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Biomedical subjects

R Ananthakrishnan

Publications and source records attributed to R Ananthakrishnan.

At least 37 records · Page 2Linked to original sources
PubMed1995

Impaired mitochondrial function in idiopathic dilated cardiomyopathy: biochemical and molecular analysis.

Mitochondrial defects at the biochemical and molecular levels are increasingly recognized in diseases involving the heart. The objective of this study was to assess the frequency and extent of mitochondrial defects in idiopathic dilated cardiomyopathy. Left ventricular tissues of 27 patients with idiopathic dilated cardiomyopathy undergoing orthotopic cardiac transplantation because of severe cardiac failure were examined to assess the specific activity levels of mitochondrial respiratory enzymes and changes in mtDNA structure and copy number. Abnormal specific activities of several mitochondrial enzymes were found in 55% of the cardiomyopathic tissues examined (15 patients), with six patients displaying single enzyme defects, including five in complex III and one in complex I. Multiple mitochondrial enzyme defects were found in nine patients, with the most frequent combination of defects seen in complex III and complex IV (5 cases). These enzymatic changes were shown not to be accompanied by changes in mtDNA copy number. In seven cases, however, including three young adults, there was a marked decrease in the levels of polymerase chain reaction products derived from specific mtDNA regions, which may be an indication of specific mtDNA damage. Specific mitochondrial abnormalities are frequently found in idiopathic dilated cardiomyopathy, with a variety of mitochondrial loci affected. These findings are not age dependent.

Adult↗
PubMed1995

Heart mitochondria response to alcohol is different than brain and liver.

Specific mitochondrial enzyme activities, mitochondrial DNA copy number, and mRNA levels were measured in heart, brain, and liver tissues of a group of alcohol-fed rats and compared with a control group. The results show a significant increase in mitochondrial enzyme activities (citrate synthase, complex IV, complex III, complex I, and complex V), as well as an increase in mitochondrial DNA in the cardiac tissue of the alcohol-fed animals. These data are indicative of an increase in mitochondrial number in the cardiac tissue that may occur as the result of an adaptive response to the alcoholic insult. However, in the liver and brain of the alcohol-treated rat, specific mitochondrial activities were decreased, in particular, complex III and ATP synthase, whereas levels of other mitochondrial enzymes (e.g., citrate synthase, specific mitochondrial transcripts, and mitochondrial DNA levels) do not seem to be affected. These data suggest that a tissue-specific response to alcohol exists that may have a common molecular mechanism in brain and liver, but is different in the heart.

Age Factors↗
PubMed1995

Localized mitochondrial dysfunction in canine myocardial ischemia.

Effects of myocardial ischemia on mitochondrial enzymes and mitochondrial DNA (mtDNA) were examined using the model of Ameroid constriction of canine cardiac vessels. Endocardium supplied by constricted coronary arteries was found to have significantly lower citrate synthase and complex IV activities compared to values obtained from either epicardium supplied by constricted vessels or endocardium supplied by unconstricted coronary arteries. Neither significant differences in mtDNA copy number nor changes in respiratory complexes I, III and V were detected. These results suggest that highly localized, specific mitochondrial enzyme changes result from chronic myocardial ischemia.

Animals↗
PubMed1994

Mitochondrial gene expression during bovine cardiac growth and development.

The expression of both mitochondrial and nuclear genes encoding enzymes involved in electron transport and oxidative phosphorylation was examined in bovine cardiac tissue during early growth, development and aging. The steady state level of mRNAs for mitochondrial genes including ATPase 6. COXII and cyt b increased 2.5-4-fold relative to early fetal levels in late fetal and young adult tissues and showed a marked decline (30-50%) in older adult tissues. Similar results were found with the nuclear genes, COXVB and ATP-beta synthase showing coordinate regulation of the two genomes. An increase in mtDNA copy number correlated with the increase in transcript level. Enzyme activity levels for NADH dehydrogenase and cytochrome c oxidase showed a similar trend, albeit of lesser magnitude. These activity levels contrasted with the activity level of an entirely nuclear-encoded mitochondrial enzyme, citrate synthase, which increased not only throughout development but in the older adult tissue. This study indicates that there is a pattern of increasing mitochondrial and nuclear gene expression for OXPHOS enzymes in developing cardiac tissue and decreasing OXPHOS gene expression in the aging heart.

Animals↗
PubMed1994

Presence of a mitochondrial DNA deletion in fetal and adult bovine cardiac tissue.

A deletion of about 5.3 kilobases has been detected in the mitochondrial DNA of bovine cardiac tissue. This deletion appears to be somatic in origin given its sporadic presence in the various heart compartments examined. Cardiac tissue derived from developmental stages including fetal, early and older adult animals harbored this mutation with increased levels (100-1000 fold) found in older adults. The deleted region of the mitochondrial genome maps to relatively the same area (deleting ATPase6, COXIII, ND2, ND4 and a portion of ND5) as the common 5 kb deletion reported in humans, but its presence in fetal tissue, as well as its decreased age dependence distinguish it relative to the reported human deletion.

Aging↗
PubMed1992

Effects of pravastatin on cholesterol metabolism in Watanabe heritable hyperlipidemic rabbits.

Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We studied the effect of pravastatin on several aspects of cholesterol metabolism in WHHL rabbits. Cholesterol synthesis was measured by intraperitoneal injection of radioacetate and determination of its incorporation into the nonsaponifiable lipid fraction of liver, plasma, adrenal glands and gonads. A single dose of pravastatin (25 mg/kg) caused statistically significant inhibition of hepatic cholesterol synthesis at 2, 6, 12, and 24 hours following oral administration. By 48 hours, the inhibitory effect of the drug was no longer demonstrable. The pattern of radioactivity in the plasma was similar to that in the liver. The drug had no statistically significant effect on cholesterol synthesis in adrenal glands and gonads, suggesting a selective effect on the liver. Cholesterol absorption was studied after simultaneous oral administration of [3H] cholesterol and [14C] beta-sitosterol. Pravastatin, 50 mg/kg for 10 days had no effect on fecal excretion of the radiolabelled steroids over 4 days. At 24 hours the plasma level of [14C] cholesterol was 1/3 that of control in pravastatin treated animals (p < 0.05) but did not undergo an accelerated decline over 6 days. The activity of acyl CoA: cholesterol acyltransferase (ACAT) in intestinal mucosa and the concentration of hepatic cholesterol were similar in animals treated over one year with pravastatin 50 mg/kg/day or with placebo. Our data do not allow us to make definitive conclusions about the effect of pravastatin on cholesterol absorption but are compatible with the hypothesis that the drug inhibits the hepatic synthesis as well as the assembly of cholesterol into lipoproteins.

Absorption↗
PubMed1991

Impaired adrenergic response to prolonged exercise in type I diabetes.

Patients with type I diabetes mellitus commonly experience hypoglycemia related to physical activity. We investigated the metabolic and hormonal response to exercise in type I diabetics, normal controls, and controls exercising under hypoglycemic conditions. All subjects exercise for 60 minutes at 60% to 65% of their VO2max while insulin concentrations were clamped at basal or hyperinsulinemic levels. With low-dose insulin infusion, despite similar free insulin levels, diabetics had a greater decrease in plasma glucose concentrations during exercise than controls. Nevertheless, the increments of epinephrine (E) and norepinephrine (NE) during exercise tended to be less in the diabetic subjects. Circulating levels of free fatty acids (FFA) were lower in diabetics, especially during early recovery from exercise. To better compare responses, a group of normal controls exercised during an infusion of insulin, which resulted in a similar decrease in plasma glucose to that of exercising diabetics. While exercising during a similar degree of hypoglycemia, diabetics had a significantly smaller increment of E and NE compared with controls. Increments of glucagon (GL) and growth hormone (GH) were not different. These studies suggest that there is a subnormal catecholamine response to exercise under hypoglycemic conditions in some patients with type I diabetes. The hypoglycemia during and after exercise in these individuals is probably the result of multiple factors, including relative hyperinsulinemia, decreased increment in catecholamines, and decreased availability of FFA.

Blood Glucose↗
PubMed1991

Pravastatin decreases serum lipids and vascular cholesterol deposition in Watanabe heritable hyperlipidemic (WHHL) rabbits.

The effects of long term administration of pravastatin (a competitive inhibitor of hydroxymethylglutaryl CoA reductase) were assessed by measuring serum lipids and aortic and coronary atherosclerosis in Watanabe Heritable Hyperlipidemic (WHHL) rabbits. Six-month-old WHHL rabbits were given either 50 mg/kg/day of the drug or vehicle. The rabbits were sacrificed following 6 or 12 months of treatment and serum cholesterol and triglycerides and aortic cholesterol and hydroxyproline were measured. Atherosclerotic plaques in the aorta and coronary arteries were quantified with morphometric methods. Mean serum cholesterol +/- SEM (n) in the control vs. pravastatin groups after 6 months were: 535 +/- 34 (11) vs. 411 +/- 22 (12) (p less than 0.005) and after 12 months 458 +/- 43 (9) vs. 309 +/- 29 mg/dl (12) (p less than 0.005). In the pravastatin group, percent aortic area covered with plaque and aortic cholesterol content were reduced 35% (ns) and 55% (p less than 0.05) at 6 months, and 26% (ns) and 44% (ns) at 12 months, respectively. Little difference was found in serum triglycerides and aortic hydroxyproline in the 2 groups. There was strong correlation of serum cholesterol with aortic cholesterol content (r = 0.61, p less than 0.003) and with the percent aortic plaque area (r = 0.67, p less than 0.001), at 12 months. Morphometric analysis of wall thickness and lumen area of major coronary arteries revealed no significant differences in the 2 groups. In conclusion, pravastatin effectively lowered the serum cholesterol level in an animal model defective in low density lipoprotein receptors; this reduction was strongly correlated with amelioration of such atherosclerotic processes as lipid deposition and plaque formation.

Animals↗
PubMed1980

Antiproteases and Down's syndrome in an Australian population.

alpha 1-Antitrypsin phenotypes and alpha 2-macroglobulin concentrations were determined for an Australian population of 286 Down's syndrome patients, 296 newborn babies, and 193 patients with non-specific mental retardation. There was no significant difference between the groups in the distribution of the phenotypes or level of heterozygosity. The phenotypic frequencies were 89.5% PiMM, 8.0% PiMS and 1.0% PiMZ among controls. The mean alpha 2-macroglobulin concentrations were investigated and it was shown that PiMZ phenotypes had a higher concentration, 2.67 +/- 0.27 g/l (newborns) and 2.74 +/- 0.32 g/l (Down's syndrome), in comparison with PiMS, PiSS, and PiMM.

Adult↗
PubMed1979

Role of nucleic acids and cytoskeleton in nuclear refringence phenomenon (nrp) of human peripheral blood lymphocytes.

Nuclear refringence is a phenomenon visible by light microscopy that is correlated with lymphocyte maturation and activation. The present study, in employing isolated nuclei as well as intact lymphocytes, confirms the nuclear basis of the phenomenon. Enzymatic degradation of nucleic acids in isolated nuclei attenuates refringence, providing presumptive evidence for the involvement of chromatin in refringence. Cytoplasmic events involving RNA and protein synthesis and microtubular, but not microfilament, function are necessary for the maintenance of refringence. These studies provide the basis for evaluating refringence within the context of nuclear protein changes known to occur during lymphocyte activation and for determining its usefulness as a simple test of the dynamic state of the lymphocyte nucleus.

Amanitins↗
PubMed1979

Affinity chromatography in the separation of human alpha 1-antitrypsin (alpha 1-AT) and antithrombin-III (AT-III).

The two antiproteases alpha 1-antitrypsin (alpha 1-AT) and antithrombin-III (AT-III) have been purified simultaneously from human plasma. Purification procedure consisted of gel filtration on Sephadex G-200 after initial processing of plasma, followed by ion exchange chromatography on DEAE-Sephadex A50 and DEAE-Cellulose, at a pH of 9.0 and pH 8.3 respectively. The two proteins could not be separated by any of these procedures including a lower pH (7.4) in ion exchange chromatography. Affinity chromatography on heparin-Sepharose separated the proteins since alpha 1-AT did not bind to the matrix. Alpha 1-AT unbound to the heparin-Sepharose was subsequently purified through con A-Sepharose affinity column. The final yield of both the proteins was about 20%. The molecular weight estimated on SDS electrophoresis for AT-III and alpha 1-AT was 63,000 and 50,000, respectively.

Antithrombin III↗
PubMed1979

Some aspects of the occurrence of new mutations in haemophilia.

Using the data available on a group of carriers of haemophilia, the mutation rate in the male germ line was compared with that of the female germ line. The mutation rate among the male germ line was about 1-2 times that in the female germ line. An assessment of grandparental ages as a factor in the production of new mutations of haemophilia was also investigated.

Adolescent↗
PubMed1978

Effect of phospholipases on factor-VIII activity.

The effect of the enzymes phospholipases C and D on Factor VIII were investigated. Phospholipase D was found to activate the partially purified intact Factor-VIII molecule maximally at a final concentration of 0.6 U/ml. Neither the dissociated small molecular weight component nor the high molecular weight component were activated. Phospholipase C, on the other hand, inactivated both the intact and the dissociated Factor-VIII molecule. Phospholipase D, however, had no effect on the haemophilic cryoprecipitate or the partially purified haemophilic Factor VIII. The implications of these results for the genetic control of the Factor-VIII molecule are discussed. In this connection, haemophilia A is hypothesized to be caused by an X-linked enzyme effect that impairs phospholipid assembly of the Factor-VIII protein, whereas von Willebrand's disease might be due to a structural defect of the Factor-VIII protein.

Factor VIII↗