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Biomedical subjects

C J Limas

Publications and source records attributed to C J Limas.

At least 73 records · Page 4Linked to original sources
PubMed1980

Increased phospholipid methylation in the myocardium of hyperthyroid rats.

Administration of L-thyroxine (1 mg/kg) to adult rats results in cardiac hypertrophy and enhanced contractility. Phosphatidylcholine synthesis through methylation of phosphatidylethanolamine by S-adenosylmetionine in enhanced in the myocardium of hyperthyroid rats. Increased microsomal methylation occurs pari passu with the development of cardiac hypertrophy and may be partly responsible for preservation of cardiac performance.

Animals↗
PubMed1980

Ribonucleic acid synthesis in the myocardium of spontaneously hypertensive rats. Quantification of transcribing ribonucleic acid polymerases.

Cardiac hypertrophy accompanies the progressive rise in blood pressure in spontaneously hypertensive rats. The role of endogenous RNA polymerases in this process was examined in nuclei from isolated cardiac myocytes of 20-week-old spontaneously hypertensive rats and normotensive Wistar-Kyoto controls. Both template-engaged (involved in transcription) and free (loosely attached to endogenous template, transcribing only with exogenous templates) RNA polymerases were increased in spontaneously hypertensive rats. In addition, the ratio of RNA polymerases I/II was lower in the spontaneously hypertensive rats for both functional pools of the enzyme. Endogenous transcribing RNA polymerases were quantified by t.l.c. of RNA-hydrolysis products. Increased numbers of enzyme molecules were present in nuclei from spontaneously hypertensive rats, without appreciable change in the rate of polyribonucleotide-chain elongation. These results could not be explained by differences in the activities of contaminating phosphatases or ribonucleases, nor by changes in endogenous nucleoside pools or recoveries of labelled nucleosides. Enhanced myocardial RNA synthesis in the spontaneously hypertensive rats at the stage of established cardiac hypertrophy is associated with increased numbers of RNA polymerase molecules. This increase may, in turn, reflect altered chromatin structure, resulting in increased polymerase binding and/or chain initiation.

Animals↗
PubMed1980

Effect of antihypertensive therapy on calcium transport by cardiac sarcoplasmic reticulum of SHRs.

Cardiac hypertrophy develops during the course of blood pressure elevation in spontaneously hypertensive rats (SHRs) and is associated with defective calcium transport by cardiac sarcoplasmic reticulum (SR). AT 20 weeks of age, calcium uptake is reduced in SHRs (42 +/- 1.3 vs 64 +/- 1.6 nmol X mg-1 X min-1 in age-matched normotensive Wistar-Kyoto rats, P less than 0.01), while Ca2+ ATPase activity is enhanced (44 +/- 1.1 vs 35 +/- 0.7 nmol X mg-1 X min-1 in WKYs, P = 0.02); this results in low stoichiometry between calcium uptake and ATP hydrolysis in SHRs. The steady-state levels of the phosphoprotein intermediate [EP] of the transport ATPase are higher in normotensive rats (0.97 +/- 0.1 vs 0.67 +/- 0.08 nmol X mg-1 in SHRs, P less than 0.01) but the Ca2+- and ATP-dependency are similar in the two groups. In order to study the relative roles of hypertension and cardiac hypertrophy in the depression of SHR function, 20-week old SHRs and normotensive rats were treated for 10 weeks with either hydralazine (100 mg X litre-1) or alpha-methyldopa (8 g X litre-1). Both therapeutic regimens resulted in near normalisation of blood pressure of SHRs (hydralazine: 18.1 +/- 0.5 kPa [136 +/- 4 mmHg]; alpha-methyldopa 17.6 +/- kPa [132 +/- 3 mmHg]). Regression of cardiac hypertrophy, however, was seen only in the alpha-methyldopa-treated group, as judged by changes in left ventricular weight, RNA/DNA ratio, and hydroxyproline content. Furthermore, improvement in calcium transport capacity by the SHR, as reflected in higher calcium uptake and stoichiometric ratio between uptake and ATP hydrolysis, was found after alpha-methyldopa, but not hydralazine treatment. These results indicate that reversal of cardiac hypertrophy is required for improvement in calcium transport by cardiac SR after antihypertensive therapy of SHRs.

Adenosine Triphosphatases↗
PubMed1980

Cytoplasmic control of DNA synthesis by myocardial nuclei.

In vitro DNA synthesis by isolated myocardial nuclei declines rapidly during postnatal growth. To study the mechanism(s) responsible for this decline, cytoplasmic extracts (CE) were prepared from isolated rat myocytes at different times after birth. CE from 2-day-old rats stimulated in vitro DNA synthesis by myocardial nuclei from adult (6 mo old) rats (55 +/- 6 pmol[3H]dTMP . mg DNA-1 . 15 min-1 vs. 32 +/- 4 pmol [3H]dTMP . mg DNA-1 . 15 min-1 in untreated controls, P less than 0.01). The ability of cytoplasmic extracts of stimulate DNA synthesis decreased with age, from 73 +/- 9% over controls at age 2 days to 18 +/- 6 at 28 days; adult myocytes were essentially ineffective. Pulse-chase experiments demonstrated that CE-directed DNA synthesis was replicative and discontinuous. CE stimulatory activity was heat-labile, nondialyzable, trypsin-sensitive, and distinct from DNA polymerases. The results indicate that a) adult myocyte nuclei can be induced to synthesize DNA by cytoplasmic extracts from neonatal rats, and b) that absence of regulatory cytoplasmic factor(s) may, in part, explain the age-dependent decline in myocardial DNA synthesis.

Aging↗
PubMed1980

Effect of phospholipid methylation on beta-adrenergic receptors in the normal and hypertrophied rat myocardium.

Abdominal aortic constriction in rats results in mild cardiac hypertrophy (20% increase in left ventricular weight compared to sham-operated controls) which is associated with increased numbers of beta-adrenergic receptors (123 +/- 7.3 fmol/mg protein (mean +/- SE) vs. 87 +/- 4.3 fmol/mg in controls, P < 0.01) without changes in their affinities for dihydroalprenolol. In vitro synthesis of phosphatidylcholine through successive methylation of phosphatidylethanolamine by S-adenosyl-L-methionine is enhanced in the hypertrophied myocardium) 0.38 +/- 0.03 nmol/mg per 30 minutes vs. 0.23 +/- 0.03 nmol/mg per 30 minutes in controls, P < 0.01). In both experimental groups, methyltransferase activity has a high affinity for S-adenosyl-L-methionine (Km = 6.8 microM), depends on Mg2+, is optimal around pH 9.0, and is inhibited by S-adenosyl-L-homocysteine (ki = 8.3 microM). The possible relationship between phospholipid methylation and changes in myocardial beta-adrenergic receptors was studied in both normal and hypertrophied hearts. Preincubation of cardiac membranes with S-adenosyl-L-methionine increased the numbers of b eta-adrenergic receptors in proportion to the duration of incubation and the concentration of S-adenosyl-L-methionine. In both groups, S-adenosyl-homocysteine, but not 5'-AMP or L-methionine, attenuated the increase in beta-adrenoreceptors. These results indicate that phospholipid methylation may be an important mechanism for regulation of beta-adrenergic mechanisms in both normal and hypertrophied myocardium.

Animals↗
PubMed1980

The evolution of vascular changes in the spontaneously hypertensive rat.

A longitudinal study on the development of vascular lesions was carried out in the spontaneously hypertensive rat (SHR) of the Aoki-Okamoto strain. The aorta and intrarenal arterial vessels were examined at different ages, from 5 to 48 weeks, by light and electron microscopy. Endothelial permeability to injected horseradish peroxidase (HRP) was evaluated in 20-week-old animals. Morphologic differences between vessels of SHRs and age-matched normotensive controls (Wistar-Kyoto strain) were first noted at 10 weeks of age and became more pronounced with time. Vascular pathology involved both intima and media. Medial thickening was seen in both aorta and peripheral arteries and, in the latter, was associated with decreased luminal diameters. These medial changes may contribute to the maintenance of the elevated blood pressure. Intimal lesions affected predominantly the aorta and were characterized by an expansion of the subendothelial space with deposition of acid mucopolysaccharides. There was increased accumulation of tracer HRP in the expanded subendothelium, which suggested enhanced permeability and/or retention of the tracer. In animal species susceptible to atherosclerosis, these intimal changes could serve as the structural basis for the higher propensity for atheromatous lesions in hypertensive individuals. In the SHR, despite stabilization of systolic blood pressure at about 20 weeks of age, both intimal and medial lesions continue to progress and become more extensive and severe; this suggests that not only the severity of hypertension but also its duration are significant determinants of the degree of vascular damage.

Animals↗
PubMed1979

Increased number of beta-adrenergic receptors in the hypertrophied myocardium.

Development of cardiac hypertrophy is associated with depletion of endogenous catecholamine stores and increased inotropic response to exogenous catecholamines. A biochemical basis for these changes is provided by the observation that the number of cardiac beta-adrenergic receptors - as reflected in specific [3H]dihydroalprenolol binding - is increased in hypertrophy without a change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. This change in beta-receptor numbers may be an important adaptive mechanism for preserving the contractile performance of the hypertrophied myocardium.

Alprenolol↗
PubMed1979

Selective stimulation by tri-iodothyronine of myocardial deoxyribonucleic acid polymerase-alpha in neonatal rats.

Three forms of DNA polymerase (alpha, beta and gamma) were separated from isolated rat myocardial cells on the basis of template, pH and ionic requirements, sensitivity to N-ethylmaleimide and position on sucrose gradients. Tri-iodothyronine administration (20mug/100g intraperitoneally) to 3-week-old rats resulted in selective stimulation of DNA polymerase-alpha (198+/-7.1 versus 102+/-5.8pmol of [(3)H]dTMP/30min per mg of protein in untreated controls, P<0.01), with no change in polymerases-beta and -gamma. [(3)H]Thymidine incorporation into myocardial DNA was also enhanced in tri-iodothyronine-treated neonatal rats (132+/-11.2 versus 53+/-4.1c.p.m./mug of DNA in controls, P<0.001). Increased incorporation was associated with an expansion of deoxyribonucleoside 5'-triphosphate pools, especially that of dTTP (24+/-1.6 versus 10+/-1.1pmol/mg of DNA, P<0.01). Neither DNA polymerase activities nor [(3)H]thymidine incorporation were changed in 6-month-old rats in response to tri-iodothyronine. Unstimulated adult myocardial cells had DNA polymerase activities comparable with those in 3-week-old animals, but significantly lower [(3)H]-thymidine incorporation and deoxyribonucleoside triphosphate concentrations. Enhancement of both DNA polymerase-alpha activity and [(3)H]thymidine incorporation in tri-iodothyronine-treated young rats was prevented by concomitant administration of either vinblastine (1mug/g) or daunomycin (2mug/g); actinomycin D (0.1mug/g) or cycloheximide (8mug/g), on the other hand, prevented the increase in [(3)H]thymidine incorporation, but not DNA polymerase-alpha activation. These results demonstrate an age-dependent stimulation of myocardial DNA replication by tri-iodothyronine and suggest an inter-relationship between DNA synthesis and subsequent entry into mitosis.

Age Factors↗
PubMed1979

Decreased number of beta-adrenergic receptors in hypertensive vessels.

Responsiveness to inotropic agents is altered in hypertension and may contribute to its initiation and maintenance. A biochemical basis for this change was provided by the observation that the number of beta-adrenergic receptors, as reflected in specific [3H]dihydroalprenolol binding, was diminished in both arteries and veins of spontaneously hypertensive rats. There was no change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in beta-adrenergic receptor numbers is not secondary to blood pressure elevation but may, instead, contribute to the pathogenesis of hypertension.

Alprenolol↗
PubMed1978

Nuclear chromatin changes during post-natal myocardial development.

The proliferative capacity of rat myocardium declines rapidly during the first few weeks of post-natal life. In order to gain insight into the mechanisms involved in this decline, we studied the structure and function of nuclear chromatin from isolated rat myocardial cells during post-natal growth. Chromatin template activity decreased progressively (7.5 +/- 0.3 pmol [3H]UTP/microgram DNA per min at age 5 days compared to 2.2 +/- 0.1 pmol [3H]UTP/microgram DNA per min at age 6 months) and was associated with a decrease in the number of transcription initiation sites. This decline was accompanied by changes in chromatin structure as evidenced by: (a) decreased susceptibility to DNAase I digestion with advancing age, (b) decreased poly-L-lysine binding (60% decrease between day 5 and six months of age), (c) progressive decline in positive ellipticity of circular dichroism spectra between 250--300 nm, and (d) derivative melting profiles showing a decrease in DNA regions bound by non-histone proteins and concomitant increase in histone-bound regions. The protein composition of myocardial chromatin also changed during post-natal development, chiefly due to a progressive increase in the histone/DNA ratio. These results indicate substantial changes in the organization and functional capacity of myocardial chromatin during early post-natal growth. These changes accompany, and may contribute to, the restriction in the proliferative capacity of myocardial cells.

Aging↗