Dietary Magnesium Supplementation Attenuates Ethanol-Induced Myocardial Dysfunction

Hypomagnesemia is positively correlated with a number of cardiovascular abnormalities and recent evidence suggests that magnesium supplementation prevents ethanol-induced development of hypertension. The purpose of our study was to assess whether dietary magnesium supplementation effectively reverses or attenuates chronic ethanol-induced cardiac dysfunction, both at the tissue and the cellular level. Therefore, the influence of dietary magnesium supplementation during chronic ethanol ingestion on the mechanical properties of cardiac muscle was studied using isolated papillary muscles and ventricular myocytes from rat heart. In addition, the acute effects of ethanol on cardiac muscle from animals chronically exposed to ethanol in the absence and presence of dietary magnesium supplementation were also examined. Chronic ethanol exposure caused significant cardiac, hepatic, and renal enlargement, increased systolic blood pressure, and produced hypomagnesemia. After chronic ethanol exposure, the baseline force generating capacity of papillary muscles was markedly depressed and was associated with a significant slowing in the maximum velocities of contraction and relaxation. By contrast, in isolated myocytes, long-term ethanol exposure increased the extent of cell shortening associated with a significant reduction in the duration of relengthening and an increase in both the maximum velocities of shortening and relengthening. Dietary magnesium supplementation among animals chronically ingesting ethanol effectively normalized heart size, systolic blood pressure, and reduced plasma ethanol concentration. Magnesium supplementation also attenuated chronic ethanol-induced depression of contractile force and increased the extent of cell shortening. As expected, acute ethanol exposure caused a dose-dependent inhibition of both isometric force and isotonic shortening associated with a decrease in the intracellular calcium transient. However, the extent of the acute ethanol-induced reduction in isometric force and isotonic shortening was always slightly greater among preparations from animals chronically exposed to ethanol. Dietary magnesium supplementation normalized the acute inhibitory action of ethanol on isometric force, isotonic shortening, and the intracellular calcium transient. Our results suggest that dietary magnesium supplementation may attenuate chronic ethanol-induced alterations in baseline myocardial mechanical function and normalize the cardiac response to acute ethanol exposure.     

Ethanol and Cocaine Cause Additive Inhibitory Effects on the Calcium Transients and Contraction in Single Cardiomyocytes

The heart is a major locus for the toxic actions of cocaine and ethanol, each of which has been shown to interfere with excitation-contraction coupling in cardiac muscle cells. Because these drugs are frequently used in combination, the present study was designed to investigate how they interact to modify the Ca²⁺ transient and associated contraction in fura2-loaded cardiomyocytes. A high-speed imaging technique using a charge-coupled device as detector and short-term image store was used to measure cytosolic Ca²⁺ and contraction simultaneously from fluorescence images obtained during the contractile cycle. Ethanol (100 mM) and cocaine (50 μM) caused reversible reductions in Ca²⁺ transient amplitude of 24.3 ± 3.0% and 25.1 ± 3.6%, respectively. Neither agent modified basal Ca²⁺. Ethanol treatment decreased peak shortening by 44.3 ± 3.5%, whereas the contractile depression by cocaine was 31.4 ± 5.3%. The relatively greater effect of ethanol on contraction resulted from a Ca²⁺-independent component of ethanol action on contractility. When cardiomyocytes were exposed simultaneously to ethanol and cocaine, Ca²⁺ transient amplitude was reduced by 38.7 ± 3.0%, and peak contraction was decreased by 55.1 ± 3.5%. These values represent a significantly greater inhibition than observed with either drug alone (p < 0.02) and are compatible with additive effects of the two drugs acting at distinct loci within the excitation-contraction coupling pathway. Thus, simultaneous use of cocaine and ethanol leads to an enhanced depression of myocardial contractility, which is likely to contribute to the cardiotoxic actions of the combination of these two drugs.     

Chronic ethanol enhances adenosine antiadrenergic actions in the isolated rat heart

BACKGROUND: Chronic alcohol consumption elicits an increase in catecholamine release, which may be detrimental to heart function. Adenosine attenuates adrenergic stimulation via an adenosine receptor-mediated antiadrenergic action. This study investigated the effect of ethanol on adenosine antiadrenergic actions and adenosine release in the rat heart. METHODS: Rats were pair-fed a liquid diet with or without ethanol for 4 weeks or 8 months. Hearts were isolated for determination of contractile function, and coronary effluents were collected for adenosine content. Dose-response relationships for phenylisopropyladenosine (PIA) were determined for hearts adrenergically stimulated by isoproterenol. Experiments were also conducted with normal hearts with or without ethanol (25 mM) administered acutely. The effect of PIA on adenylyl cyclase activities of adrenergic-stimulated crude membrane preparations obtained from alcoholic and nonalcoholic hearts was determined. RESULTS: Acute ethanol reduced basal adenosine release by 39%, but it did not significantly decrease adenosine release during adrenergic stimulation. In hearts chronically treated with ethanol for 4 weeks, adenosine release values before and during adrenergic stimulation were significantly reduced from control values. After 8 months of ethanol, adenosine release was similar with or without adrenergic stimulation. PIA 50% inhibiting concentration (IC50) values for contractile function were reduced from pair-fed control values. Acute ethanol did not significantly change the PIA IC50 value. Chronic ethanol reduced the PIA IC50 for adenylyl cyclase by 96%. CONCLUSIONS: Chronic ethanol treatment increases the antiadrenergic action of adenosine by mechanisms that seem independent of changes in adenosine concentration. Therefore, adenosine-induced cardioprotection against increased catecholamine stimulation is enhanced by ethanol.     

Peripheral and Cerebrovascular Actions of Ethanol, Acetaldehyde, and Acetate: Relationship to Divalent Cations

Inasmuch as ethanol is thought to exert its major effects in the autonomic and central nervous systems, it is important to determine whether acute versus chronic ingestion of this abused substance exerts any direct actions on peripheral and cerebral blood vessels. Since the chronic effects of ethanol on the cardiovascular system appear to be pivotal in the etiology of hypertension, coronary heart disease, and strokelike events, it is important to elucidate and understand the effects of chronic ethanol abuse and its mechanism(s) of action on the peripheral and cerebral blood vessels. Data are reviewed which suggest that the peripheral vasodilation and hypotension which result from acute ingestion (or administration) of ethanol may, in large part, be a consequence of its direct actions on vascular smooth muscle cells, both at the macro- and microcirculatory levels. At least two mechanisms appear to contribute to this vasodilator effect: inhibition of the normal rhythm or vasomotion (spontaneous mechanical activity) of vascular smooth muscle, and depression of the contractile responses to endogenous neurohumoral substances that play a role in maintaining vascular tone and regulation of blood flow. The data acquired so far suggest that the dilator actions are related causally to interference with movement and/or translocation of Ca2+ across the vascular membranes. In addition, these actions appear to resemble the peripheral vascular effects of general anesthetics. Evidence is also reviewed which indicate that ethanol, in contrast to acting as a vasodilator in the splanchnic vasculature, is often a potent and concentration-dependent constrictor of arterioles and venules in the skeletal muscle vasculature. Direct in situ observations on the rat brain, using high resolution, quantitative TV image-intensification microscopy, indicates that administration of ethanol, irrespective of the route of administration (e.g., perivascularly, intraarterially, or systemically), produces graded concentration-dependent spasms of arterioles and venules. Concentrations of ethanol approximately equal to greater than 250 mg/dl produce intense spasms resulting in rupture of these vessels. Recent in situ studies in conscious dogs, using radiolabeled microspheres, also indicate that ethanol can produce deficits in regional brain blood flow. Studies with isolated canine middle cerebral and basilar arteries clearly demonstrate that low concentrations of ethanol (e.g., less than 10 mM) can produce concentration-dependent spasms by a direct vascular action.(ABSTRACT TRUNCATED AT 400 WORDS)     

Metabolic Abnormalities in the Diabetic Heart

Congestive heart failure is a major health problem in the diabetic. Diabetics have a high incidence of heart disease, including an increased incidence and severity of congestive heart failure than the non-diabetic. Progression to heart failure after an acute myocardial infarction is also more frequent in diabetics then non-diabetics. While atherosclerosis and ischemic injury are important contributing factors to this high in incidence of heart failure, another important factor is diabetes-induced changes within the heart itself. A prominent change that occurs in the diabetic is a switch in cardiac energy metabolism. Increases in fatty acid oxidation accompanied by decreases in glucose metabolism can result in the myocardium becoming almost entirely reliant on fatty acid oxidation as a source of energy. This switch in energy metabolism contributes to congestive heart failure by increasing the severity of injury following an acute myocardial infarction, and by having direct negative effects on contractile function. This paper will review the evidence linking alterations in energy metabolism to alterations in contractile function in the diabetic.     

Endothelial cells are required for the cAMP regulation of cardiac contractile proteins.

The contractile proteins in mammalian cardiac muscle are regulated by a cAMP-dependent reaction that alters the activity of the actomyosin ATPase. The ATPase activity of cardiac actomyosin has also been shown to depend on factors released by small arteries in the myocardial tissue. Endothelial cells have been implicated in the regulation of the contractile force developed by isolated cardiac tissue. To determine whether endothelial cells are required for the cAMP-dependent regulation of the contractile proteins, the effect of cAMP on the actomyosin ATPase activity was measured in cryostatic sections of isolated, quickly frozen rat ventricular trabeculae. In half of the trabeculae, the endocardial endothelial cells had been damaged by a 1-sec exposure to 0.5% Triton X-100. In trabeculae with intact endothelial cells, cAMP increased actomyosin ATPase activity toward an apparently maximum value. In trabeculae with damaged endothelial cells, cAMP did not change actomyosin ATPase activity. The coronary venous effluent from an isolated heart has already been shown to modify the maximum isometric force developed by an isolated trabecula. The extent to which the force of the isolated trabecula is changed by the coronary venous effluent is closely related to the degree to which cAMP has up-regulated the actomyosin ATPase activity in the isolated heart donating the coronary effluent: the greater the degree of up-regulation of ATPase activity, the greater the increase in force produced by the effluent. These results indicate that endothelial cells are required for the cAMP-dependent regulation of cardiac contractile proteins to function, and these results further suggest that the myocardium autoregulates by modulating the cAMP regulation of contractile proteins with endothelial-derived factors.     

New developments in the understanding of the actions of the digitalis glycosides

In recent years it has become clear that the fundamental action of digitalis in the relief of congestive heart failure is its ability to enhance the contractile state of the ventricle. This positive inotropic effect is a direct action of the drug and is observed in both the failing and normal heart. In patients without a lowered cardiac output, the contractile effect is not translated into an elevation of total blood flow, principally due to the direct arteriolar constrictor action of the drug which increases the resistance to ventricular ejection, and perhaps the constrictor effect on the hepatic veins which results in little change or a decline in venous return to the heart. In contrast, in patients with congestive heart failure, the glycoside produces a marked rise in the reduced cardiac output and thereby allows relaxation of the intense sympathetic-mediated vasocontriction characteristic of the heart failure state; thus, arteriolar and venous dilation due to reflex withdrawal overrides the mild direct vasoconstrictor effect of the drug. From these observations, it is concluded that the digitalis glycosides have important direct and indirect actions on the heart and peripheral circulation, and the overal effects of these agents on the cardiac output and other hemodynamic variables are dependent on the presence or absence of heart failure at the time the drugs are administered. Thus, the glycosides' enhancement of the contractile state of the heart, viewed as a muscle and considered in terms of the mechanics of contraction, is observed as an improvement of the heart examined as a pump only when there is abnormal cardiac performance.

Present evidence implies that the basic contractile action of digitalis rests upon its cellular effect of potentiating excitation-contraction coupling. This effect appears to be mediated by glycoside-induced enhancement of the intracytoplasmic concentration of calcium ions around the myofibrils during electrical activation, thereby potentiating contraction. More specifically, it is speculated that digitalis has the ability to alter the configuration of the cell membrane of cardiac muscle, thus increasing calcium and sodium influx during depolarization; these cations then are taken up by sarcoplasmic reticulum which results in the release of microsomal-bound calcium into the myoplasm surrounding the contractile machinery. It is likely that the arrhythmia-provoking properties of digitalis are related to the loss of intracellular potassium and the inhibition of the membrane pump ATPase system required for maintaining intracellular potassium concentrations. This postulation that the inotropic and certain toxic actions of digitalis are mediated by different mechanisms is important clinically, since the two properties of the glycoside can be dissociated by the administration of potassium. The increase in myocardial contractility produced by digitalis requires an increase in myocardial oxygen consumption, as it does for other inotropic agents. In the presence of heart failure, this direct effect on myocardial oxygen consumption may be masked by the drug's favorable indirect effects on certain hemodynamic variables which result in the reduction of total myocardial oxygen requirements. From the above observations, it is apparent that a thorough understanding of the hemodynamic and cellular actions of the glycosides is essential for the proper application of these extraordinarily beneficial drugs in patients.     

A protective effect of coenzyme Q10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart

Experiments were undertaken to determine if pretreating the animal with coenzyme Q₁₀ (CoQ) protected the cardiac muscle of the isolated heart from the acute toxic injury induced by perfusion with adriamycin.CoQ (15 mg/kg/day) or vehicle alone was injected intraperitoneally into male rats for 7 days. Two hours after the last injection, the hearts were excised and perfused by Langendorff's technique. Perfusion with various concentrations of adriamycin (5, 10, 20, 30 or 50 μg of adriamycin/ml of perfusate) induced a dose-dependent decline in the contractile tension development and a dose-dependent elevation in the resting tension. When adriamycin in perfusate was 10 μg/ml or less than that, the coronary flow rate remained almost constant during the perfusion. No significant recovery in the contractile tension development and the resting tension was obtained by subsequent perfusion without adriamycin. The contractile tension development of the CoQ-pretreated hearts was significantly greater than that of the vehicle-pretreated hearts both during the perfusion with adriamycin (10 μg/ml) for 60 min and during the subsequent adriamycin-free perfusion for 30 min. After 60 min of perfusion with adriamycin, the cardiac stores of ATP, total adenine nucleotide and nicotinamide adenine dinucleotide in the CoQ-pretreated group were significantly higher than those in the vehicle-pretreated group.These results indicate that exogenous CoQ protects the cardiac muscle from the deterioraion in mechanical function induced by adriamycin. Better mechanical function of CoQ-pretreated hearts was attributable to relatively higher ATP stores presumably due to lesser loss of adenine nucleotide pool from the cardiac cells.     

心肌细胞和非心肌细胞在心力衰竭发展中的作用

心脏包含各种类型的细胞,包括心肌细胞、心肌成纤维细胞、各种免疫细胞和血管细胞.最初的研究主要集中于心肌细胞,因为它直接反映了心脏的收缩功能.最近研究发现,心肌成纤维细胞的主要作用是维护心脏功能,参与心脏生理性和病理性重构.这些发现促使人们从研究心肌细胞转向了非心肌细胞,以及他们之间的相互作用 现将对心肌细胞与非心肌细胞间,主要是与心肌成纤维细胞,在心脏重塑和心力衰竭发展中的相互作用做一综述.     

Measurement of the circulatory effects of dobutamine, a new inotropic agent, in patients following cardiac surgery

The use of an extractable aortic electromagnetic flow probe to provide a continuous on-line display of ascending aortic flow and cardiac output following open heart surgery is described. Utilizing this equipment, the hemodynamic actions of dobutamine and isoprenaline are compared in 14 patients immediately following cardiac surgery. The study confirmed an inotropic action produced by dobutamine at a heart rate 10 to 15 per cent lower than isoprenaline, with less peripheral vascular action. Arterial and coronary sinus blood analyses revealed little difference in the myocardial metabolic actions of either drug. Because inotropic drugs produce only relatively small increases in stroke volume in this group of patients, the rise in cardiac output caused by these agents is more dependent on the effects upon heart rate rather than improved myocardial contractile state and consequently dobutamine has little advantage over isoprenaline in this situation.     

Hybrid Gel Composed of Native Heart Matrix and Collagen Induces Cardiac Differentiation of Human Embryonic Stem Cells without Supplemental Growth Factors

Our goal was to assess the ability of native heart extracellular matrix (ECM) to direct cardiac differentiation of human embryonic stem cells (hESCs) in vitro. In order to probe the effects of cardiac matrix on hESC differentiation, a series of hydrogels was prepared from decellularized ECM from porcine hearts by mixing ECM and collagen type I at varying ratios. Maturation of cardiac function in embryoid bodies formed from hESCs was documented in terms of spontaneous contractile behavior and the mRNA and protein expression of cardiac markers. Hydrogel with high ECM content (75% ECM, 25% collagen, no supplemental soluble factors) increased the fraction of cells expressing cardiac marker troponin T, when compared with either hydrogel with low ECM content (25% ECM, 75% collagen, no supplemental soluble factors) or collagen hydrogel (100% collagen, with supplemental soluble factors). Furthermore, cardiac maturation was promoted in high-ECM content hydrogels, as evidenced by the striation patterns of cardiac troponin I and by upregulation of Cx43 gene. Consistently, high-ECM content hydrogels improved the contractile function of cardiac cells, as evidenced by increased numbers of contracting cells and increased contraction amplitudes. The ability of native ECM hydrogel to induce cardiac differentiation of hESCs without the addition of soluble factors makes it an attractive biomaterial system for basic studies of cardiac development and potentially for the delivery of therapeutic cells into the heart.     

The cardiac endothelium: Cardioactive mediators

Endothelial cells within the heart release a number of substances that modulate myocardial contractile function. These agents include nitric oxide, endothelin, prostanoids, adenylpurines, and other substances that have so far been characterized only in bioassay studies. A notable feature of many of these agents is that they influence contractile behavior predominantly by modifying cardiac myofilament properties rather than altering cytosolic Ca²⁺ transients. A consequence of this subcellular action is often a disproportionate effect on myocardial relaxation and diastolic tone. The paracrine modulation of cardiac myocyte function by endothelial cell factors is likely to be an important mechanism contributing to the overall regulation of cardiac contractile function, both physiologically and in pathological states.     

The contractile behavior of the heart and its functional coupling to the circulation

The integrated function of the heart and lungs provides for the transfer of O₂ from the atmosphere, for its delivery to the metabolizing tissues, and for the removal of CO₂. When cardiac output is compromised as in heart failure, a series of reflexive and neurohumoral adjustments follow with activation of the adrenergic and renin-angiotensin systems. The resultant vasoconstriction constrains the performance of the failing heart. Accordingly, vasodilators have been used to attenuate this vasoconstriction and to improve cardiac performance in patients with cardiac failure. An understanding of the physiologic consequences of vasodilation, as well as the selection of the most appropriate vasodilator for these patients, requires an understanding of the contractile behavior of the normal and failing heart and of the factors that regulate their performance.Because the myocardium is composed largely of cardiac muscle, muscle force, length, and shortening are used to describe its contractile behavior. Myocardial contractile behavior is a function of: (A) instantaneous shortening load, or the ejection force (afterload), which the muscular wall has to support during its contraction; (b) shortening length; and (c) myocardial contractile state. The failing myocardium characteristically has both a depressed contractile state and an abnormal shortening load.In order to describe the functional coupling of the heart to its arterial and venous circulations, the concept of a mechanical pump having elastic and resistive properties is used. These mechanical properties of the pump determine its ability to generate pressure and flow. Unlike the normal heart, the failing pump with its decreased elastance (i.e., increased volume at normal chamber pressure) is more sensitive to vascular loading, and hence its more favorable response to vasodilators.Finally, the performance of the heart is determined by the coordination and integration of the right and left hearts that result from their anatomical arrangement and the mobile interventricular septum, the pericardium, and the pleural pressure surrounding the heart and lungs. Vasodilators improve the pump function of the failing heart by reducing ventricular interaction and by augmenting chamber distensibility.The consequences of pharmacologic vasodilation in heart failure, then, can best be appreciated by understanding the intrinsic properties of cardiac muscle, the functional coupling of the heart to the arterial and venous circulations, the interplay between ventricles, and the interaction of the heart with its pericardium and with pleural pressure.     

Molecular biology and its impact for the future

Several changes in neuroendocrine activity follow failure of cardiac function to satisfy peripheral requirements and contribute to the clinical syndromes of heart failure. Afferent pathways are poorly understood and triggers are both central and peripheral, involving attenuation of atrial and arterial baroreceptor activity. Efferent sympathetic activity is generally increased with resulting vasoconstriction, but responses are organ-specific and differ among heart, kidney, lung and skeletal muscle. Changes in cardiac sympathetic activity are inadequately understood. Enhanced cardiac norepinephrine spillover contrasts with reduced tissue concentration and impaired activity of synthetic enzymes and neuronal catecholamine uptake. Beta-receptor down-regulation further complicates overall adrenergic responsiveness and the balance between enhancement of contractile function and reduction in arrhythmia threshold. Activation of the renin-angiotensin system is potentiated by the sympathetic nervous system and may contribute to vasoconstrictor hyporesponsiveness. Angiotensin II may in turn facilitate the central and peripheral effects of sympathetic activation and the release of vasopressin from the pituitary. Our understanding of the role of vasodilator peptides in heart failure remains rudimentary. It is likely that vasoconstrictor neuroendocrine response adversely influences optimal cardiac function in heart failure and may promote arrhythmogenesis. The neuroendocrine response in individual organs, however, requires intensive study.     

Effects of dopamine on left ventricular afterload and contractile state in heart failure: relation to the activation of beta 1-adrenoceptors and dopamine receptors

Although long-term therapy with oral beta-adrenoceptor agonists in patients with heart failure is generally associated with the development of diminished pharmacologic efficacy, the ingestion of levodopa, which is decarboxylated endogenously to dopamine, is associated with a sustained improvement in cardiac function. The beneficial hemodynamic actions of dopamine in patients with heart failure have been attributed to a positive inotropic effect that is mediated through activation of beta 1-adrenoceptors. However, a reduction in left ventricular afterload resulting from the activation of dopamine receptors may also lead to an improvement in the performance of the failing heart. To ascertain the relative importance of the positive inotropic and afterload-reducing effects of dopamine in patients with heart failure, dopamine (2, 4, 6 micrograms/kg per min), dobutamine (2, 6, 10 micrograms/kg per min) and nitroprusside (0.125 to 2.0 micrograms/kg per min) were administered to 13 patients with dilated cardiomyopathy while monitoring left ventricular wall thickness and dimensions by echocardiography and left ventricular and aortic pressures with a micromanometer-tipped catheter. Altering left ventricular afterload, quantified as end-systolic circumferential wall stress, with nitroprusside allowed generation of the left ventricular end-systolic circumferential wall stress-velocity of fiber shortening relation that represented the baseline contractile state of the myocardium. Left ventricular velocity of fiber shortening was elevated during the administration of dobutamine and dopamine when compared with measurements obtained with nitroprusside at the same left ventricular end-systolic circumferential wall stress. Furthermore, left ventricular end-systolic wall stress decreased with dopamine but not with dobutamine. Thus, the beta 1-adrenoceptor activity of dopamine and dobutamine augmented the contractile state of the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of carvedilol action in human congestive heart failure

The precise mechanism by which beta-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, beta2-adrenoceptor-mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17+/-1% to 28+/-3%; P<0.01) and left ventricular stroke work (87+/-13 to 119+/-21 g. m per beat; P<0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33+/-0.04 to 0.42+/-0.04; P=0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.     

Combined use of glucagon and strophanthin in myocardial infarct complicated by severe cardiac insufficiency]

The effects of isolated and combined use of strophanthin and glucagon on the values of central hemodynamics and cardiac contractile function were compared. The study was conducted on patients with myocardial infarction complicated by congestive heart failure in the acute period of the disease. It was found that a combination of these drugs had a synergic inotropic effect. A conclusion was drawn on the advantages of the combined use of strophanthin and glucagon in the treatment of severe congestive heart failure in the acute period of myocardial infarction.     

Acute myocardial effects of mitoxantrone in the rabbit

Some clinical studies that were performed for the purpose of assessing the potential cardiotoxicity of mitoxantrone (DHAD) have shown that repeated administrations of the drugs in some patients cause a mild impairment of cardiac functions and morphological changes in the myocardial cells qualitatively similar to those elicited by anthracyclines. Since doxorubicin has been reported to cause acute cardiac effects, probably related to its chronic cardiotoxicity, experiments were carried out on the rabbit heart to investigate whether DHAD is also able to induce acute cardiac effects. Our results show that this drug caused a reversible dose-related impairment of cardiac contractility on the isolated and perfused rabbit heart while it was not able to induce ECG alterations in normal rabbits. These findings demonstrate that in the rabbit DHAD induces an acute cardiac activity qualitatively similar to that of doxorubicin and suggest that this animal model could be a useful tool to study the cardiac actions and related pathogenetic mechanism(s) of this antitumor drug.