP decreased .<br />
the R/PCr and PCr/ATP rrtios generally did not change significantly .<br />
Cortelation of P,/PCr ratios and PCr/ATP ratios viih HR x SBP was done for all<br />
cats and data are presented in Figs . 6 and 7 . For tsll cats, excepl cat 3 . the P,/PCr vs<br />
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150 OSB{KKEx ET AL<br />
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Cot 4<br />
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e P./PCr ,<br />
• PCr/0.TP<br />
Cot7 nleRwSBP<br />
- ~ccccxsrcas =f - F .^ asa stffc }<br />
FlG. 5 . Metabolic and meAunrral respnmrs to araje anenal-trnout shunts L41'SI in sr .en pn. Data<br />
tle pesented as pr+KnLigt changt from cnntrul (Su Y, J. 3- and 6 genenllv had an mctrase ,n HR x SBP<br />
during rmpoutlon of thunr tondmonf Cars 2 . l and 7 genrmlh had a dernaac m HR x SBP dunng<br />
impovuon nf .hunt eondniom The meut+obc pnameten IP,/PCr and PL-r/ATPI Parallel rhanges on mt .<br />
duniul panmeten tHR x SRPI: that is, am mivease in HR N SBr,canmmed .nlh am mmase in P{PCr<br />
end d.ertase in PCr/ATP nuos A derrease in HR x SBP is generally auwnaud ..iM a sl,ght ,nneau .<br />
drnrate. on rw change tn O,/P('r arM a 9rgln derrtau, mrrease, or no change on PCR!ATP ranos . P, .<br />
Inorgamr phosphate: PCr. phouphoc¢aone: ATP, denoune ttiphmPhn2 HR. hean ratr. and SBP-slxobr<br />
blood pnssure .<br />
HR x SBP relationship appeared to be quite stable : i.e. . there was minimal change in<br />
P/PCr for any change in the HR x SOP (Fig . 6) . The PCr/ATP vs HR x SOP r41ationship<br />
also appeared to be quite stable . with very little change in PCr/ATP with a<br />
change in HR x SBP (Fig. 7/.<br />
Evaluation of comMned cat data . for the entire volume loading time . demonslrated<br />
that PCr/ATP almosl always decreased (even if the decrease oas sometimes small)<br />
after opening of the AV shums. regardless of the HR x SBP /esponse (Fig . 8). In<br />
addition. P,/PCr generally increased in conjunction with a decrease in PCr/ATP for<br />
all points of time throughout acu7e volume loading (Rg . 9) . When changes in P,/f°Cr<br />
were eorrelated with changes in HR x SBP for all points in time for the entire grolap .<br />
there appeared to be a trend towald linearity (Fig . 10) t+'ith P,/PCr increasing as 11R<br />
x SOP increased .<br />
DISiL351O.`t<br />
There are a number of hypotheses concerning the tissue events which may lead In<br />
myroeardial eell damage and/or death (-'8--i1): ischemia . hypoxia . acidemia. oxygen<br />
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VOLUME LOADING EFFFCfS ON THE HEART USING 'P Nh/R<br />
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frcc mdicals. abnomlal calcium metabolism, lactate accumulation . pusrinsult Vascular<br />
changea, and possibly bioencrgetic changes. There have been many inveatigations tonmrning<br />
the eBccts of ischemia and/or h,vpoxia on energv metabolism of dte hean . h<br />
~ is now known that both of thesr conditions are associated aith changes in oxidative<br />
phosphorylation (dd-33). Although much is understood about rhe ellects of these<br />
stresses on energy metabolism. less is known about the'etTecl of other types of stress .<br />
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Flc. 6. forrelaron of HR X SBP rirh P,IPCr fou se.en sau durins acme aruriol-nnom shunung . Note<br />
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VOLUME LOADING EFFEe'fS ON THE HEART USING "P NMR<br />
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FiG . 10. Relatiomhiptaher AV alunl openedl d,htpenYn4yee chynPe frum eunlm7 ofP,/P(Y to pefeenteae<br />
ehang from eontrol of HR a SBP for all points,n time dur,np olume loading for all u .tn alt, Nme thn<br />
then appears to be a Iinear tetannn .hip 4vuxn tAerc pnropcd vrfaMet narch wat not ew{hm w-hen<br />
individual data utrc anaretd :,.e .. as HR x SBP increased P,/P(T intremed Thn indican tnn as rn&<br />
load mcro0.s. meaboOa mdummi, Iregulnionl of oudun .e phorpnmllmion is prubabl) appmpuate for<br />
the incrnsad merhamcal orL loads .<br />
Acute volume loaditly produced by creation of abdominal aona .•vena cava shunts<br />
(12. ?1 . 36) was associated with variable changes in NR x SBP . some cats with an<br />
increase and some wilh a decrease in HR x SBP . These responses were probxbly<br />
closely relaed to each animal's baseline homcostalic condition and/or ability ofregex<br />
recruitmem secondarc to volume loading . Metabolic responses to .nlume overload<br />
as reflected by changes in P./PCr and PCr/ATP generally paralleled mechanical re•<br />
sponses : i.e. . an increase in HR x SRP was associated with an increase in P,/PCr and<br />
a decrease in PCr/ATP and a decrease in HR x SBP was associated with a slight<br />
inerease . decrease . or no change in P,/PCr and a slighl decrease. inerease. or no change<br />
in PCr/ATP. Hoariern when group data were analyzed<br />
. the P,/PCr ratio wasgenemlhincreased during volume loading and appeared to be Iinearl,v related to HR X SBP•<br />
even though this relationship was not linear in each individual animal . This indicates<br />
that the P,/PCr ratio may be a go,x1 measure of metabolic induction and stability<br />
during myocardial loading conditions (when _^,3•DPG does not obscure the P, peak) .<br />
The P,/PCr response to volume loading generally appeared to be greater than the<br />
PCr/ATP response. This is reasonable because both parameters (P, and PCrI of the<br />
P,/PCr ratio change during intenenlion . whereas only one parameter of the PCr/ATP<br />
catio ostensibly changes. These changes in P,/PCr and/or PCr/ATP ratios may regulate<br />
the increase in oxidame phosphor)1ation whice may result from increasing the work<br />
of the hean: i .e. . phosphorylation potential as eslimated by P,/PCr and ADP cmncen•<br />
nation as estimated b. PCr/ATP appear to be regulators of myocardial metabolism<br />
during acute volume loading .<br />
In conclusion . acute .rolumc loading in cats uus associated with hioenergetic changes<br />
as measured by "P NhlR . Oxidative phospor.lafion . asestimated by P,/PCr and PCr/<br />
d,TP ratios. eas changed during acute snlume overload as dem,mstrated Man increase<br />
and/la decrease in P,/PCr and PCr/ATP. The changes in P,IPCr and PCr/ATP may<br />
ah as mesxngers for enryme induction to ultimately increase oxidative phosphory-<br />
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154 OSBAKKEN ET AL<br />
Idtion (state 4 to state 3 : inactive to aetire state . although since hean is always working,<br />
it is always in some sense in slate 3) and protein synthesis, which are compensatory<br />
mechanisms associated with more ehornic volume loading conditions If the work<br />
Iqad increased (} HR X SBP). there would be greater activation of oxidative phos .<br />
phorylation ; if work load did not change signigcantly. there would be no need for<br />
flhnher activation of oxidative phosphorylotion . It may be possible m use measurement<br />
of these phenomena in the following way to estimate the noetabolic reserve and/or<br />
viability of the hean under clinical conditions where changes in myocardial loading<br />
occur. Small changes in P,/PCr and/ar PCr/ATP ratios may indicate that there is<br />
considerable metabolic reserve and thus myocardial function 6s stable . Larger changes<br />
in these ratios may indicate that myocardial metabolism is strverdy tased and there<br />
is minimal metabolic rcsen•e, thus making myocardial function relatively tess stable.<br />
Fa,nher studies using J' P NMR techniques will be needed to rnore speciflplly suppon<br />
tlv.ese hypotheses .<br />
ACKNOWLEDGMENTS<br />
The wthnD7lunkluhn HaH18rDte and laek L
http://legacy.library.ucsf.edu/tid/fpe59c00/pdf<br />
VOLUME WADING EFfECFS ON THE HEART IISING "P NMR 155<br />
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