Browsing by Author "JALIL, JE"

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    AMIODARONE PROTECTION AGAINST MYOCARDIAL INJURY AND FIBROSIS INDUCED BY ISOPRENALINE IS ABOLISHED BY THYROID-HORMONE
    (1994) DUSSAILLANT, G; JALIL, JE; CESPEDES, C
    Objective: Catecholamines induce myocyte necrosis and myocardial fibrosis. These effects are probably related to beta adrenergic receptor stimulation and to thyroid hormonal status. The aim of the study was to test the hypothesis that amiodarone prevents myocardial damage induced by isoprenaline and that these effects are not observed when thyroid hormone is administered. Methods: Myocardial injury was assessed in the first experiment. Isoprenaline (1 mg.kg(-1) subcutaneously once) was given to two groups of rats which received monoclonal antimyosin. Group 1 (n = 5 was pretreated with amiodarone and group 2 (n = 6) received only isoprenaline. In the second experiment the effects of amiodarone on isoprenaline induced myocardial fibrosis and of supplementary triiodothyronine (T3) were examined. Group 3 (n = 10) received only isoprenaline for 4 d. Group 4 (n = 10) received amiodarone for 14 d and isoprenaline during 4 d. Group 5 (n = 8) received amiodarone and isoprenaline like group 4, plus T3. Untreated rats served as controls (group 6; n = 10). Collagen volume fraction (CVF) was measured in each heart. Results: No rats pretreated with amiodarone showed antimyosin labelling, while the mean score of rats receiving only isoprenaline was 2.8 (p < 0.05), indicating the presence of significant myocyte injury. In group 3, CVF was significantly higher than in controls, at 7.63(SEM 0.89)% v 1.74(0.07)%, p < 0.001, whereas rats pretreated with amiodarone (group 4) showed significantly less fibrosis [CVF 2.96(0.19)%]. This protective effect was lost when amiodarone and T3 were given together [CVF 7.92(1.8)%, p < 0.005 between groups 4 and 6]. Conclusions: By preventing isoprenaline induced myocardial injury and fibrosis. amiodarone may have a cardioprotective role. This effect is completely abolished by thyroid hormone.
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    CARDIAC MYOCYTE NECROSIS INDUCED BY ANGIOTENSIN-II
    (LIPPINCOTT WILLIAMS & WILKINS, 1991) TAN, LB; JALIL, JE; PICK, R; JANICKI, JS; WEBER, KT
    Although the role of angiotensin II (Ang II) in the pathogenesis and progression of the failing heart is uncertain, previous reports have suggested that myocyte injury may be a component in this process. In this study, we investigated this possibility in more detail. Cardiotoxic effects of nonacutely hypertensive doses of Ang II were examined in 90 rats, including those receiving an angiotensin infusion (200 ng/min i.p.) and those with renovascular hypertension, where endogenous stimulation of Ang II occurred. Myocyte injury and wound healing resulting from these treatments were evaluated by 1) immunofluorescence after in vivo monoclonal antibody labeling of myosin to detect abnormal sarcolemmal permeability, 2) [H-3]thymidine incorporation into DNA, to detect fibroblast proliferation, and 3) light microscopic evidence of myocytolysis and subsequent scar formation. We found that exogenous Ang II produced multifocal antimyosin labeling of cardiac myocytes and myocytolysis, which were maximal on days 1-2 of the infusion. Subsequently, DNA synthesis rates were increased, with fibroblast proliferation reaching peak levels on day 2 (Ang II-treated rats, 90.0 +/- 18.6 cpm/mu-g DNA; control rats, 11.4 +/- 2.3 cpm/mu-g DNA; p < 0.05); microscopic scarring was found on day 14 and represented 0.12 +/- 0.02% of the myocardium. Concurrent treatment with both propranolol (30 mg/kg/day s.c.) and phenoxybenzamine (5 mg/kg/day i.m.) did not attenuate Ang II-induced antimyosin labeling. Increased endogenous Ang II, resulting from renal ischemia after abdominal aortic constriction, produced both antimyosin labeling and increased rates of DNA synthesis like that observed with Ang II infusion. Both myocyte injury and fibroplasia were prevented with captopril (65 mg/day p.o.), but this protective effect was not seen with reserpine pretreatment. Infrarenal aortic banding without renal ischemia, on the other hand, produced hypertension without necrosis. We conclude that pathophysiological levels of endogenous as well as low-dose exogenous Ang II were associated with altered sarcolemmal permeability and myocytolysis with subsequent fibroblast proliferation and scar formation. Myocyte injury was unrelated to the hypertensive or enhanced adrenergic effects of Ang II or to hypertension per se. Captopril was effective in preventing myocyte injury in renovascular hypertension. The mechanism(s) responsible for Ang II-induced necrosis will require further study.
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    CHANGES IN CYCLIC-AMP-DEPENDENT PROTEIN-KINASE AND ACTIVE STIFFNESS IN THE RAT VOLUME OVERLOAD MODEL OF HEART HYPERTROPHY
    (ELSEVIER SCIENCE BV, 1993) LAVANDERO, S; CARTAGENA, G; GUARDA, E; CORBALAN, R; GODOY, I; SAPAGHAGAR, M; JALIL, JE
    Objective: The aim was to clarify the role of cyclic AMP dependent protein kinase (PKA) and changes in mechanical heart function during development of cardiac hypertrophy induced by volume overload. Methods: Protein and DNA contents, PKA activity, and peak systolic stress-strain relationships in hearts from animals submitted to aortocaval shunt were assessed as a function of time. Sham operated (control) rats were used as controls. Results: Heart weight to body weight ratio and cardiac protein content per heart increased from d 7 (p<0.005 and p<0.01, respectively) reaching their highest values by d 56; the same occurred with cardiac DNA content. PKA activity.g-1 tissue in soluble extracts of hearts from rats with aortocaval shunt increased by 2.7-fold on d 2 (p<0.005), reached a ninefold peak increase by d 7 (p<0.0001) and declined to fourfold by d 56 with respect to control values. The end peak systolic stress-strain relation slopes were: control, 368(SEM 14) g.cm-2 (n=16); aortocaval shunt values: 2 d, 514(28) g.cm-2 (n=6); 7 d, 579(10) g.cm-2 (n=7); and 56 d, 554(28) g.cm-2 (n=7). The force generating capacity at 0% strain was also significantly higher in the shunt groups as compared to sham operated controls (p<0.01). Early activation of PKA was also confirmed through endogenous cardiac protein phosphorylation. SDS-PAGE gel electrophoretogram and autoradiography showed more heavily phosphorylated bands in aortocaval shunt hearts than in the control group. Conclusions: PKA activity and the slope of systolic stress-strain regression line followed a similar trend throughout the study, with an early increase in both variables by d 2 in the shunt group, reaching a peak at d 7, and decreasing thereafter but remaining higher than in controls. PKA activity appears to be related to increased force generating capacity rather than to hypertrophy or increased cardiac protein content. Thus PKA activation is an early biochemical event after aortocaval shunt, followed later by cardiac hypertrophy. Changes in PKA activity showed a similar trend to mechanical heart function over time. These findings help to explain the changes in the mechanical properties of the heart preceding the development of cardiac hypertrophy in the rat model of volume overload.