Cardiotoxic effects of catecholamines in guinea-pig (Cavia porcellus) and in albino rat (Rattus norvegicus). A comparative study.

1. Cardiotoxic effects of catecholamines in guinea-pigs and rats were compared. Substantially lesser cardiotoxic effects of isoprenaline (2 X 40 mg/kg b.w.) were found in guinea-pigs, as judged by morphologic examination. 2. When isolated hearts were perfused in vitro, noradrenaline (5 X 10(-6) M) induced less damage, judged by enzyme leakage (ASAT) and electron microscopy analysis. 3. Myocardial ATP and creatine phosphate are normally higher in guinea-pigs than in rats, and no difference was found between the two species when subjected to noradrenaline. 4. Glycogen was higher in guinea-pig myocardium, and glycogenolysis during noradrenaline perfusion was substantially greater in guinea-pig hearts than in rat hearts. 5. Obtained data are interpreted with respect to the recent findings that, not only natural history, but also some physiological traits [blood gas transporting system (Kreuzer and Turek, 1981, Medizinische Aspekte der Höhe, pp. 15-23)] make guinea-pigs similar to high altitude mammals, and to earlier findings that high altitude hypoxia adapted rats display lesser vulnerability of cardiac muscle by anoxia and by catecholamines.

Calcium paradox from cyclostome to man: a comparative study.

In seven poikilotherm species, i.e. cyclostome, Myxine glutinosa; teleosts, Gadus morrhua; Platichtys flesus; amphibia, R. pipiens; R. temporaria; Xenopus laevis; reptiles, Vipera berus. Ca paradox could not be obtained in ventricular strips at 8-12 degrees C. In similar preparations from human atria at 30 degrees C and 37 degrees, Ca paradox was obtained similarly as in other homoiotherms. In homoiotherms, lowered temperature (below 30 degrees C) has a protective effect. Viper myocardium did not display Ca paradox at 12, 22 or 32 degrees C, whereas human myocardium displayed Ca paradox even at 30 C. It is postulated that the absence of Ca paradox in poikilotherms is not due to the low temperature. In hagfish (Myxine glutinosa) the absence of Ca paradox seems to be due to the specific conditions concerning Ca exchange in the myocardial cell (large glycocalyx).

Cardiac beat frequency and oxygen supply: a comparative study.

The length of diastole in mammals varies between approx 1 s (elephant) and 38 ms (shrew) which makes oxygen supply in high speed cardiac pumps in very small mammals precarious. High capillary density and high blood P50 are reported in mammals with high frequency cardiac cycle. Both are probably insufficient when cardiac frequency is exceedingly high (shrew: 1000 min-1). High respiratory efficiency due to large relative mitochondrial volume per cell (greater than 50%) seems to be preferential solution to maintain sufficient O2-gradient. Similar strategy, i.e. high relative cardiac mitochondrial volume was reported in analogous situation in ice-fish (Chaenocephalus aceratus) where O2 cardiac cell supply is difficult due to the absence of hemoglobin and cardiac myoglobin.

Absence of calcium paradox in the cardiac ventricle of the Atlantic hagfish (Myxine glutinosa).

Spontaneously beating strips of the cardiac ventricle of the cyclostome Myxine glutinosa were characterized with respect to dependence on extracellular calcium for the cardiac contractility at 8 degrees C. The force developing (Tmax) was reduced by 20-50% when exposed to calcium-free medium (+/- 10(-3)M EDTA) for 15-60 min. Return to normal Myxine Ringer (4.5 mM Ca2+) resulted in 120-130% recovery to Tmax without change in resting tension. These experiments show that the heart of this primitive vertebrate, analogous to that of other poikilotherms, does not display the "Ca-paradox" phenomenon. Being relatively insensitive to changes in extracellular Ca2+ the Myxine myocardium differs from that in most poikilotherms in other respects, e.g. in the mechanisms regulating beat to beat changes in intracellular Ca2+.

The calcium paradox and its protection by hypothermia in human myocardium.

The 'calcium paradox', i.e. irreversible loss of mechanical and electrical activity after a few minutes Ca2+-free perfusion and subsequent reperfusion with Ca2+-containing medium, was originally demonstrated in rat heart and later in other homoiotherms. It was absent in poikilotherms. The present paper describes the effect of Ca2+-free superfusion on human myocardium at normo- and hypothermia using isometrically mounted, stimulated strips from auricular tissue excised during cardiac surgery. The experiments (including equilibration period) were performed at 37 degrees C, 30 degrees or 25 degrees C. When Ca2+-free and EGTA-containing solution was introduced the force decline started immediately. After 10 min Ca2+-containing medium was reintroduced. Force recovery within 40 min was at 37 degrees C 16% and at 30 degrees C 28% of initial force value. Force recovery in 25 degrees C group was substantially better. Contracture which occurred when Ca2+-containing solution was reintroduced was very strong at 37 degrees C (+ 102%) and weaker at lower temperatures (30 degrees C +48% and 25 degrees C +17%). The extent of loss of mechanical activity and of contracture following the period of Ca2+-free superfusion give evidence that calcium paradox can be provoked in human myocardium and can be prevented by hypothermia.

Comparative and scaling aspects of heart and body weights with reference to blood supply of cardiac fibers.

Relative heart weight (RHW) differs in vertebrates with the ratio 1:20 between extremes (bottom bound fishes--Pleuronectidae--and birds). When plotting heart weight (HW) against body weight (BW) one obtains channels which contain not only vertebrates of the same classes (poikilotherms, small and big mammals and birds) but also animals belonging to different classes: tuna fish data are located in the "small mammalian channel" together with data of large tropical snakes while large mammals (upwards 4000 g) belong to the "bird channel". Reasons for such groupings are not clear and physical activity seems not to be the only reason. When comparing active and non active vertebrates one finds that the RHW is as a rule greater in physically more active poikilotherms and homoiotherms. The RHW is also higher in wild than in domesticated forms the differences appearing after weaning (wild vs laboratory rat). In spongy type of myocardium the growth of cardiac fibers results in restriction of the blood flow through lacunae and the contact between endothelial cells lining growing strands of musculature probably provokes formation of capillaries. The appearance of mixed type of myocardium (outer compact and inner spongy compartments) is not bound to the water to land transition since it occurs also in some fishes; it does not occur or is rare in amphibia and is frequent in reptiles. The compact outer layer comprises a different proportion of the cardiac wall volume (5-73%). Metabolic differences were described between cardiac cells in compact and spongy compartments.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis and cardiac muscle contractility: comparative aspects.

The evolutionary step involving transition from water- to air-breathing exposed the vertebrate cell to an increased risk of becoming acidotic. This is due to the fact that water-breathers generally excrete CO2 more easily than air-breathers. CO2 rapidly diffuses into the cell, where it may result in an excess of hydrogen ions. This is of interest as to the cardiac muscle, since these ions depress contractility, to a large extent probably by inhibiting the inotropic action of calcium ions in a competitive way. The present review, however, concerns the fact that the heart muscle may have an inherent ability to resist the negative inotropic effects of hydrogen ions. This is not a general property of the vertebrate heart, as it shows a clear tendency to be present in most air-breathers, whereas it is absent in most pure water-breathers, i.e. in most fishes. Measurements of the intracellular pH and of the tissue buffer capacity indicate that this ability to maintain force at a normal level in spite of an ongoing CO2-acidosis involves neither neutralization nor excretion of excess hydrogen ions. Instead, studies involving calcium-flux measurements and interventions in the cellular calcium-distribution suggest that the intracellular calcium ion deficit due to acidosis is compensated for by an increase of the calcium pool involved in the beat to beat regulation of cardiac force. How this is accomplished is unclear, although evidence was obtained that mitochondrial calcium stores may be involved.

Heart lesions in the frog at high environmental temperature.

Frogs (R. pipiens) adapted to 12 degrees C were exposed to increased environmental temperature during 2 hr. At 33 degrees C gross heart lesions started to appear in a few cases and at 37 degrees C, 71% of the frogs showed ventricular aneurysms and some died. Critical thermal maximum (CTM) was around 37 degrees C in autumn, winter and early spring, whereas in late spring and summer CTM was at 39 degrees C and during these last-mentioned periods of the year gross heart lesions at high temperature did not start until at 37 degrees C. After 2 hr at 37 and 39 degrees C respectively, ECG-abnormalities occurred indicating myocardial injury. Isolated strips of the heart ventricle from frogs with gross heart lesions showed a deteriorated resistance towards cyanide anoxia as measured by an isometric procedure. The ultrastructure was deranged by the high temperature, the changes mainly involving the mitochondria and the myofibrils. These alterations were focal but depletion of glycogen particles was diffuse. As the high temperature induced changes similar to those provoked by catecholamines, propranolol was given in some frogs before the heat exposure. This beta-adrenoceptor blockade did only reduce some of the abnormal changes by 37 degrees C.

Studies on the calcium paradox phenomenon in cardiac muscle strips of poikilotherms.

Compared with hearts of homoiotherms at their body temperature, isometric strips from hearts of poikilotherms (G. morhua, P. flesus, R. pipiens, R. temporaria, X. laevis and V. berus) at their physiological temperatures showed an insignificant calcium paradox. In all strips Tmax (maximal contractile tension at Lmax) decreased rapidly upon Ca2+-deprivation. Upon Ca2+-restitution the recovery of Tmax generally decreased--but seldom stopped--with increased length of the Ca2+-free period. Quantitative differences in recovery were observed between the species. P (resting tension) was either unchanged or decreased during Ca2+-deprivation. During Ca2+-restitution P increased initially and thereafter decreased again. In most species the recovery of Tmax was the same at 22 degrees C as at 12 degrees C. Even at 32 and 36 degrees C (V. berus and R. pipiens, respectively) Tmax recovered somewhat. Ultrastructural effects of the Ca2+-deprivation-restitution--studied on R. pipiens--were most marked in the mitochondria, especially at 22 degrees C. At 36 degrees C even the controls were damaged.

The healing of frog heart lesions induced by isoproterenol injections.

Isoproterenol (IPR) induces myocardial lesions in R. pipiens adapted to +25 degrees C, but not to +8 degrees C. The spontaneous healing of these lesions in the form of ventricular wall aneurysms occurs during the first three weeks after IPR, and the ultrastructure of the myocardial cells in fully restored from the fourth week after IPR. Leukocytes, adhering to the lacunar endothelium and including phagocytic vacuoles, appear 8-15 days after IPR. Severely altered heart muscle cells then contain myelin figures or a pyknotic nucleus. In the acute stage of the IPR-lesions, heart muscle preparations from the ventricular wall show a very lowered resistance towards cyanide anoxia as judged from the isometric force decay. During the seven weeks of observation after IPR the resistance to cyanide anoxia is continuously improved almost to normal values. Thus restoration of structure and function occurs in parallel.

Cardiac lesions in the frog induced by adrenaline.

Adrenaline (A) causes gross lesions of the ventricular wall in frogs living both at 12 degrees and 25 degrees. At 12 degrees the sensitivity of the heart to A is higher than at 25 degrees. Single or multiple ventricular aneurysm, provided by A could not be prevented by propranolol. The resistance of the myocardium towards cyanide anoxia is lowered after A especially at 25 degrees. In preliminary experiments with noradrenaline the same cardiotoxic effects are observed.

Effects of calcium and pH on the mechanical performance of heart muscle in the frog, Rana temporaria, during anoxia and subsequent recovery.

Heart ventricular muscle strips from Rana temporaria recover their isometric contractile tension completely within 20 min of reoxygenation following an anoxic period of 60 min in a physiological solution at pH 7.6. Corresponding recovery at pH 6.6 is only 43% of pretreatment values. High calcium concentration during the period of anoxia at pH 6.6 and subsequent recovery, returns contractile tension to almost pre-anoxic values within 1 h. If, however, the calcium concentration is increased at the moment of reoxygenation, contractile tension is restored even faster than if high calcium levels were present during anoxia. The loss of contractile tension caused by anoxia is the same at both pH 7.6 and 6.6 with the same calcium concentration. Comparison of the velocity parameters between high and low calcium experiments always shows a greater difference for the contraction velocities than for the corresponding relaxation velocities, independently of the pH. The quotient of these two velocities is used as an index of their relative rate of change. The results are interpreted in terms of calcium and hydrogen ion competition at various subcellular structures and the different influences these ions may have on contractile tension and both contraction and relaxation velocities.

Myocardial inotrophy of CO2 in water- and air-breathing vertebrates.

A negative-inotropic effect of CO2 on myocardial contractility presumably occurs because increasing H+ concentration competes with Ca2+ at cellular membranes and proteins. Since air-breathing vertebrates have higher blood and tissue CO2 concentration than water breathers the question was raised whether the cardiac cell has a modified sensitivity to CO2 correlated with the evolutionary transition of vertebrates from water breathers to air breathers. The water-breathing fish, Salmo gairdneri, and the air-breathing turtle, Pseudemys scripta, were selected as experimental animals, since their total CO2 concentration differs markedly (3.0 and 16.0 mmol.kg-1). Electrically paced isometric ventricular strips from both species were subjected to a stepwise increase in PCO2 from 25 to 114 Torr (pH0 7.80 to 7.0; HCO3- 30 mM). Trout were additionally exposed to the same pH0 changes at 5 mM HCO3- by a stepwise increase in PCO2 (4.5-12 Torr). At each increase in PCO2 the turtle heart showed a lesser negative inotropic effect than trout. The present findings offer direct evidence that the negative inotropic effect of CO2 on heart muscle is inversely proportional to the in vivo levels of tissue CO2 concentration. The results obtained are discussed in relation to phylogenetical and ecological aspects of acid-base balance.

Effect of time on the response to cyanide anoxia of frog heart damaged by isoproterenol.

Isoproterenol (IPR) induces damage to the heart of frogs living at 25 degrees. The resistance of an isometric ventricular strip to histotoxic anoxia induced by cyanide is significantly reduced 4 hours after one injection of IPR and still more after repeated injections. Macroscopically visible heart lesions are observed only on the first two days after the second injection of IPR. The response of the heart muscle preparation to cyanide is then continuously improved during 3-4 weeks after IPR and the disturbance of the myocardial function is thus only temporary and may at least partly be induced by metabolites of the catecholamine.

Ultrastructural and functional aspects of frog heart lesions after isoproterenol.

The purpose of the present study was to explore the possible correlation between the ultrastructural changes and the functional changes induced by isoproterenol (IPR) in the myocardium of the frog. The study was performed on winter frogs (R. pipiens), The experimental animals wend then given 2 daily doses of IPR (200 mg/kg b,w.). Twenty-four hours after the second IPR dose, specimens were taken from the heart ventricle and subjected to electron microscopical examination and to analysis of the isometric force decay in response to anoxia produced by sodium cyanide. Specimens were taken from macroscopically non-damaged portions of the ventricle as well as from aneurysms. Control animals were kept at + 8 degrees C and + 25 degrees C and injected with saline. In all IPR-injected animals the specimens from macroscopically non-damaged parts of the myocardium showed ultrastructural changes characterized by a relative increase in mitochondrial mass and a pronounced reduction of glycogen. Specimens from aneurysms showed similar changes but in some fibres signs of more severe injury were observed such as fragmentation of the cristae of the mitochondria and disintegration of myofibrils. The functional analyses showed that the isometric force decay of the heart muscle strips induced by the respiratory block by cyanide was much greater in specimens from IPR-treated animals than in those from control frogs. The augmented force decay was found in both strips from macroscopically normal parts of the myocardium and in those from aneurysms although it was somewhat greater and more rapid in the latter. The observed, minor functional difference between macroscopically non-damaged portions of the myocardium and aneurysms is remarkable with respect to the different preservation of myofilaments in these regions. This similarity in functional decline could possibly be due to the observed homogenous reduction of glycogen in the IPR-exposed myocardium since glycogen was the only source of ATP under the experimental conditions of current interest.