Effect of doxorubicin on calcium binding sites in guinea-pig heart.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
F Piccinini
Publications and source records attributed to F Piccinini.
Determination of doxorubicin and doxorubicin-3-ol in rat heart.
The discovery of a delayed form of DXR-induced cardiotoxicity raises the question whether the presence of the drug or of metabolites in myocardial cells is necessary for the development of cardiotoxicity. The present investigations deal with a new method for the determination of DXR and of its main metabolite, DXR-3-ol, in cardiac cells. Rat hearts "ex-vivo", isolated 24 h after i.v. administration of 6 mg/kg DXR and 20 micro C of DXR-14C, were perfused with ice-cold Tyrode solution, which releases anthracyclines from extracellular spaces. After homogenization DXR and DXR-3-ol were extracted from the cell at room temperature. The separation was carried out by HPLC; the recovery was about 95%, measured by the extracted radioactivity compared with that of the pellet residue.
Animals↗
Myocardial contractility and heart pharmacokinetics of adriamycin following a single administration in rat.
A single administration of adriamycin (DXR) 6.0 mg/kg i.v. to rats brings about a biphasic impairment of the maximal myocardial contractile performance, measured as dF/dt of ex vivo isolated atria incubated in the presence of calcium concentrations varying up to 12 mM. The initial impairment of the contractile performance peaks 1 week after DXR administration and recovers within 3 weeks (acute phase of cardiotoxicity). After this time and up to the end of the observation period (8 weeks after treatment), delayed cardiotoxicity occurs, showing a progressive and irreversible impairment of the contractile performance of the atria. This behaviour parallels the previously shown ECG and morphological abnormalities. Tissue determinations of DXR showed that the drug is present in myocardium during the acute phase of cardiotoxicity, while the metabolite adriamycinol is not detectable 1 week after DXR administration. These data show that the presence of DXR and/or metabolites in heart muscle is not necessary for the delayed form of cardiotoxicity to become apparent and suggest that this form of cardiotoxicity is related to a mechanism different from that involved in acute cardiotoxicity.
Animals↗
Effect of suloctidil on cerebral circulation patterns of conscious rabbits.
Suloctidil (SUL) produces calcium antagonistic and antispasmodic effects on peripheral and pial arteries. The present studies were performed with the aim of evaluating the action of SUL on cerebral blood flow (CBF), which was taken as an index for evaluating the cerebral circulation. The drug was administered by rapid intravenous injection to groups of unanaesthetized rabbits at doses of 100-200 micrograms/kg and by intravenous infusion at doses of 10-20 micrograms/kg/min. In other experiments, SUL was chronically administered p.o. to normal rabbits and to rabbits receiving Kritchevsky's atherogenic diet; the daily dose of the drug was about 16 mg/kg. Cerebral blood flow and its compartmental distribution were determined in unanaesthetized animals by the intracarotid 133Xe clearance method. The data demonstrate that the atherogenic diet brings about a significant impairment of CBF; SUL is inactive in normal rabbits, while in the atherosclerotic rabbits it induces a pronounced increase in cerebral blood flow in the grey matter and an enhancement of the corresponding circulatory compartment. These changes are less evident in the white matter.
Anesthesia↗
Preliminary evaluation of myocardial toxicity of 4'-deoxydoxorubicin: experimental and clinical results.
4'-deoxydoxorubicin (4'-deoxy-DXR), a new doxorubicin (DXR) analogue with interesting antineoplastic activity, was tested for its cardiotoxicity in guinea pigs and humans. In experiments on isolated guinea pig heart, which is considered a highly predictive model of acute anthracycline cardiotoxicity in humans, 4'-deoxy-DXR was found to be significantly less cardiotoxic than DXR. This effect was correlated with a lower degree of inhibition of the fast-exchanging calcium compartment and of the low affinity sarcolemmal calcium-binding sites. The preliminary study on 4'-deoxy-DXR in humans was conducted on 117 patients affected by advanced malignancies resistant to conventional chemotherapy. The drug was administered by bolus i.v. injection in doses ranging from 10 to 40 mg/m2 in the phase I study and in doses of 35 mg/m2 in the phase II study, which is still ongoing. Cardiologic evaluation consisted of recording of EKG, left ventricular systolic time intervals (STI), echocardiography and radionuclide ejection fraction. Preliminary data indicated a lower percentage of EKG abnormalities in comparison not only with DXR but also with other anthracycline analogues. Analysis of STI recorded 1 h after different doses of 4'-deoxy-DXR failed to show the dose-dependent effect on left ventricular function which has been described for DXR, thus confirming the lower acute cardiotoxic effect. Functional parameters serially measured to evaluate chronic cardiotoxicity in 15 patients who received more than 200 mg/m2 were not significantly different from basal values.
Adult↗
Role of the fast-exchanging calcium compartment in the early cardiotoxicity of anthracycline analogs.
Two new anthracycline analogs, 4'-epi-doxorubicin and 4'-deoxydoxorubicin, were tested for their cardiotoxicity and their activity on calcium turnover in guinea pig heart. The df/dt was used as an index of contractile force; calcium turnover was studied by means of a radioisotopic technique. 4'-Epi-doxorubicin was found less cardiotoxic than doxorubicin, whereas 4'-deoxydoxorubicin was found almost completely devoid of cardiotoxicity. The different cardiotoxic activity was found to be linearly correlated with the relative capacity to inhibit the fast-exchanging calcium compartment in cardiac muscle: doxorubicin greater than 4'-epi-doxorubicin greater than 4'-deoxydoxorubicin. This result supports that the inhibition of calcium exchange is involved in development of the early cardiotoxicity of anthracyclines.
Animals↗
Interaction between doxorubicin and mitomycin C on mortality and myocardial contractility in guinea pig.
The present investigations were carried out in guinea pig to ascertain whether mitomycin C has a direct cardiotoxic effect or interacts with doxorubicin-induced cardiotoxicity. I.p. administration of mitomycin C did not modify the survival rate up to 30 days, whereas the combined administration of doxorubicin and mitomycin C significantly decreased the survival time in comparison to the doxorubicin-treated group. On isolated atria, mitomycin C did not cause significant inhibition of the contractile force or an enhancement of the doxorubicin-induced negative inotropic effect. These results do not support the possibility that mitomycin C potentiates the acute cardiotoxic effects produced by doxorubicin.
Animals↗
Comparative evaluation of different methods for calculation of cerebral blood flow (CBF) in nonanesthetized rabbits.
The measurement of cerebral blood flow (CBF) by the extracranial detection of the radioactivity of 133Xe injected into an internal carotid artery has proved to be of considerable value for the investigation of cerebral circulation in conscious rabbits. Methods are described for calculating CBF from the curves of clearance of 133Xe, and include exponential analysis (two-component model), initial slope, and stochastic method. The different methods of curve analysis were compared in order to evaluate the fitness with the theoretical model. The initial slope and stochastic methods, compared with the biexponential model, underestimate the CBF by 35% and 46% respectively. Furthermore, the validity of recording the clearance curve for 10 min was tested by comparing these CBF values with those obtained from the whole curve. CBF values calculated with the shortened procedure are overestimated by 17%. A correlation exists between the "10 min" CBF values and the CBF calculated from the whole curve; in spite of that, the values are not accurate for limited animal populations or for single animals. The extent of the two main compartments into which the CBF is divided was also measured. There is no correlation between CBF values and the extent of the relative compartment. This fact suggests that these two parameters correspond to different biological entities.
Anesthesia↗
The effects of ethanol on the responses of the vascular musculature to norepinephrine.
Intravenous infusion of ethanol (EtOH) (up to 0.1 ml kg-1 min-1) does not modify the blood pressure in conscious rabbits. In this range of doses, EtOH brings about an increase of the pressure responses induced by norepinephrine (NE) with respect to values obtained in the absence of EtOH. Similar experiments have been performed on the isolated rat tail artery: EtOH perfusion does not modify the basal tone of the preparation up to 2% concentration, while the contractile response to NE administration is potentiated. The supersensitivity of the arteries to NE induced by EtOH, is a function of EtOH concentration and can be represented by a bellshaped curve reaching the maximal value at 1% EtOH, whereby concentrations larger than 2% induce an inhibition of NE activity. The present experiments suggest that the potentiation of the contractile effects of NE induced by EtOH might be related to an enhancement of the rate of calcium transport due to the increase in cell membrane plasticity induced by EtOH.
Animals↗
Effects of experimental atherosclerosis on cerebral blood flow in rabbits. Reversal by sorbinicate.
The present investigations were performed in conscious rabbits with the aim of determining the effects of an atherogenic diet (AD) on the cerebral blood flow (CBF) and of a nicotinic acid derivative (SN) on the CBF alterations induced by the diet. Experimental atherosclerosis reduces the blood flow in the rapidly exchanging cerebrovascular compartment; SN largely counteracts this effect. The experimental data suggest that the effect of this antiatherogenic drug is not due to vasoactive properties.
Animals↗
Relationship between the effect on calcium turnover and early cardiotoxicity of doxorubicin and 4'-epi-doxorubicin in guinea pig heart muscle.
Doxorubicin and 4'-epi-doxorubicin, two anthracycline derivatives with different cardiotoxic effects in experimental models, were found to decrease myocardial contractility in isolated guinea pig atria by significantly modifying calcium turnover. This effect seems to be mainly localized on the fast exchanging membrane-bound calcium, while these drugs do not significantly influence the intracellular stores of calcium. 4'-epi-doxorubicin, which induces a less negative inotropic effect than doxorubicin, produces a smaller inhibition of calcium turnover. This supports the hypothesis that the inhibition of calcium turnover and particularly of the fast exchanging calcium compartment is a general mechanism involved in the early anthracycline-induced cardiotoxicity.
Animals↗
Method for the determination of cerebral blood flow in conscious rabbits.
A procedure for the determination of cerebral blood flow by the local clearance method after intracarotid injection of 133Xe in the conscious rabbit is described. The inert radioactive indicator is injected into a permanent nylon catheter equipped with a two-way Gordth's needle inserted into the common carotid artery and filled with heparin, emerging behind the shoulders of the animals. All branches of the homolateral common carotid artery except the internal carotid artery were ligated. Studies of the distribution of colored tracers (dark blue ink) and radioactive tracers (99mTc albumin microspheres) show that the main localization of the injected indicator is within the homolateral hemisphere. Brain to blood partition coefficients of 133Xe are worked out for rabbit's gray matter (0.576 +/- 0.048) and white matter (0.808 +/- 0.023). The slope method for first and second component of the wash-out Xenon curve is used for CBF calculations. CBF determinations in 9 normal rabbits result in 84.27 +/- 5.59 and 16.69 +/- 2.44 ml/min x 100 g tissue, respectively, for the fast and slow component. Significant changes do not occur in serial determinations within 2 hr.
Anesthesia↗
Uptake and intracellular distribution of lanthanum.
The present investigation of the cellular distribution of lanthanum was undertaken in order to control the validity of the "Lanthanum method" used for the study of the cell calcium compartments. The presence of lanthanum was evaluated in the isolated guinea-pig heart and its subcellular fractions perfused with a lanthanum-containing Tyrode solution. Lanthanum was determined by instrumental neutron activation analysis. Under the adopted experimental conditions (30-min incubation in the presence of 12.5 microM lanthanum), lanthanum is carried across the cell membrane and is taken up by subcellular organelles. These results confirm the limited validity of investigations based on of the "Lanthanum method".
Animals↗
Influence of adriamycin on calcium exchangeability in cardiac muscle and its modification by ouabain.
Explore the source record for details and available documents.
Animals↗
Experimental investigations on the contraction induced by lead in arterial smooth muscle.
Previous observations suggested that the turnover of tissue calcium might be involved in the mechanism of smooth muscle contraction induced by lead. In the present investigations, the effect of lead on calcium exchangeability has been studied in the isolated rat tail artery. Experimental results suggest that the mechanism of lead action might be identified with a tissue calcium accumulation and with a lead-to-calcium competition. Evidence exists that the site of action is located in the cell membrane, where lead inhibits the processes of calcium extrusion, and in the intracellular calcium stores, whose calcium binding capacity is lowered; both processes induce an increase of the cellular exchangeable calcium available for contraction.
Animals↗
On the validity of the experimental conditions used for the study of the calcium turnover in isolated rat tail artery by the "lanthanum method".
Explore the source record for details and available documents.
Animals↗
Effect of lanthanum on the turnover of calcium in rat uterus.
Previous investigations suggest that lanthanum might enter uterine smooth muscle cells and work as intracellular calcium displacing agent. The present investigation had been carried out in order to confirm if lanthanum develops an intracellular effect. Experiments show that lanthanum brings about a marked increase of the intracellular calcium; the comparison of the uptake and of the wash-out curve of 45Ca shows that lanthanum induces a lowering of the rapid phase of 45Ca release from rat uterus, while the uptake of the labelled ion is not modified or is even enhanced. The present data demonstrate that the action of lanthanum in rat uterus is limited to the cell membrane, whose calcium extruding properties are inhibited.
Animals↗
Experimental investigations on the contraction induced by lead in arterial smooth muscle.
Explore the source record for details and available documents.
Animals↗