Doxorubicin (DXR) (0.17 x 10(-4) M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the S alpha T segment, with a decrease in force derivatives and in the coronary flow. Concurrent perfusion with fructose-1,6-diphosphate (FDP) (10(-5)-10(-4) M) dose-dependently reduces the S alpha T enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration

BERNARDINI MC

BERNARDINI N

DANESI R

DEL TACCA M

English

BERNARDINI, NUNZIA

DANESI, ROMANO

DEL TACCA M.

Archivio della Ricerca - Università di Pisa

tO00 Experientia 44 (1988), Birkh~user Verlag, CH-4010 Basel/Switzer}and Short Communications f _.p- g..--...-- ~00ms li;0,A '_f ~+/+8 HP=-50rnV Figure 3. Comparison of Ca-dependent K-currents in control saline (A) and in the presence of 10 nM CARP (B) at different voltages. Numbers on the right to the voltage curves show values by which the neurone was depolarized from the holding potential (t-IP = - 50 mV). D-cluster neu- ]~oTle. Since both Ca-inward and Ca-activated K-currents de- creased simultaneously in the presence of  CARP, so that the relationship between them was linear, it is suggested that depression of K(Ca) current is merely the consequence of  Ca-inward current inhibition. Recently it has became evident that neuronal membranes possess two types ofvoItage-sensi- five calcium channels: a transient, and a slowly inactivating one. In conclusion, the data presented above suggest a specific blocking action of the CARP on slowly inactivating Ca-current component. It is proposed therefore that CARP could be a selective Ca-channel blocker. Our experiments revealed that CARP strongly depresses the Ca-dependent K-current and the slowly inactivating Ca-in- ward current of snail neurones. In both cases the (Ca)~ may decrease, which is consistent with the idea proposed by Twarog 4, 5 for the relaxation mechanism of  catch. Acknowledgment. I am indebted to Dr Y. Muneoka (Hiroshima Univer- sity) and Dr I. Kubota (Suntory Institute, Osaka) for their kind donation of CARP for this study. i Hirata, T., Kawahara, A., and Muneoka, Y., Hiroshima J. med. Sci. 35 (1986) 397. 2 Hirata, T., Kubota, I., Takabatake, L, Kawahara, A., Shimamoto, N., and Muneoka, Y., Brain Res. 422 (1987) 374. 3 Twarog, B. M., J. cell. comp. Physiol. 44 (1954) 14l. 4 Twarog, B. M., Life Sci. 5 (1966) 1201. 5 Twarog, B. M., J. gen. Physiol. 50 (1967) 157. 6 Sakharov, D. A., and Sal~nki, J., Acta physiol, hung. 35 (1969) 19. 7 Gola, M., Hussy, N., Crest, M., and Ducreux, C., Neurosci, Lett. 70 (1986) 354. 8 L~':, D. H., and Hofmeier, G., Pfl~igers Arch. 394 (1982) 70. 9 Nowycky, M. C., Fox, P. A., and Tsien, R. W., Nature 316 (1985) 440. 0014-4754/88{11-120998-0351.50 + 0.20/0 9 Birkh~iuser Verlag Basel, 1988 Fructose-l,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart N. Bernardini, R, Danesi, M, C. Bernardini and M. Del Tacea Institute o f  Medical Pharmacology, Pisa University, Via Roma 55, 1-56100 Pisa (Italy) Received 22 April 1988; accepted 27 July 1988 Summary. Doxorubicin (DXR) (0.17 x 10 -4 M) induces an acute cardiotoxicity in isolated rat heart; there is a progressive widening of the SaT  segment, with a decrease in force derivatives and in the coronary flow, Concurrent perfusion with fructose-l,6-diphosphate (FDP) (10-~--10 -~ M) dose-dependently reduces the SaT enlargement but fails to affect the reduction in force derivatives and coronary flow. The target of cardiac protection by FDP might be the ionic mechanisms underlying the action potential configuration. Key words. Isolated rat heart; doxorubicin; acute cardiotoxicity; fructose-l,6-diphosphate. Doxorubicin (DXR) produces both acute and chronic car- diotoxic effects which are associated with marked ECG and hemodynamic changes in animals and in humans ~. Various pathogenetic mechanisms have been proposed to explain the acute cardiac damage, such as free radical production 2, membrane phospholipid peroxidation ~, intracellular ATP decrease r and histamine release s. Fructose-l,6-diphosphate (FDP) is a metabolic regulator which has been successfully emploTyed in acute myocardial ischemia 6 and in hemorrhagic shock , which are both characterized by a significant de- crease in energy supply. Under these conditions, FDP causes a regression of electrocardiographic (ECG) ischemic changes and prevents arrhythmias in acute myocardial infarction 6, 7. In the present study, the effects of  F D P  on isolated rat hearts perfused with DXR are investigated. It appears from these experiments that FDP is able to reduce ECG alterations but not the contractile force changes induced by DXR.  Materials and methods. Isolated hearts. Female Sprague- Dawley rats (250-300 g) were injected with heparin 500 IU/  kg i.p. and then killed by cervical dislocation. Hearts were rapidly removed and placed in a cold physiological solution; then the aorta was cannulated to allow retrograde coronary perfusion with Locke solution at 37 ~ aerated with 100 % 02,  pH 7.4, in a Langendorff apparatus (perfusion pressure 60 mm Hg). Locke solution had the following composition (raM/l): NaC1 153.97, KCI 5.63, CaC1 z 2.18, NaHCO 3 1.78, glucose 5.09, The hearts were perfused for an initial 30-rain stabilization period. Cardiac parameters. The cardiac electric activity was record- ed by a computerized on-line evaluation system to allow the measurement of various ECG parameters s. ECG monitor- ing was performed before and during perfusion with the drugs (1 h), by means of 2 atraumatic electrodes 9, one recording from the right atrium and the other from the heart apex, This system was used to measure heart rate (beats/ rain), the S~T segment duration (ms) and T-wave voltage (mV). The contractile function was recorded by an isometric transducer (Basile DY2) directly connected to an ADCI/T channel of  a Battaglia Rangoni ESO 600 polygraph, The first derivative of  the contraction or relaxation over the time (_+ dF/dt)  was determined starting from the force signal elab- orated by an AO/DP/NS operational channel (Battaglia- Short  C o m m u n i c a t i o n s  Experientia 44 (1988), Birkhiiuser Verlag, CH-4010 Basel/Switzerland 1001 Effects of DXR (0.17 x 10 -4 M), FDP (10 -s  - 5 x 10 -5 - 1 0  - 4  M) and DXR + FDP on SeT segment (SET) (ms), T-wave (Tw) (mV), heart rate (HR) (beats/rain), contractile force (F) (g), +_dF/dt (g/s), and coronary flow (CF) (ml/min) in isolated perfused rat heart. C, hearts perfused with drug-frce Locke solution. Time (min) Basal 5 15 30 45 60 SeT C 13.1 5 :0 .4  0.15• 0 . 0 1  - 0 . 1 0 •  0.08 0.20-+ 0 . 0 9  -0.15_+ 0.08 FDP 10 -5 12.2 5:0.25 0.08 • 0.03 0.12 • 0.08 0.10-+ 0.04 -0.06 • 0.01 F D P 5 x l 0  -s  12.5• 0.25 0 • 0 0.25• 0 . 0 8  -0.10-+ 0 . 0 3  =0 .25•  0.01 FDP 10 -4 14.7 • 3.7 0 + 0 --0.25 • 0.25 0.25 • 0 . 2 5  -0.08 • 0,04 DXR 12.8_+ 1.1 0.80+ 0.30 1.3 • 0.33* 2.1 • 0.43* 2.7 -+ 0.51" D X R + F D P 1 0  -5 15.5-+ 0.67 0,75• 0.25 1.4 _+ 0.47* 1.9 • 0.47* 2.2 -t- 0.47* D X R + F D P 5 x l 0  -5 11.4_+ 1.4 0.62+ 0.31 1.0 4- 0.20* 1.2 -+ 0.14" 1.6 • 0.31" D X R + F D P 1 0  -4 13.5• 0.66 0.65• 0.15 0,95-+ 0.18" 1.1 • 0.21" 1.4 • 0.31" Tw C 1.9 • 0.12 -0.05 + 0.01 -0.05 • 0 . 0 1  -0.12-+ 0 . 0 6  -0.20___ 0.05 FDP 10 -5 1.1 _-+ 0.14 0.07 • 0.02 0.07 • 0.02 -0.06 • 0 . 0 1  --0.15___ 0.05 F D P 5 x l 0  -5 2.7• 1.2 - 0 . 0 5 +  0 . 0 5  - 0 . 0 5 +  0 . 0 5  -0.25+_ 0 .05  - 0 . 5 5 •  0.25 FDP 10 -4 2.0 • 0.40 0.50 + 0 . 0 8  -0.05 + 0 . 0 5  -0 . I0  • 0 . 0 3  -0.15 • 0.05 DXR 1.9 • 0.19 -0.06 + 0.06 -0.07 • 0 . 0 6  -0.18 _ 0 . 0 7  -0.26 • 0.09 DXR + FDP 10 -s  2.0 + 0.26 --0,02 • 0 . 0 5  -0.10 + 0.04 -0.17 -+ 0.06 --0~27 • 0.02 D X R + F D P 5 x l 0  -s  1.6• 0 , 0 9  -0.05-+ 0 . 0 9  - 0 . 0 5 +  0 . 0 1  - 0 . 1 5 •  0 . 0 1  - 0 . 2 0 +  0.01 DXR + FDP 10 -4 2,0 • 0,15 0.05 + 0.04 -0.03 -+ 0 . 0 2  -0.10 • 0 . 0 3  -0.18 • 0,06 HR C 222.0• -4.8 + 4.4 -6 .2  -+ 2.8 -11.5 • 4.9 -20.7 • 3.0 FDP10 -5 207.0• 2.3 -1 .9  + 0.70 -18.0 • 2.0 --35.5 • -35.5 • F D P 5 x l 0  -s  204.5• -26.0 • -33.0 • -37.0 • --37.0 • FDP10 -r 253,0• 0 + 0 --12.6 -+ 8.2 -24.5 • 10 ,5  --25.7 • DXR 225,8• -12.8 • 4.8 --22,8 -+ 3.5 -35.0 • 8,1 --49.4 • D X R + F D P 1 0  -s  237,0• --43.5 • 9.7* --65.2 -+15.3" -73.7 +15,8" --91.2 •  D X R + F D P 5 x l 0  -~ 221.5• --28.0 • 5.4* --46.0 5: 8.6* -42.0 • 8.6* --63.0 •  D X R + F D P 1 0  242.2• -20.6 + 5.3 -39.0 • 6.2* -61.5 •  --81.0 _+16.3" F C 1.5• 0.16 -0.01 • 0.04 - 0 . 0 8 +  0.06 - 0 . 0 7 •  0 . 0 8  --0.07• 0.11 FDP 10 -5 1.9 • 0.11 0,02 • 0.01 0.03 • 0.01 0.01 • 0.01 0.05 • 0.02 F D P 5 x I 0  -5 1.3• 0 . 2 5  -0,12-+ 0.05 0.04_+ 0 . 0 1  -0.15_+ 0 . 1 0  - 0 . 2 0 •  0.18 FDP 10-'* 1.4 • 0.10 0.05 • 0.01 0.10 • 0.01 0.10 • 0.02 0.15 • 0.05 DXR 1.3 • 0.09 -0,12 • 0 . 0 5  -0.18 • 0 . 1 1  -0.30___ 0 . 1 5  -0.47 • 0.18 D X R + F D P 1 0  -5 1.8 _ 0 . 3 0  -0.30-+ 0.06 - 0 . 2 2 +  0 . 0 6  --0.22-+ 0 . 0 7  - 0 . 3 2 •  0.14 DXR + FDP 5 x 10 -5 1.7 • 0.28 -0.32 • 0.11 -0.28 • 0 . 0 9  -0.29 • 0 . 0 9  -0.39 • 0.18 DXR + FDP 10 -4 1.6 -+ 0.06 -0,26 • 0 . 0 8  -0.30-+ 0.06 -0.41 • 0 . 1 2  --0.46 _+ 0.14 + dF/dt C 63.9• 4.1 -1 .8  • 1.1 -6.1 • 1.7 -5.5 -+ 2.6 -7 .4  -+ 2.9 FDPI0  -s  40.3-+ 0.85 0 -+ 0 1.3 • 0.50 1.1 + 0 . 0 8  - 0 . 8 0 •  0.05 F D P 5 x l 0  -5 31.2• 2.9 --2.3 • 0.90 1.1 -+ 0.02 -1 .0  -+ 0.05 -2 .5  • 0.50 FDP10 -r 61.1 • 6.1 2.5 • 0.91 3.5 • 0.80 4.6 • 0.35 3.4 • 0.91 DXR 53.3-t- 3.5 -6 .9  • 5.4 -11.4 • 4.9 -16.2 • 6.5 -23.5 -+ 7.3* D X R + F D P 1 0  -5 61.3• -7 .4  -+ 4.1 -14.7 • 4.3 --16.9 • 4,9 -23.4 -+ 8.7* D X R + F D P 5 x l 0  -s  39.1__ 8.0 -5 .3  -+ 1.3 -7 .8  -+ 2.3 -9.1 -+ 2.8 -13.1 • 4.4 D X R + F D P 1 0  -4 66.3• 3.6 -11.3 -+ 4.5 -16.1 • 2.7 -21.1 • 5.1 -19.2 _+ 5.9 - d F / d t  C 40.1 • 2.5 - 0 . 3 2 •  2.2 -2 .5  • 1.5 -4 .2  • 3.4 -4 .5  • 3.5 FDP10 -s  47.2-+ 0.22 -1 ,4  • 0.21 -2 .8  -+ 0,10 5.5 • 0.25 -7 .0  • 1.1 F D P 5 x I 0  -5 29.t+_ 7.3 -5.1 ~ 1.0 -2 .3  -+ 0,05 -4 ,9  • 0.80 -8 .0  • 0,90 FDPI0  -4 34,8-+ 0.15 0 -+ 0 1.2 • 0,05 -1 .4  • 0.01 --0.8 -+ 0.02 DXR 38.6• 4,5 -4 .4  • 2.1 -5 .7  • 1,0 -10.7 • 1.8 -18.9 • 3.9* D X R + F D P I 0  -5 43.6• 9,3 -9.1 • 2.6 --10.8 _ 312 -12.5 • 4,4 -18.9 • 6.8* D X R + F D P 5 x l 0  -5 39.5• 6.9 -7 .2  • 2.5 --9.1 + 2,4 -9 .6  -+ 2,1 -13,0 -+ 3.2 D X R + F D P I 0  -4 44.7-+ 3.1 --11.2 • 3.5 -14.9 • 3,7* -17.4 • 5.3* -16.9 • 4,7* CF C 5.2 + 0.48 -0.05 + 0 . 0 5  -0.1") • 0A0 -0.32 • 0 . 1 3  -0.45 • 0.16 FDP 10 -5 5.7 • 0.25 --0.10 • 0 . 0 1  --0.17 • 0.02 --0.15 ___ 0 . 0 3  --0.45 • 0.09 F D P 5 x l 0  -5 5.3• 0 . 1 5  - 0 . 1 6 •  0 . 0 1  - 0 . 1 0 •  0 . 0 1  - 0 . 1 5 •  0 . 0 3  - 0 . 4 8 •  0.02 FDP 10 -4 5.2 • 0.75 0 -+ 0 -0.15 • 0.01 -0.15 • 0 . 0 2  -0.30-+ 0.06 DXR 5.6• 0.50 - 0 . 7 6 •  0 . 1 8  -0.74-+ 0.24 -1.1 • 0.33 -1 .5  • 0.21" D X R + F D P 1 0  -5 5.4_+ 0.56 -1 .7  • 0.35* -1 .8  • 0.38* --1.9 • 0.43* -2 .2  • 0.52* D X R + F D P 5 x l 0  -5 4.9•  0 . 5 0  - 0 . 7 2 •  0 . 2 8  - 0 . 9 2 •  0 . 3 7  - 0 . 8 7 •  0.40 -1 .6  • 0.72* D X R + F D P I O  -~" 5.6• 0 . 2 0  --0.96• 0.26* -1 .5  • 0.24* -1 .9  ___ 0.17" -2.5 • 0.32* 0.08 • 0.05 0.05 • 0.10 0.03 • 0.02 -0.08 • 0.08 3.3 • 0.54* 2.7 • 0.59* 1.9 • 0.51" 1.6 • 0.33* -0.32 • 0.04 -0.15 + 0.04 -0.55 • 0.25 -0.25 ___ 0.05 -0.34 • 0.11 -0.35 • 0.06 -0.20 • 0.02 -0.25 • 0.07 -20.2 + 6.8 -40.5 • 26.5 -42.0 • 20.1 -35.5 • 17.7 -66.6 • 16.1" -100.2 + 25.6* -79.2 -t-16.3" -103.0 -I-21.5" --0.13+ --0.05 • --0.20 • 0.12 + --0.63 + --0.55 • --0.50 • -0.52 • --7.4 _+ --1.5 _+ --4.6 _ 3,4 _+ --27.6 • --23.2 • --15.8 • -25.7 + -7 .5  +_ -8 .5  • -9.1 _+ -1 .5  _+ -24.5 + -22.4 _+ -17.3 _+ -22.5 _+ -0,60 _+ -0.50 + -0.60 + -0,45 + -2 ,2  --+ -2 .5  _ -1 ,8  • -2 ,5  • 0.10 0.01 0.19 0.02 0.19 0.23 0,14 0.12 3.3 0.90 0.51 0.92 6.5* 8.4* 3.9 5.6* 2.5 0,50 0.31 0.9 5.3* 8.0* 3.1" 4.6* 0.13 0.13 0,07 0.05 0.17' 0.53* 0,70" 0.43 * Data are mean + SE changes from basal values. Each value represents the mean of n = 5 (control and FDP) and n = 10 (DXR Student's t-test for grouped data: * p < 0,05 vs control values. and DXR + FDP) experiments. 1002 Experientia 44 (1988), Birkh/iuser Verlag, CH-4010 Basel/Switzerland S h o r t  C o m m u n i c a t i o n s  Rangoni, Bologna, Italy). The coronary flow was measured by determining the volume of the solution spontaneously drained by the heart in 1 rain. Drugs. DXR-HC1 (Farmitalia-Carlo Erba, Milano, Italy) and FDP (Biomedica Foscama, Ferentino, Italy) were dis- solved in distilled water and then added to Locke solution. The final concentrations were respectively 0.17 • 10 - 4  M for DXR-HC1 and 10 - 5 -  5x10 - s -  10-4M for FDP. The concentration of DXR was selected on the basis of dose-re- sponse curves which indicated that this dose was associated with significant changes of ECG and contractile force during the whole of the experimental procedure. Moreover the dose of DXR used in our study is in the range employed by vari- ous authors in experiments on anthracycline cardiotoxicity in vitro lo, 11. Higher doses produced excessive cardiotoxici- ty signs. The addition of FDP and/or DXR did not apprecia- bly change the pH and the osmolality of the Locke solution. All other chemicals were of analytical grade. Statistical analysis. The data are presented as means _+ SE. Student's t-test for paired or grouped data was used to deter- mine the significance of differences and p values less than 0.05 were considered to be significant; n indicates the num- ber of the experiments. Results. No changes were observed in any of the parameters examined, either in controls or in hearts perfused with FDP. Although DXR did not significantly modify the contractile force and the T-wave, it induced a progressive widening of the SaT segment which became significant 15 rain after the beginning of the perfusion (table). This effect was dose- dependently reduced by FDP (fig.), whereas DXR-induced decrease in the heart rate, +dF/dt, -dF /d t  and in the coro- nary flow was not prevented by FDP (table). The same de- gree of protection was obtained with FDP given before or in combination with DXR. Discussion. The present study shows that FDP reduces the SeT widening induced by DXR, but fails to affect the other parameters recorded. The enlargement of the SaT segment might depend on the altered repolarization phase of cardiac cells 13,14 due to the inhibition of Ca 2+ turnover into the sarcoplasm caused by DXR 12 In addition to this, the inhibi- tion of Ca 2 + transport across sarcolemmal membranes 15 and the impairment of energy production by rat heart slices exposed to D X R  r could participate in the SaT segment prolongation. The activity of FDP in improving the ATP production by the glycolytic pathway may explain the pro- tective effect of the drug on the SaT segment, since it has been shown that ATP production by glycolysis is effective in preserving membrane function, which could include the maintenance of Ca 2 + ion homeostasis 16. An additional pro- tective mechanism of FDP is likely to accord with the stimu- lation of MgZ+-dependent CaZ+-ATPase activity in cell membranes 17 The failure of FDP to prevent the reduction of cardiac con- tractile force derivatives induced by DXR might depend on the multifactorial pathogenesis of cardiac damage including the formation of semiquinone and oxygen radicals 2 and lipid peroxidation 3. As the pathogenetic mechanisms of acute cardiotoxicity by DXR may be involved in DXR chronic effects 18, the protec- tive action of FDP against DXR acute alterations might be useful in fimiting chronic cardiac damage. 3,5 2.5 v 1.5 <3 0.5 -0.5 I 9 I I f 9 I F ~ L ! 5 15 30 45 60 Tlme (mln) Changes in the SaT interval from basal value in hearts perfnsed with Locke solution (control) (T), FDP 10 -5 M (IS]), FDP 5 x 10 -5 M (11), FDP 10 -4 M (O), DXR 0.17 x 10 -4 M (~),  DXR + FDP 10 -3 M (At), D X R + F D P 5 x I 0 - S M  (9 and D X R + F D P 1 0 - 4 M  (O). Each point represents the mean ofn  = 5 (control and FDP) and n = 10 (DXR and DXR + FDP) experiments • SE (vertical bars). Student's t-test for grouped data: * p < 0.05 vs DXR values. Acknowledgments. This work was performed with the collaboration and the technical assistence of Mr B. Stacehini. N. Bernardini and R. Danesi are recipients of a fellowship from the Italian Association for Cancer Research (A.I.R.C.). 1 Young, R. C., Ozols, R. F., and Myers, C. E., N. Engl. J. Med. 305 (1981) 139. 2 Doroshow, J. H., Cancer Res. 43 (1983) 460. 3 Myers, C. E., McGuire, W. P., Liss, R. H., Ifrim, I., Grotzinger, K., and Young, R. C., Science 197 (1977) 3[65. 4 Neff, B., Cini-Neri, G., and D'Alterio, M., Biochem. biophys. Res. Commun. 125 (1984) 954. 5 Klugmann, F. B., Decorti, G., Candussio, L., Grill, V., Mallardi F., and Baldini, L., Br. J. Cancer 54 (1986) 743. 6 Markow, A. K., Oglethorpe, N. C., Blake, M. I., Lehan, P. H., and Hellems, H. K., Am. Heart J. 100 (1980) 639. 7 Markow, A. K., Oglethorpe, N., Young, B. Y., and Hellems, K. H., Circ. Shock 8 (1981) 9. 8 Danesi, R., Del Tacca, M., and Soldani, G., J. pharmac. Meth. 16 (1986) 251. 9 Curtis, M. J., Macleod, B. A., Tabrizchi, R., and Walker, M. J. A., J. pharmac. Meth. 15 (1985) 87. 10 Okano, C., Kwok, O., Hokama, Y., and Chou, S. C., Res. Commun. chem. Path. Pharrnac. 45 (1984) 279. 11 Saman, S., Jacobs0 P., and Opie, L. H., Cancer Res. 44 (1984) 1316. 12 Monti, E., Piccinini, F., Favalli, L., and Villani, F., Biochem. Phar- mac. 32 (1983) 3303. 13 Jensen, R. A,, Acton, E. M., and Peters, J. H., J. cardiovasc. Phar- mac. 6 (1984) 186. 14 Bernardini, C., Del Tacca, M., Danesi, R., and Della Torte, P., Archs int. Pharmacodyn. 283 (1986) 243. 15 Caroni, P., Villani, F., and Carafoli, E., FEBS Lett. 130 (1981) 184. 16 Goto, M.,Yatani,-A., and Tsuda, Y., Jap. J. Physiol. 27 (1977) 81. 17 Galzigna, L., and Rigobello, M. P., Experientia 42 (1986) 138. 18 Doroshow, J. H., Locker, G.Y., and Myers, C.E., Cancer Treat. Rep. 63 (1979) 855. 0014-4754/88/11-12/1000-0351.50 + 0.20/0 O Birkhauser Verlag Basel, 1988 

Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart

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Fructose-1,6-diphosphate reduces acute ECG changes due to doxorubicin in isolated rat heart

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