Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit.

Recently, vitamin E has been proposed to protect against Adriamycin-induced cardiotoxicity. We studied contractile decline and ultramicroscopic alterations of the heart of rabbits chronically treated with Adriamycin up to a cumulative dose of 400 mg/sq m. High doses of vitamin E did not protect against the Adriamycin-induced development of severe contractile decline as evaluated by means of measurement of the interval-force relationship curve. Light and electron microscopic analysis did not show any signs of protection against Adriamycin-induced morphological alterations. Biochemical and hematological alterations. Biochemical and hematological alterations caused by the antineoplastic agent were similar in both Adriamycin-treated animal groups. Coadministration of vitamin E did result in an increased life span. This study indicates that vitamin E does not protect against the development of cardiomyopathy and contractile decline after chronic exposure to Adriamycin.

Pericardiocentesis guided by a pulse generator.

This study was performed to compare pericardiocentesis guided by a pacing current applied through the pericardiocentesis needle with the traditional method of monitoring ST segment elevation from the needle tip electrogram. ST segment elevation was measured at 3 mm from the epicardium, after epicardial contact, after epicardial penetration and again at 3 mm from the epicardium after epicardial penetration. Two millivolts of ST segment elevation gave the highest combined positive (86%) and negative (79%) predictive value for epicardial contact by the pericardiocentesis needle between the two groups with the largest difference: 3 mm from the epicardium before contact and after epicardial penetration. Therefore, ST segment monitoring cannot reliably determine the point of epicardial contact. To determine the optimal stimulus strength for pulse generator-guided pericardiocentesis, pacing studies were performed using 2, 4, 6, 8 and 10 mA unipolar stimulus strengths. The pacing studies were performed both with and without a hemodynamically significant pericardial effusion to determine if increased pericardial pressure altered the pacing threshold. A 4 mA unipolar cathodal stimulus was chosen because it captured the ventricle only with direct contact of the epicardium. Ten dogs were instrumented and cardiac tamponade produced so that a subxiphoid approach to the epicardium with the pacing needle electrode could be attempted. During pericardiocentesis, needle tip electrograms were recorded, alternating with pacing attempts using a 4 mA unipolar stimulus. In all 10 dogs, the effusion was entered and epicardium was contacted as indicated by capture. No myocardial perforation or coronary artery or venous injuries were produced. These findings support the use of a pulse generator to guide pericardiocentesis.

Acute voltage, charge, and energy thresholds as functions of electrode size for electrical stimulation of the canine heart.

This paper analyses the relationships between electrode size and charge, voltage, and energy thresholds in acute animal experiments. Cathodal stimuli of 1 ms duration are applied to canine hearts by using epicardial disc electrodes. Threshold charge in constant current and in constant voltage stimulation proves to be proportional to the electrode radius (a) to the power 1.5 for a greater than 0.4 mm and to be independent of electrode size for a less than 0.2 mm. Voltage and energy thresholds are proportional to square root a and a2 respectively for a greater than 1 mm. Voltage thresholds show a minimum at a radius of about 0.5 mm, energy thresholds at about 0.3 mm. These results are explained by using two principles. The first is that the charge applied to the heart determines the response of the tissue to a stimulus and the second, that electrode impedance may be described by an RC-series circuit in these experiments. The resistance in this circuit is inversely proportional to electrode radius, in agreement with calculation of the electric field around the electrode. Electrode capacity depends linearly on electrode surface area. Stimulation is most efficient under the circumstances mentioned above for an electrode radius of about 0.3 mm.

Ca2+-free perfusion of isolated rat heart: early irreversible changes and discrepancy between functional impairments and release of cellular constituents.

The effects of repeated (10 X), brief Ca2+-free perfusions (20 to 120 s) on myocardial contractility, coronary flow and release of cellular constituents of isolated rat heart were investigated. Ten successive Ca2+-deprivations of 20 or 40 s had no irreversible influences on cardiac performance. Ca2+-deprivations, however, of 60 s or longer, resulted in a substantial depression of contractile activity during recovery, which effect was parallelled by the development of myocardial contracture. Both effects appeared to be additive in character (and thus irreversible) and were dependent upon the duration and number of Ca2+-deprivations. The effect on coronary flow was biphasic: after an initial, rapid increase coronary flow steadily declined and was almost normal at the end of the experiments. The release of cellular constituents into the coronary effluent only occurred during reperfusion with Ca2+ after Ca2+-free periods of 60 s or longer. This loss of cellular material from the heart was observed mainly after the first Ca2+-deprivation and was only small or even negligible during the subsequent Ca2+-deprivations. The overall release of cellular material was clearly dependent on the duration of the Ca2+-free period, but was badly related to the overall loss in contractile activity. It was concluded that a relatively brief Ca2+-free perfusion period may induce a small but irreversible damage to the heart. This damage becomes visible, and more deleterious, when the brief Ca2+-washout is repeated several times. In addition, it was concluded that Ca2+-free-induced functional impairments and the release of cellular constituents of the heart are badly correlated and may be caused by two separate, but probably interrelated, mechanisms.

Site of initial excitation and current threshold as a function of electrode radius in heart muscle.

End-diastolic current thresholds have been measured in 13 open chested dogs as a function of electrode radius by stimulating the left ventricle with epicardial disc electrodes ranging in a radius from 0-3 mm to 9 mm. Thresholds for cathodal rectangular short stimuli as well as specifically for cathodal make stimulation, proved to be proportional to the electrode radius to the power 1-5. This relationship between radius and threshold can be explained theoretically, assuming that electrical stimulation results in a propagated depolarization front if a critical current density is reached somewhere in the myocardium. The current distribution measured over the electrode and the site of initial depolarization in the tissue are in accordance with this theoretical explanation.

Autogenous vein graft thrombosis following exposure to calcium-free solutions (calcium paradox).

The morphological and functional effects of calcium-free and calcium-containing solutions on canine jugular vein intima were examined under conditions which closely resemble those techniques currently employed in peripheral vascular and aortocoronary bypass surgery. Veins that had been exposed only to calcium-containing solutions remained patent for the duration of the experimental period. Vein perfusion with a calcium-free solution, however, resulted in disruption of the jugular vein intima once calcium ions were reintroduced. Autogenous as a femoral arterial graft became thrombosed within 60 minutes. It is therefore suggested that vein grafts of autogenous origin be irrigated with calcium-containing solutions to prevent intimal damage and thrombosis.

Hemodynamic and metabolic consequences of hemodilution with different diluents.

Hemodilution was performed with the crystalloid Ringer's lactate (n = 6) and the colloid Haemaccel (n = 5) in dogs during automatically controlled total cardiopulmonary bypass with constant arterial and venous pressures. Single observations were made with Macrodex and Rheomacrodex hemodilution. Hemoglobin concentration and hematocrit were used as parameters for hemodilution. Total plasma protein proved to be unsuitable. The volume needed to induce the same level of hemodilution with lactated Ringer's and Haemaccel was twice the volume needed with Macrodex and Rheomacrodex. The volume shift from intravascular to extravascular was larger during Ringer's lactate hemodilution than during Haemaccel hemodilution. The amount of volume shift was clearly related to changes in colloid osmotic pressure. Lowering of total peripheral vascular resistance, with increased arterial line flow during controlled constant arterial and venous pressures was seen during hemodilution with each of the above materials. Potassium and calcium concentrations in the blood increased significantly during hemodilution with Haemaccel. Base excess was constant during hemodilution with lactated Ringer's but decreased in all other cases. A decrease in oxygen consumption was common, and most pronounced during hemodilution with Haemaccel.

The influence of biperiden in overdose on respiration and circulation in the dog.

Biperiden lactate was administered intravenously in overdose to dogs under general anaesthesia. Biperiden appeared to have a toxic influence on respiration and circulation independently. Respiratory arrest occurred at a dose of 33 +/- 10 mg/kg and has probably a central origin. When artificial ventilation was instituted circulatory standstill occurred at a dose of 45 +/- 5 mg/kg. The toxic influence of biperiden is characterised by a decrease of heart rate and of left ventricular contractility resulting in cardiogenic shock. Biperiden is compared with orphenadrine as far as its potential hazard is concerned for patients trying to commit suicide by ingesting an overdose.

Influence of ATP or oxygen plus substrate on occurrence of the calcium paradox.

Reperfusion of Ca2+-deprived rat hearts with Ca2+-containing medium results in irreversible cell damage (calcium paradox). In this study this type of cell damage was studied in the anoxic rat heart, in the presence and absence of glucose. Creatine kinase (CK) release was used to define cell damage. Hearts were perfused successively with Ca2+-containing medium (30 min), Ca2+-free medium (5 min), and Ca2+-containing medium (5 min). In the presence of glucose, myocardial ATP was maintained at a fairly high concentration. Reperfusion with Ca2+ resulted in an immediate and massive release of CK. In the absence of glucose, the ATP concentration was almost zero after 30 min. Reperfusion with Ca2+ did not result in release of CK. Massive release occurred as soon as these hearts were reoxygenated. It is concluded that this type of calcium-induced cell damage only occurs in the presence of ATP, or oxygen plus substrate. Mitochondria most likely play a major role in the occurrence of the calcium paradox because of their ability to accumulate huge amounts of Ca2+ under these conditions.

The calcium paradox: a reaffirmation.

Perfusion of isolated rat hearts with a Ca-2+-containing medium, after a Ca2+-free perfusion period, results in an irreversible loss of electrical and mechanical activity of the heart, as well as a large release of intracellular components such as lactate dehydrogenase. These phenomena can be evoked, when hearts are perfused at a constant perfusion pressure or at a constant flow rate. Evidence is provided that recovery of the mechanical activity of the heart is not a requisite for lactate dehydrogenase release.

Cardioplegia in the presence or absence of calcium.

The effect of the Bretschneider procedure of myocardial protection on the recovery of dog hearts in the postischemic phase after 90 min of aortic occlusion was studied. In one series of experiments, Bretschneider's calcium-free cardioplegic solution HTP was used; in a second series, 5 X 10(-5) M CaCl2 was added to this solution. The coronary system was perfused with cardioplegic solution (6 degrees C) for 6 min at the onset and for 1 min after 30 and 60 min of ischemic arrest. Functional recovery of the heart and plasma creatine kinase activity during the postischemic phase were not significantly different in the two groups of dogs. It is concluded that low temperature, mode of administration, and composition of Bretschneider's cardioplegic solution HTP protect the heart against the potential danger of exposure to a calcium-free solution.

A concentration-dependent biphasic positive inotropic action of ouabain on isolated heart of rat and guinea-pig.

Log dose-response curves of ouabain on rat and guinea-pig heart revealed the existence of a concentration-dependent, biphasic inotropic effect of ouabain. With rat as with guinea pig heart the "first" effect observed at the lowest concentrations of ouabain, was relatively small (rat: 115% of control, at 10(-6) M ouabain; guinea-pig: 110% of control, at 6.25.10(-10) M ouabain) but statistically highly significant (p less than or equal to 0.001). The shape of the concentration-effect relationship for this first action differed between species. With rat heart it was sigmoid in character and had a flat slope, with guinea-pig on the contrary it was almost bell-shaped (i.e. the effect disappeared with increasing ouabain concentration). The shape of the concentration-effect relationship for the "second" action was sigmoid in shape for both species used (rat: between 10(-6) - 10(-4) M; guinea-pig: between 10(-8) - 10(-6) M ouabain). From the results is was concluded that the dual positive inotropic effect of ouabain supports the existence of at least two different mechanisms of action of this drug. Furthermore, it was suggested that a species-dependent binding of calcium to the cardiac sarcolemma may be responsible for the different shapes of the "first" positive inotropic effect of ouabain.

Clenbuterol in the prevention of muscle atrophy: a study of hindlimb-unweighted rats.

OBJECTIVE: To determine whether the administration of clenbuterol, a beta2-adrenergic agonist, prevents loss of muscle mass during a period of imposed inactivity. DESIGN: Randomized trial. SETTING: Basic laboratory research. ANIMALS: Thirty Fischer 344 Brown Norway F1 Hybrid rats, 12 and 30 months of age. INTERVENTIONS: The rats were randomly assigned to a control group, or to 1 of 2 experimental groups: hindlimb unweighted for 2 weeks (HU-2), or hindlimb unweighted with daily injections of clenbuterol for 2 weeks (HU-2Cl). MAIN OUTCOME MEASURES: Muscle mass weighed in milligrams and single fiber cross-sectional area histochemically evaluated. RESULTS: In both age groups, the HU-2 animals had greater muscle atrophy (decrease in muscle mass) in the soleus muscle than the extensor digitorum longus (EDL) muscle. In the HU-2Cl groups, the decline in muscle mass of both the soleus and EDL muscles was attenuated by about 4% to 20%. In the HU-2 group, single fiber cross-sectional area decreased for both fiber types (type I, 20%-40%; type II, 37%-50%) in both age groups. Clenbuterol retarded the inactivity-induced decline in single fiber cross-sectional area by 12% to 50%. In the EDL muscles of the HU-2Cl group, we found hypertrophy in both fiber types in the 30-month-old animals and in type I fibers in the 12-month-old animals. CONCLUSIONS: Clenbuterol attenuated the decrease in muscle mass and single fiber cross-sectional area in both age groups. By preventing the loss of muscle mass, clenbuterol administered early in rehabilitation may benefit severely debilitated patients imposed by inactivity. The attenuated muscle atrophy found with clenbuterol in the present study provides cellular evidence for the reported change in muscle strength after its administration after knee surgery. Thus, the administration of clenbuterol may lead to a more rapid rate of rehabilitation.

Magnesium and the calcium paradox: the occurrence of "spasmodic contractions" during Ca2+-Mg2+ -free perfusion of isolated rat heart.

The effects of omission of Mg2+ during Ca2+-free perfusion (3 min) of either spontaneously beating and electrically stimulated rat hearts were studied. Ca2+-free perfusion per se induced cardiac arrest and coronary vasodilation, and increased intrinsic pulse rate of the heart. Upon reperfusion with Ca2+, cardiac function was lost and parallelled by a sudden and massive release of cellular constituents ("calcium paradox"). Mg2+-free perfusion evoked effects opposite from Ca2+-free, with exception of heart rate which was increased. During Ca2+-Mg2+-free perfusion the electrocardiogram became irregular within 30 s, and this effect was followed by transient "spasmodic contractions". The effects of normal reperfusion were indistinguishable from those observed after Ca2+-free perfusion in the presence of Mg2+. Addition of Mn2+ or La3+ to the Ca2+-Mg2+-free perfusion medium completely inhibited the induction of electrical irregularities and spasmodic contractions. The typical effects of Ca2+-Mg2+-free perfusion are discussed in terms of Mg-Ca and Mg-K interactions at the sarcolemmal surface. It was concluded that our results may contribute indirectly to an explanation of the protective effect of high Mg2+-concentrations during Ca2+-free as well as ischemic perfusion of mammalian hearts.