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

Gorodetskaya, E. A.; Dugin, S. F.; Golikov, M. A.; Kapelko, V. I.; Медведев, О. С.

doi:10.1139/y90-033

Cited by 11 publications

(7 citation statements)

References 3 publications

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“…4,5 In rats, reduced baroreflex responses were observed in conditions of un- changed cardiac output or LVEDP, but in presence of increased total peripheral resistance. 22 In the present study, we did not observe changes in baroreflex control of HR, although baseline values of MAP were reduced and basal HR was increased. Moreover, cardiac output was normal compared with controls, yet in the presence of increased LVEDP.…”

Section: Discussioncontrasting

confidence: 62%

Baroreflex Sensitivity and Oxidative Stress in Adriamycin-Induced Heart Failure

et al. 2001

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Abstract-Adriamycin cardiotoxicity is associated with oxidative stress in the presence of globally depressed cardiac function. It is unknown if there is a similar profile with early diastolic changes and how it relates to baroreflex control of circulation. In this study, we evaluated baroreflex control of circulation in adriamycin-treated Wistar rats compared with controls, using invasive blood pressure recording processed by a data acquisition system (CODAS, 1 KHz). Baroreflex sensitivity was evaluated by modulating blood pressure with phenylephrine and sodium nitroprusside. Oxidative stress was quantified by chemiluminescence and by glutathione peroxidase enzyme activity. Diastolic dysfunction was characterized by increased left ventricle end-diastolic pressure in adriamycin-treated rats compared with controls with preserved ascending aortic flow. Baroreflex sensitivity in response to blood pressure elevation and reduction were similar in adriamycin (Ϫ2Ϯ0.27 and Ϫ3.19Ϯ0.56 bpm/mm Hg) and control rats (Ϫ1.35Ϯ0.15 and Ϫ2.52Ϯ0.39 bpm/mm Hg). Chemiluminescence was higher (20450Ϯ1286 versus 16517Ϯ1020 counts per second/mg protein) and glutathione peroxidase activity was lower (45.6Ϯ4.3 versus 76.4Ϯ6.9 mol ⅐ min Ϫ1 ⅐ mg Ϫ1 protein) in adriamycin rats compared with controls. Inverse correlations were observed between glutathione peroxidase activity and left ventricle Pϭ0.02), between baroreflex sensitivity to phenylephrine and left ventricle end-diastolic pressure (rϭϪ0. 77, Pϭ0.004), and between chemiluminescence and baroreflex sensitivity to sodium nitroprusside (rϭϪ0.75, Pϭ0.02), whereas a positive correlation was observed between baroreflex sensitivity to sodium nitroprusside and glutathione peroxidase activity (rϭ0.7, Pϭ0.04). Thus, adriamycin led to increased left ventricle end-diastolic pressure without changes in baroreflex sensitivity, and associated increased oxidative stress appeared to be related to reduction of reflex control of circulation. Key Words: heart failure Ⅲ blood pressure Ⅲ baroreflex Ⅲ oxidative stress Ⅲ adriamycin Ⅲ rat A driamycin-induced cardiac toxicity remains a major limitation to its use as an antineoplastic agent. In humans, this cardiac toxicity appears to be dose dependent. Total dose of 550 mg/m 2 of adriamycin is considered the upper limit to be used, because of the high risk for cardiotoxicity. The clinical course of adriamycin-induced heart failure may vary, but mortality rates can reach 20%. 1 Several mechanisms are thought to be involved in the development of adriamycin-induced heart failure. Experimental studies devoted to this issue indicate that oxidative stress injury, inflammatory injury, calcium overload, and sympathetic overdrive are likely to be involved once a systolic dysfunction is present. 2,3 In fact, impairment of baroreflex control of circulation has been demonstrated in adriamycin-treated rabbits in the presence of systolic left ventricular dysfunction. 4,5 However, as diastolic dysfunction usually occurs before systolic dysfunction in the course of heart fail...

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Section: Discussioncontrasting

confidence: 62%

Baroreflex Sensitivity and Oxidative Stress in Adriamycin-Induced Heart Failure

et al. 2001

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“…Adriamycin induces impairments of cardiac repolarization [15] and contractility [16]. This reduction of contractility is only observed in the decompensated phases; in the earlier stages, the cardiac systolic function remains normal [17], due to an activation of the sympathetic nervous system which maintains systolic ventricular pressure, despite an increase of the end‐diastolic pressure [8]. In agreement with these results, at the time of the hemodynamic evaluation, our protocol of ADR delivery induced classical hemodynamic effects, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Although non‐significant in our experimental conditions, we also observed a trend to reduction of cardiac inotropism after 5 weeks. At this stage, animals exhibit clinical signs of HF, the myocardial content of norepinephrine and myocardial response to catecholamines are reduced [17,20]. So, in these conditions, it is tempting to speculate that sympatho‐inhibitors could limit the deterioration of the hemodynamic status as well as improve the survival of the animals in this given cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular and survival effects of sympatho‐inhibitors in adriamycin‐induced cardiomyopathy in rats

Thomas

Christen

Monassier

2004

Fundamemntal Clinical Pharma

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Adriamycin (ADR) is a widely used drug for the treatments of cancers. This study evaluates the effects of moxonidine and metoprolol on cardiac hemodynamics and survival in ADR-induced left ventricular dysfunction (total dose of 20 mg/kg in a 4-week regimen). Rats were treated with the centrally acting I(1)R agonist sympatho-inhibitor, moxonidine, or with the non-selective beta-adrenergic antagonist, metoprolol, during 1 month or until death. Treatments began 1 week after the onset of the ADR administration. Low doses (0.5 and 1 mg/kg/day) of moxonidine and metoprolol (10 mg/kg/day) improved cardiovascular function. High doses of moxonidine (3 mg/kg/day) and metoprolol (150 mg/kg/day) were cardiodepressive. Moxonidine and metoprolol both failed to improve survival. These data indicate that a treatment with these sympatho-inhibitors can reduce the left ventricular dysfunction induced by ADR. Moreover, these cardioprotective effects where obtained even when ADR was used at a dose regimen usually employed for its antineoplastic effects in rodents. Nevertheless, in this particular cardiomyopathy, we did not find any association between improvements of functional parameters and survival whatever the drug and the dose used. This problem points out the difficulty to prevent, at least with sympatho-inhibitory drugs alone, the mortality linked to the chronic cardiotoxicity of ADR.

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“…Likewise, although the inorganic phosphate-to-phosphocreatine ratio for hearts from doxorubicin-treated rats is not altered at rest, there is a significant treatment-related increase at stimulated heart rates (Dekker el al., 1991). Similarly, dobutamine-induced stimulation of heart rate, increased left ventricular pressure, increased cardiac output, and both pressor and inotropic response to catecholamine injections were all lower for rats chronically treated with doxorubicin as compared with controls (Hofling et al, 1982;Gorodetskaya et al, 1990;Kawasaki et al, 1996). Although there were no differences in mechanical and hemodynamic responses at rest in chronically treated rats, both rate and maximum degree of tension development in response to dobutamine were significantly reduced in isolated papillary muscle strips from doxorubicin-treated rats (Hofling et al, 1982).…”

Section: Resultsmentioning

confidence: 85%

Mitochondria in Pathogenesis

Lemasters¹,

Nieminen²

2002

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Preface Surprisingly, the mitochondrion has emerged as a center of attention in pathophysiology, generating both excitement and controversy. Old controversies concerning the mechanism of mitochondrial energy transduction subsided with the acceptance of Peter Mitchell's hypothesis of oxidative phosphorylation, first proposed in 1961. The chemiosmotic hypothesis elegantly described how mitochondrial respiration creates an electrochemical gradient of protons across the mitochondrial inner membrane, which in turn drives ATP synthesis through the mitochondrial ATP synthase. Tight coupling of this process requires that the mitochondrial inner membrane have an exceptionally low nonspecific permeability to protons and other charged solutions. In several pathological conditions, however, the mitochondrial permeability barrier fails, leading to cell death. Indeed, in programmed cell death (apoptosis) mitochondrial membrane failure may be a key signaling event. Moreover, the same respiratory processes that generate the proton electrochemical gradient driving oxidative phosphorylation may also lead to formation of toxic reactive oxygen species that cause cellular injury. Such oxygen radicals may contribute to the decline of bioenergetic capacity with advancing age.Among the organelles of animal cells, mitochondria are unique in that they contain their own DNA. The complete nucleotide sequence of human mtDNA is established, and it encodes genes for several hydrophobic subunits of complexes I, III, IV, and V, as well as genes for ribosomal proteins and tRNA. Mutations of mtDNA have wide-ranging consequences for mitochondrial respiration and bioenergetics. Because scores of mtDNA copies are maternally inherited, in contrast to the single maternal and paternal copies of nuclear DNA, mitochondrial diseases have unusual features of incomplete penetrance, delayed expression, and heterogeneous tissue involvement. In addition, possible links between mtDNA mutations, mitochondrial free radical generation, and several neurodegenerative diseases, including Huntington, Parkinson, and Alzheimer diseases, are under investigation by several laboratories.Toxic chemicals have long been known to disrupt mitochondrial metabolism and lead to cellular injury, but the mechanisms causing the injury are turning out to be more complex than expected. For instance, calcium, oxidant chemicals, ischemia/reperfusion, and a range of other agents promote onset of the mitochondrial permeability transition ix x Preface (MPT) in mitochondria from liver, heart, and other tissues, as first characterized by Hunter and Haworth in the mid-1970s. The significance of the MPT to pathophysiological processes, however, is only now being recognized. Besides involvement of the transition in necrotic cell death, new findings implicate it in apoptosis as well. Indeed, it may be the exceptional form of cell death that does not involve transition.This book attempts to provide an overview of recent major advances in the understanding of mitochondria's numerous roles in pathop...

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

Cited by 11 publications

References 3 publications

Baroreflex Sensitivity and Oxidative Stress in Adriamycin-Induced Heart Failure

Baroreflex Sensitivity and Oxidative Stress in Adriamycin-Induced Heart Failure

Cardiovascular and survival effects of sympatho‐inhibitors in adriamycin‐induced cardiomyopathy in rats

Mitochondria in Pathogenesis

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