The cardiac contractile function and hemodynamic control in rats after chronic adriamycin treatment.

Cardiac contractile function and hemodynamic parameters of control and adriamycin-treated (2 mg/kg once a week for 10 weeks) rats were studied both in the anesthetized (hexenal, 20 mg/kg) and conscious state. Radiolabelled microspheres (diameter, 15 microns) were used to measure systemic and regional hemodynamics. No significant differences between the control and adriamycin-treated groups in cardiac contractile function, total peripheral resistance, and regional blood flow (except muscles) was found in anesthetized animals. In the conscious state, a significantly higher (+70%) total peripheral resistance combined with lower blood flow in the skin and spleen was observed in adriamycin-treated rats. The response of the heart rate to changes in the arterial pressure induced by nitroglycerin and phenylephrine injection was greatly diminished after adriamycin treatment. Isoprenaline (0.64 micrograms.kg-1.min-1) increased left ventricular contractile indices approximately twofold and heart rate by 30% in the control group, while in adriamycin-treated rats only minor changes in these parameters were observed. However, cardiac output rose by 36% and total peripheral resistance fell by 36% in these animals. Results show that prolonged adriamycin treatment leads to decreased inotropic response to beta-adrenoceptor stimulation and reduced baroreflex control. These changes occur in the stage preceding congestive heart failure.

[The regulation of systemic and regional hemodynamics in waking rats with a chronic adriamycin-induced myocardial lesion]. / Reguliatsiia sistemnoi i regionarnoi gemodinamiki u bodrstvuiushchikh krys s khronicheskim adriamitsinovym porazheniem miokarda.

Rats were given intraperitoneal injections of adriamycin (cumulative dose 20 mg/kg). Two weeks after the last injection left-ventricular function and systemic and regional hemodynamics were studied before and during isoprenaline infusion (0.64 mcg/kg/min) in conscious rats with no signs of cardiac insufficiency. In the controls isoprenaline increased the left-ventricular contractility index by 45% and the heart rate by 30%. The contractility index in rats given adriamycin did not change, the heart rate increased only by 14%, but in contrast to the controls, a significant increase of the cardiac index by 36% and diminution of total peripheral resistance by 36% were revealed. The sensitivity of the baroreflex chronotropic component in the control animals was twice that in the experimental rats. It is concluded that adriamycin cardiomyopathy in rats is attended by reduced sensitivity of the baroreflex mechanisms and diminished myocardial adrenergic reactivity.

Adaptation of cardiac contractile function to conditions of chronic energy deficiency.

Left ventricular (LV) contractile function and pump function were depressed in isolated working hearts from rats treated with either guanidinopropionic acid (GPA), an inhibitor of creatine influx, or the anthracycline antibiotic, adriamycin, for 6 and 10 weeks, respectively. In both groups of treated animals myocardial phosphocreatine content was lower than in control hearts, while ATP content was unchanged. Hearts of treated animals exhibited only a minor depression of cardiac output with a submaximal pressure load or during volume overload. However, at maximal pressure load GPA- and adriamycin-treated hearts performed 43% and 37% less pressure-volume work than control hearts. These changes were due both to decreased LV pressure development and diminished cardiac output. LV diastolic stiffness was significantly higher at the submaximal pressure load and the LV filling pressure area, which reflected LV filling, was lower in hearts of both treated groups. The differences in both indices were exaggerated when the maximal pressure load was applied. Limited LV filling due to incomplete myocardial relaxation appeared to represent the underlying cause of cardiac failure when afterload was increased. These results may be explained if adaptation of cardiac contractile function in some chronic cardiac diseases arises from a limited energy supply to the myofibrils.

Calcium-dependent changes of the myocardial contractile function at chronic adriamycin treatment.

The contractile function of hearts and atria isolated from rats treated with adriamycin (ADM, total cumulative dose 16-20 mg/kg for 8-10 weeks) was moderately lower as compared to control preparations. However, the former exhibited a relatively higher positive inotropic response to an elevation of Ca++ concentration in the perfusate of isolated hearts or paired pulse stimulation of atria so that maximally attainable values were similar in both groups. On the contrary, the depression of ADM-treated atrial contractile amplitude became even more prominent at moderate increase in stimulation rate and was associated with the apparent incomplete relaxation. Chemically skinned fibers from ADM-treated hearts began to develop force at lower Ca++ concentration and exhibited higher Ca++-sensitivity in pCA range 5.8-5.4. Results suggest that long-term ADM-treatment may be associated with a functional deficiency of Ca++-transporting mechanisms in myocardial cells which may contribute to the depression of the cardiac contractile function.

[Myocardial ultrastructure, energetics and function in chronic adriamycin-induced lesions]. / Ul'trastruktura, énergetika i funktsiia miokarda pri khronicheskom adriamitsinovom porazhenii.

The ultrastructural study of the myocardium of rats received adriamycin for 8-10 weeks revealed the picture of mosaic lesions of cardiomyocytes. Cells with little changes were coincided with apparently changed cardiomyocytes in which hypercontracted or atrophied sarcomeres with distended Z-lines, glycogen disappearance and swollen or hypertrophied mitochondria were seen. Myocardial content of ATP did not change but that of phosphocreatine was decreased by 45 percent. The pump function of the isolated heart was moderately lower that was associated with almost twofold increase in left ventricular diastolic stiffness suggesting a deterioration of its filling. A rise in Ca++ concentration in the perfusate exerted similar positive inotropic effect on hearts of both groups which was associated with a prominent fall of diastolic stiffness. Results suggest that increased diastolic stiffness in adriamycin-treated hearts may be due to both local ATP deficiency in myofibrils or incomplete Ca++ removal from them.

[Contractile function of the isolated heart in chronic adriamycin-induced myocardial lesions]. / Sokratitel'naia funktsiía izolirovannogo serdtsa pri khronicheskom porazhenii miokarda adriamitsinom.

Adriamycin, administered to rats for 4 weeks, caused insufficiency of isolated heart contractility with a twofold reduction of cardiac output in surviving animals. The same cumulative dose of adriamycin, administered to rats over 10 weeks, was not associated with any significant reduction of the heart's pumping function. However, heart rate increase by atrial electrostimulation that shortened the diastolic pause to a control level, also reduced the minute and stroke volumes by 38%, as compared to the controls. All animals showed increased diastolic stiffness of the left ventricle that must have interfered with its filling, particularly so in case of low inflow pressure, and disturbed atrial automaticity, as reflected in bradicardia in rats and supraventricular arrhythmia in guinea pigs.

[Changes in the contractile function and energy metabolism of the isolated heart in chronic adriamycin damage to the myocardium]. / Izmeneniia sokratitel'noi funktsii i énergeticheskogo metabolizma izolirovannogo serdtsa pri khronicheskom adriamitsinovom porazhenii miokarda.

4-week administration of adriamycin (20 mg/kg) to rats resulted in the death of approximately one third of the animals, the minute volume of isolated hearts of the surviving animals was less than half of the normal value and the level of phosphocreatine was decreased by one third. The hearts of the rats receiving the same dose of the drug over 10 weeks maintained the same pump function and contained the same amount of macroergic phosphates as those of the control animals. In both series of experiments there was an increase of the end-diastolic pressure and the diastolic elasticity of the left ventricle. In the isovolumic regime the hearts of the rats receiving adriamycin over 10 weeks were able to develop the same pressure only if the rate of coronary blood flow was increased by approximately 1.5 times. Myofibril sensitivity to phosphocreatine deficiency in fibers with destroyed sarcolemma was decreased. The results point to considerable compensatory resources of the heart in chronic adriamycin damage to the myocardium.

[Myocardial diastolic elasticity in chronic adriamycin lesion]. / Diastolicheskaia uprugost' miokarda pri khronicheskom adriamitsinovom porazhenii.

Isolated hearts of the majority of rats receiving 20 mg/kg adriamycin for 10 weeks exhibited normal pump function. Left ventricular diastolic stiffness of these hearts was approximately 1.5 times higher, as compared to control hearts, with the filling pressure in the range of 5 to 20 cm H2O and diastolic pause 23% longer due to bradycardia. Pacing-induced increase in the heart rate up to the control level resulted in further increase in left ventricular diastolic stiffness due to the rise in myocardial stiffness, associated with a fall in cardiac output by 36%. The heart and right atrial compliance determined in separate experiments did not differ significantly from the control. The results suggest that increased left ventricular diastolic stiffness of adriamycin-treated rats seems to be rather due to energy-dependent disturbance in myofibril relaxation than to usually arising myocardial fibrosis.

[Compensatory factors in acute failure of the isolated heart]. / Kompensatornye faktory pri ostroi nedostatochnosti izolirovannogo serdtsa.

The cardiac output of isolated guinea-pig hearts fell during progressive infusion of Ca2+-complexon, EGTA, or oxidative phosphorylation inhibitor dinitrophenol. Moderate doses of EGTA (0.3-0.6 mM) caused an apparent diminution of the left-ventricular +dP/dt and aortic pressure amplitude but did not influence cardiac output, which was maintained due to a prolongation of the contraction time. When the left-atrial cavity was greatly reduced by ligation, cardiac output fell by 40 per cent while left-ventricular systolic pressure and +dP/dt remained unchanged. In these conditions, EGTA in the same concentration reduced cardiac output by 30 per cent thus proving the important role of the left atrium in the compensation of hypocalcemic heart failure. On the contrary, the infusion of dinitrophenol shortened contraction time and increased myocardial rigidity. The latter change facilitated force development thus contributing to a lesser fall of +dP/dt and aortic pressure amplitude at equal diminution of cardiac output as compared to EGTA action. However, this compensation required a higher elevation of the filling pressure for inflow maintenance.