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L Rappaport

Publications and source records attributed to L Rappaport.

At least 55 records · Page 3Linked to original sources
PubMed1993

Diuretic effects on cardiac hypertrophy in the stroke prone spontaneously hypertensive rat.

OBJECTIVE: The aim was to compare the effects of two diuretics, indapamide and hydrochlorothiazide, on cardiac hypertrophy in stroke prone spontaneously hypertensive rats (SHR-SP). METHODS: Six week old SHR-SP, on a 1% sodium chloride water intake, were treated with oral indapamide (3 mg.kg-1 x d-1) or hydrochlorothiazide (20 mg.kg-1 x d-1) over a 44 d period. The hypertrophic process was evaluated by classical indices and by the morphological analysis of myocyte cross sectional area, coronary artery thickness, and immunohistochemical analysis of interstitial fibrosis. RESULTS: In the untreated SHR-SP on 1% sodium chloride, all animals developed severe hypertension and cardiac hypertrophy when compared to normotensive salt loaded WKY by 13 weeks of age. In salt loaded SHR-SP treated with indapamide or hydrochlorothiazide, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP, at 259(7) and 245(7) mm Hg respectively, v 300(11) mm Hg, p < or = 0.05. Myocyte enlargement appears to be the main feature involved in the development of cardiac hypertrophy in the SHR-SP. By the end of treatment both indapamide and hydrochlorothiazide prevented the development of cardiac hypertrophy evaluated by heart weight to body weight ratio [4.69(0.07) and 4.61(0.08) respectively, v 5.39(0.13), p < or = 0.001] and myocyte hypertrophy (-33% and -21% of the SHR-SP values, p < or = 0.001). Myocardial interstitial fibrosis and perivascular fibrosis were practically absent in the two treated groups. CONCLUSIONS: Our results allow the characterisation of SHR-SP cardiac hypertrophy and indicate that the two types of chronic diuretic treatment prevent SHR-SP cardiac hypertrophy with a drug specific efficiency.

Animals↗
PubMed1993

Alpha-, beta-MHC mRNA quantification in adult cardiomyocytes by in situhybridization: effect of thyroid hormone.

Cardiac myocytes isolated from adult rats and cultured for up to 5 days in a defined serum- and 3,5,3'-triiodothyronine-(T3) free medium were processed for in situ hybridization using [35S]cRNA probes specific for alpha- or beta-myosin heavy chain (MHC) mRNAs. A computer-assisted image analysis system was used to quantitate the hybridization signals within individual myocytes (100 cells/experimental point). The method was validated by comparison with dot-blot quantitation. The mean alpha-MHC mRNA density per cell decreased by 50% (P < 0.01) after 2 days in culture and remained stable thereafter, whereas the relative amount of beta-MHC mRNA did not increase until day 5. Addition of 10(-12) M T3 to the culture medium for 2 or 3 days was sufficient to maintain alpha-MHC mRNA levels similar to the day 0 values, whereas 10(-9) M T3 was necessary to completely inhibit beta-MHC mRNA expression. The independent analysis of myocytes exhibiting different morphological phenotypes with time in culture demonstrated that rounded myocytes contain relatively more alpha-MHC mRNA and were as sensitive to T3 as their rod-shaped counterparts. Their beta-MHC RNA content was similar to that found in rod-shaped cells and was still depressed by T3. In conclusion, we show that 1) physiological doses of T3 are sufficient to maintain in vitro a MHC phenotype close to that observed in vivo in adult, 2) the dose responsiveness of adult myocytes to T3 differs from that reported in neonatal myocytes, and 3) the alpha-MHC mRNA content and the T3 sensitivity of spheroidal myocytes imply that there is no alteration in their state of maturation.

Animals↗
PubMed1993

Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.

The aim of this study was to determine the phenotype of smooth muscle cells in the arteries of chronically hypertensive animals and to analyze the effects of treatments known to increase the survival of the animal without a clear effect on its hypertensive state. Stroke-prone spontaneously hypertensive rats (SHRSP) kept on a 1% sodium drinking solution were untreated or treated with one of two diuretics, indapamide (3 mg/kg per day) or hydrochlorothiazide (20 mg/kg per day), from 6 to 13 weeks of age. Phenotype was characterized by the immunolabeling of arteries with antibodies raised against a cellular form (EIIIA) of fibronectin, alpha-smooth muscle actin, and nonmuscle myosin. We demonstrated that phenotypes of smooth muscle cells of the SHRSP differ from those found in Wistar-Kyoto rats. The difference in phenotype is specific for the vessel type: ie, an increased expression of nonmuscle myosin in the aorta and of both EIIIA fibronectin and nonmuscle myosin in the coronary arteries. The two diuretics (1) had no effect on blood pressure, (2) prevented or did not prevent the increase in medial thickness, and (3) prevented changes in both smooth muscle cell phenotype and ischemic tissular lesions. Taken together, the results suggest that in SHRSP the changes in the phenotype of smooth muscle cells and the thickness of arteries are unrelated events. We propose that the maintenance of the contractile phenotype of the arterial smooth muscle cells could be an essential parameter involved in the prevention of the deleterious consequences characteristic of a severe hypertensive state.

Actins↗
PubMed1993

Comparative effects of indapamide and hydrochlorothiazide on cardiac hypertrophy and vascular smooth-muscle phenotype in the stroke-prone, spontaneously hypertensive rat.

The effects of two diuretics, indapamide (3 mg/kg/day) and hydrochlorothiazide (20 mg/kg/day), were analyzed over a 44-day period on the cardiovascular hypertrophy of stroke-prone spontaneously hypertensive rats (SHR-SP). Untreated SHR-SP developed severe hypertension and cardiac hypertrophy when compared to normotensive Wistar-Kyoto (WKY) rats after 8 weeks on 1% sodium chloride. In diuretic-treated animals, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP (-13 and -18%, respectively, p < or = 0.05). Morphometric analysis of myocyte cross-sectional areas evidenced that indapamide was the most effective in preventing myocyte hypertrophy (-33%, p < or = 0.0001). Small coronary artery wall thickness was efficiently prevented in the two treated groups, but medial hypertrophy was prevented by hydrochlorothiazide only. Among markers of smooth-muscle cell phenotype (contractile or extracellular matrix proteins) EIIIA-fibronectin (FN), one FN cellular isoform, was shown to be the most sensitive marker by an immunohistochemical technic. Medial expression of EIIIA-FN, which was characteristic of SHR-SP coronary arteries, was prevented by the two treatments. The two diuretic treatments, despite similar effects on blood pressure and smooth-muscle phenotype, prevent SHR-SP cardiovascular hypertrophy with a drug-specific efficiency.

Animals↗
PubMed1992

Correlates of medical compliance among hemophilic boys.

Twenty-nine males with hemophilia completed the Medical Compliance Incomplete Stories Test (M-CIST), and their scores were correlated with health care professionals' ratings of four aspects of medical compliance, along with measures of possible moderating variables. The results indicated that significant associations were found between most of the M-CIST category scores, particularly the Compliance/coping subscale, and the health care specialists' ratings of how well the children exhibited compliant responses to bleeding episodes, and inverse associations with the incidence of monthly bleeding episodes. The findings suggested that the M-CIST continues to demonstrate promise as an instrument to be used in studies of compliance among pediatric chronic illness patients.

Achievement↗
PubMed1992

Pyrimidine nucleotide synthesis is preferentially supplied by exogenous cytidine in adult rat cultured cardiomyocytes.

The metabolism of pyrimidine nucleotides was studied in non-contracting myocytes isolated from adult rat hearts and compared to that observed in freshly prepared myocardium. The myocytes were cultured for up to 96 hrs in a commercial medium containing 50 microM cytidine, uridine, adenosine and adenine; 20 microM guanosine, thymidine and D-ribose; and 5 microM hypoxanthine, xanthine, guanine, thymine and uracil. Nucleotide pool sizes were measured by HPLC. Nucleotide and RNA labelling were followed by incorporation of [U-14C]-cytidine or [U-14C]-uridine added in trace amounts to the medium. The adenine nucleotide pool was 2.4-fold larger than in situ after 7 hrs of incubation and then returned to values 30% higher than that found in the myocardium after 25 hrs. Cytosine and uracil nucleotide pools after 25 hrs of culture were respectively 2 and 4-fold larger than in situ and remained at these levels thereafter. Intracellular cytidylate and uridylate equilibrated very rapidly with exogenous [U-14C]-cytidine but not with [U-14C]-uridine. We conclude that, under the experimental conditions used here, the synthesis of pyrimidine nucleotides in isolated myocytes is mainly supplied by exogenous nucleosides. Furthermore, extracellular cytidine is rapidly converted to both uracil and cytosine nucleotides while uridine serves only as the precursor for uracil nucleotide synthesis.

Adenine Nucleotides↗
PubMed1992

Behavioral consequences of illness: childhood asthma as a model.

Several areas of research on childhood asthma are discussed within a transactional model of asthma. The model emphasizes the multidirectional influences that affect the severity of asthma and associated behavioral disability. The initial focus is on how the clinical presentation and morbidity of asthma are affected both by somatic predisposition and by interactions with multiple internal and external elements. Specific elements include emotional factors, neuroimmunology, temperament, and medication side effects. Second, the impact of asthma on the child, his or her family, and segments of the community are described, as are consequences of the disorder on quality of life. Third, there is a synopsis of preventative interventions for reducing the medical and behavioral impact of childhood asthma. The motif is that the interaction of medical and behavioral procedures can improve the management of asthma while consequences of the disorder are mollified. Finally, as examples of a transactional model of asthma, self-management programs for teaching children to become partners with their physicians in establishing and maintaining control over the disorder are described. A representative of self-management--the ACT (Asthma Care Training) program--is described, along with the impact such programs have on children, their families, and institutions. The conclusion emphasizes that asthma is a complicated and unpredictable disorder that puzzles physicians, behavioral scientists, and patients. Although new treatments may be over the horizon, controlling childhood asthma and its consequences currently rests on the cooperation and increased interaction of medical and behavioral scientists.

Asthma↗
PubMed1992

[Changes in heart genome expression in hypertensive diseases].

Chronic increases in haemodynamic load modify the expression of cardiac genes, leading to cardiac hypertrophy and a new phenotype. As an example, changes in the expression of the genes encoding the main contractile proteins, the isomyosin heavy chains, have been associated with modifications of the physiological properties of cardiac muscle. The cellular and molecular mechanisms which either do or do not initiate and maintain these changes in cardiac genomic expression remain to be elucidated. Using in situ hybridization we show that mRNAs encoding a cellular form of fibronectin (c-FN), a protein of the basal membrane which is not or poorly expressed in adult rat heart, are reexpressed as a result of severe hypertension with a similar time course than the beta-heavy chain of myosin (beta-MHC), also mostly expressed in fetal heart. The accumulation of the c-FN mRNAs was found in the wall of coronary arteries whilst that of the beta-MHC mRNAs occurred in the myocytes at the border zone of these arteries. Thus a high pressure in the arteries could be the trigger inducing the synthesis of factors which could, through a gradient, modulate the phenotype of both the smooth muscle cells of the media and the cardiocytes. Besides, using a model of cultured adult rat cardiocytes, we show that the differential expression of the MHC isoforms is dependent on the beta-adrenergic stimulation but that the regulation depends on the stage of development of the cells and differs for the alpha and beta MHC. These 2 complementary approaches for identifying the molecular mechanisms that control cardiac muscle growth should help for understanding cardiac adaptation triggered by haemodynamic overload, such as arterial hypertension as well as cardiac failure.

Animals↗
PubMed1991

Stimulant medication and attention deficit-hyperactivity disorder. The child's perspective.

Fifty-eight children receiving stimulant medication for attention deficit-hyperactivity disorder at referral clinics for learning disabilities at two teaching hospitals in Massachusetts were invited to participate in a study of their knowledge and attitudes. The 45 respondents and parents completed separate questionnaires concerning how they felt about receiving stimulant medication. Eighty-nine percent of the children felt that the medication was helpful and 78% liked or were indifferent to it despite a high rate (85%) of reported side effects. The five children (11%) who responded that they would stop taking stimulant medication if they could were more likely to perceive the medication as unhelpful and were receiving standard methylphenidate hydrochloride rather than a long-acting preparation. We conclude that children's perspectives on medication should be elicited directly and sustained-release medication may be more acceptable to children with attention deficit-hyperactivity disorder.

Adolescent↗
PubMed1991

Mechanogenetic regulation of transcription.

In many biological systems mechanical forces regulate gene expression: in bacteria changes in turgor pressure cause a deformation of the membrane and induce the expression of osmoregulatory genes; in plants gravity regulates cell growth ('geotropism'); in mammals stretching a muscle induces hypertrophy which is accompanied by qualitative changes in protein synthesis. Consequently, the term 'mechanogenetic control' seems to be a suitable common name for all these processes. The mechanism by which mechanical factors modulate transcriptional activity is still unknown. The purpose of this review is to bring together data from different fields in order to obtain a better understanding of the mechanogenetic control of cell growth.

Animals↗
PubMed1991

Expression and cellular distribution of heat-shock and nuclear oncogene proteins in rat hearts.

An early, transient accumulation of mRNAs of the protooncogenes c-fos and c-myc and the heat-shock protein HSP70 has been described in hypertrophying rat hearts. It is unclear 1) in which cardiac cell type-these gene activations occur and 2) whether the corresponding proteins are translated. We studied protein expression in rat hearts during ontogenic development and under stress conditions associated with pressure overload with the use of immunofluorescent techniques. During cardiac development no HSP70 could be detected. c-Fos was expressed consistently after birth but only in coronary smooth muscle cells, and c-Myc was found exclusively in adult coronary endothelium and myocardial nonmuscle cells. In adult rats, HSP70 and, to a lesser extent, c-Fos were induced in myocardial muscle and some nonmuscle cells within 3 h following methohexital sodium anesthesia. A similar, more intense immunolabeling of these peptides was observed after thoracotomy and/or aortic stenosis. The coronary c-Fos and c-Myc labeling remained unchanged in these conditions. Thus the expression in cardiac muscle and nonmuscle cells of the three peptides differs and depends on different triggers.

Aging↗
PubMed1991

Accumulation of fetal fibronectin mRNAs during the development of rat cardiac hypertrophy induced by pressure overload.

Cardiac pressure overload induces a shift towards the fetal form of major proteins expressed by the myocytes, and an accumulation of extracellular matrix proteins. One of them, fibronectin (FN), accumulates soon after the imposition of pressure overload. Because FN exists both as cellular FN (c-FN) locally synthesized by nonmuscle cells and as "plasma-FN" (p-FN) synthesized by the hepatocytes, the first issue of this study was to determine whether FN accumulation within the myocardium in response to pressure overload is paralleled by a local increase in mRNA. The expression of c-FN isoforms being developmentally regulated in a tissue-specific manner, the types of FN exons expressed by cardiac cells were analyzed. Pressure overload was induced in 25-d-old rats by stenosis of the thoracic aorta. Using in situ hybridization, we show that the mRNAs encoding the fetal forms of c-FN are accumulated in the interstitial tissue of fetal rat hearts but are absent in adult. 1-3 d after aortic stenosis, the fetal forms of c-FN mRNAs were found in the wall of coronary arteries and in focal areas of the myocardium. Thus nonmuscle cells and smooth muscle cells, like myocytes, do respond to pressure overload by reexpressing fetal gene transcripts.

Animals↗
PubMed1991

Specific alterations in the distribution of extracellular matrix components within rat myocardium during the development of pressure overload.

Cardiac hypertrophy secondary to a sudden aortic pressure overload results in the remodeling of myocytes and extracellular matrix components. Hydroxyproline quantitation to evaluate total collagen content and immunocytochemistry procedures were used to analyze the temporal appearance and regional distribution of collagen, laminin, and fibronectin during the early stages of pressure overload. The study was performed in 25-day-old rats submitted to a thoracic aortic stenosis and killed from 1 day to 18 days after surgery. Cardiac hypertrophy reached 24.5% by day 2 and 75.5% by day 15. Each extracellular matrix component showed a unique distribution throughout the myocardium: in normal hearts, type I/III collagens appeared mainly as large strands or waves around groups of myocytes, fibronectin predominated around small and large vessels, while laminin surrounded both myocytes and capillaries. As early as 2 days after surgery, fibronectin and type I/III collagens, but not laminin, accumulated in focal areas. Thereafter, these areas increased in size and number within the inner part of the left ventricle, and progressively affected the whole left ventricle. Fibronectin accumulation preceded that of collagen and occupied larger areas. The measure of hydroxyproline content demonstrated that during the 1st week after surgery the increase in collagen content is correlated with the increase in heart weight. In conclusion, the three components of the extracellular matrix studied here develop a specific pattern of accumulation in response to a sudden pressure overload that induces cardiac hypertrophy. Both fibronectin and collagen changes participate in the healing of focal myocardial necrosis secondary to the increased hemodynamic work and fibronectin appeared as a more sensitive marker of the cardiac lesions than collagen.

Animals↗
PubMed1990

Biological signals of cardiac hypertrophy.

Chronic increases in haemodynamic load modify the expression of cardiac genes, leading to a new phenotype better adapted to the new functional demand. Several mechanisms such as the global activation of genes, the modulation of single genes and/or differential expression of multigene families may account for these modifications. Changes in gene expression of isomyosin shift are permanent and have been associated with modifications of the physiological properties of cardiac muscle. The exact cellular and molecular mechanisms which either do or do not initiate and maintain these changes in cardiac expression remain to be elucidated. Recent technical advances in cellular and molecular biology provide a foundation for understanding those cellular mechanisms that control cardiac muscle growth. This is a review of some transient changes in gene expression induced by mechanical overload such as the expression of cellular oncogenes, heat shock protein and alpha-skeletal actin genes. The biological functions of these genes are not yet precisely defined, some of them could interfere in the process of myocyte hypertrophy.

Actins↗
PubMed1990

Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat.

The reduction in Ca2+ concentration during diastole and relaxation occurs differently in normal hearts and in hypertrophied hearts secondary to pressure overload. We have studied some possible molecular mechanisms underlying these differences by examining the function of the sarcoplasmic reticulum and the expression of the gene encoding its Ca2(+)-ATPase in rat hearts with mild and severe compensatory hypertrophy induced by abdominal aortic constriction. Twelve sham-operated rats and 31 operated rats were studied 1 month after surgery. Eighteen animals exhibited mild hypertrophy (left ventricular wt/body wt less than 2.6) and 13 animals severe hypertrophy (left ventricular wt/body wt greater than 2.6). During hypertrophy we observed a decline in the function of the sarcoplasmic reticulum as assessed by the oxalate-stimulated Ca2+ uptake of homogenates of the left ventricle. Values decreased from 12.1 +/- 1.2 nmol Ca2+/mg protein/min in sham-operated rats to 9.1 +/- 1.5 and 6.7 +/- 1.1 in rats with mild and severe hypertrophy, respectively (p less than 0.001 and p less than 0.001, respectively, vs. shams). This decrease was accompanied by a parallel reduction in the number of functionally active CA2(+)-ATPase molecules, as determined by the level of Ca2(+)-dependent phosphorylated intermediate: 58.8 +/- 7.4 and 48.1 +/- 13.5 pmol P/mg protein in mild and severe hypertrophy, respectively, compared with 69.7 +/- 8.2 in shams (p less than 0.05 and p less than 0.01, respectively, vs. shams). Using S1 nuclease mapping, we observed that the Ca2(+)-ATPase messenger RNA (mRNA) from sham-operated and hypertrophied hearts was identical. Finally, the relative level of expression of the Ca2(+)-ATPase gene was studied by dot blot analysis at both the mRNA and protein levels using complementary DNA clones and a monoclonal antibody specific to the sarcoplasmic reticulum Ca2(+)-ATPase. In mild hypertrophy, the concentrations of Ca2(+)-ATPase mRNA and protein in the left ventricle were unchanged when compared with shams (mRNA, 93.8 +/- 10.6% vs. sham, NS; protein, 105.5 +/- 14% vs. sham, NS). in severe hypertrophy, the concentration of Ca2(+)-ATPase mRNA decreased to 68.7 +/- 12.9% and that of protein to 80.1 +/- 15.5% (p less than 0.001 and p less than 0.05, respectively), whereas the total amount of mRNA and enzyme per left ventricle was either unchanged or slightly increased. The slow velocity of relaxation of severely hypertrophied heart can be at least partially explained by the absence of an increase in the expression of the Ca2(+)-ATPase gene and by the relative diminution in the density of the Ca2+ pumps.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Beta-adrenergic agonists stimulate the synthesis of noncontractile but not contractile proteins in cultured myocytes isolated from adult rat heart.

The effect of catecholamines on adult myocardial protein synthetic activity was studied by use of an experimental model of isolated adult rat cardiac myocytes maintained in culture for 1-6 days. During this period, the majority of myocytes retained their rod-shaped morphology, but the cell number decreased progressively (50% of the initial density after 2 days in culture). Between day 1 and day 3 in culture, the specific synthetic activities of total proteins and of electrophoretically purified myosin heavy chain and actin ([14C] phenylalanine incorporation into protein, in disintegrations per minute per microgram protein) decreased (-19%,-32%, and -73%, respectively). Addition of isoproterenol or norepinephrine (10 nM) from the onset of the culture for 3 days increased the specific activity of both total and noncontractile proteins (greater than 20%) but had no effect on the specific activity of myosin heavy chain and actin when compared with 3-day cultured control cells. beta-Adrenergic receptors are specifically required to mediate this increase in total protein synthesis. This finding was demonstrated by the inhibitory effects of propranolol; neither prazosin nor yohimbine showed any effect. The pattern of synthesized protein during adrenergic stimulation was qualitatively evaluated by use of [35S]methionine incorporation and gel electrophoresis. The general pattern of labeled proteins did not differ significantly from that of control cells; this occurrence suggests that isoproterenol harmoniously stimulates the synthesis of noncontractile proteins. These findings demonstrate that low doses of beta-adrenergic agonists have an anabolic effect on adult cardiac quiescent myocytes that do not affect the major contractile proteins. Regulation of myofibrillar protein synthesis may be more dependent on myocyte contractile activity.

Adrenergic beta-Agonists↗