Biomedical subjects

N S Dhalla

Publications and source records attributed to N S Dhalla.

421 records · Page 24Linked to original sources

PubMedDate not supplied

Impairment of mitochondrial and sarcoplasmic reticular functions during the development of heart failure in cardiomyopathic (UM-X7.1) hamsters.

The oxidative phosphorylation as well as calcium transporting properties of heart mitochondria and calcium transport activities of the fragments of the sarcoplasmic reticulum (microsomes) were studied during the life span of cardiomyopathic hamsters (UM-X7.1). Control healthy hamsters of the same age group were used for comparison. No changes in the oxidative phosphorylation ability of cardiomyopathic mitochondria were seen at early and moderate stages of heart failure; however, at severe stages, mitochondrial respiratory functions, but not the ADP:0 ratio, were impaired. Both creatine phosphate and ATP contents were decreased without any significant changes in the ATPase activities of myofibrils from the failing hearts. Heart mitochondria from cardiomyopathic animals at severe stages of failure exhibited less calcium binding and uptake activities in comparison with the control values whereas no changes in the mitochondrial calcium binding and uptake were seen in cardiomyopathic hamsters which showed no clinical signs of heart failure. Although mitochondrial calcium binding in cardiomyopathic hearts at early and moderate stages of failure was decreased, mitochondrial calcium uptake was not significantly different from the control. Microsomal calcium binding activity, unlike calcium uptake activity, was decreased in the hearts of cardiomyopathic hamsters without any signs of heart failure. Both calcium binding and calcium uptake activities of microsomes from animals with early, moderate and severe heart failure were less in comparison with the control values but were not associated with any changes in the Ca2+-stimulated ATPase activity. These results suggest that changes in the process of mitochondrial energy production and mitochondrial Ca2+-transport may be secondary to other factors whereas alterations in the sarcoplasmic reticular Ca2+-transport may lead to the development of heart failure in the cardiomyopathic hamsters.

Adenosine Triphosphatases↗

PubMedDate not supplied

Heart sarcolemmal ATPase and calcium binding activities in rats fed a high cholesterol diet.

ATPase and calcium binding activities were studied in sarcolemmal membranes from hearts of male rats fed either a control or 2% cholesterol diet for different time periods. Studies with isolated membrane revealed a significant increase in Na+-K+ ATPase activity, sialic acid content and ATP-independent calcium binding capacity in the presence of 1.25 mM CaCl2 in the 6 week cholesterol fed group. By 12 weeks, Na+-K+ ATPase, Mg2+-ATPase and Ca2+-ATPase activities as well as ATP-independent calcium binding in the presence of 0.05 mM CaCl2 were increased in membranes from cholesterol fed rats. A significant increase (P less than 0.05) in the sarcolemmal cholesterol/phospholipid molar ratio, which is an indicator of a decrease in membrane fluidity, was also noted in the 12 week cholesterol fed group. Concanavalin A, which is believed to decrease membrane fluidity, stimulated both Mg2+ and Ca2+-dependent ATPase activities and increased ATP-independent calcium binding in control sarcolemmal preparations and these changes resembled those observed in the sarcolemma from cholesterol fed rats. Since concanavalin A did not alter the activity of Na+-K+ ATPase, it appears that some of the observed differences in sarcolemmal activities upon cholesterol feeding did not correlate well with changes in membrane order. At 24 weeks, there was a generalized depression in the sarcolemmal ATPase activities of the cholesterol group; both Mg2+ ATPase and Ca2+ ATPase were significantly less than in control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗

PubMedDate not supplied

Sarcolemmal Ca2+-binding and enzyme activities in myocardium from hypothyroid rat.

Effects of hypothyroidism on heart sarcolemmal activities were examined by using membrane preparations obtained by two different methods from rats treated with propylthiouracil for 6 to 8 weeks. ATP-independent Ca2+ binding, sialic acid and phospholipid content, Ca2+ ATPase, Mg2+ ATPase and adenylate-cyclase were not altered in membranes isolated by the hypotonic shock-LiBr treatment method from hypothyroid hearts. On the other hand, depressed activities of ouabain sensitive Na+-K+ ATPase and 5'-nucleotidase were observed in this hypothyroid preparation. Sarcolemma isolated by the sucrose density gradient procedure from hypothyroid hearts exhibited lower ouabain-sensitive Na+-K+ ATPase and higher ATP-dependent Ca2+ binding as well as Ca2+ stimulated ATPase without any changes in the 5'-nucleotidase, adenylate cyclase and Mg2+-ATPase activities. The activation of ATP-dependent Ca2+ binding and Ca2+ stimulated ATPase by calmodulin in the hypothyroid preparation was greater than the control; these effects of calmodulin were blocked by trifluoperazine. The results suggest some specific changes in the heart sarcolemmal Ca2+-pump during the development of hypothyroidism.

Animals↗

PubMedDate not supplied

Effect of adrenochrome on adenine nucleotides and mitochondrial oxidative phosphorylation in rat heart.

Effects of adrenochrome, an oxidation product of epinephrine, on myocardial energy production were investigated by studying changes in adenine nucleotide content and mitochondrial oxidative phosphorylation activities in the isolated rat heart. Perfusion of the heart with 50 mg/L adrenochrome induced a marked decline in contractile force within 5 min and this was associated with a rapid decline in the myocardial ATP/AMP ratio. A significant decrease in ATP and ATP/ADP ratio as well as a significant increase in ADP and AMP content was observed at 10 min of perfusion with adrenochrome. Furthermore, mitochondrial oxidative phosphorylation activities were unchanged except that an increase in state 4 respiration and a decrease in RCI value were seen in the heart perfused with adrenochrome for 10 min. Autoradiography of the sections from hearts perfused with 14C-adrenochrome revealed the localization of a significant amount of radioactivity on mitochondria. Adrenochrome at concentrations of 20 mg/L or higher was found to inhibit the oxidative phosphorylation activities of heart mitochondria under in vitro conditions. The depressant effects of adrenochrome on mitochondrial oxidative phosphorylation were additive to those seen with calcium. These data suggest that adrenochrome in the presence of excess calcium in the myocardial cell may impair the process of energy production in mitochondria and this may result in contractile failure of hearts exposed to this cardiotoxic metabolite of epinephrine.

Adenosine Diphosphate↗

PubMedDate not supplied

Pathogenesis of cardiac dysfunction in diabetes mellitus.

The use of insulin by diabetics has largely removed the threat of death from ketotic coma but cardiovascular dysfunction remains a major cause of death in patients with diabetes. Recent research has indicated a generalized membrane defect, which may cause abnormalities of calcium metabolism in nerves, cardiac and smooth muscle as well as endothelial cells and thus may lead respectively to the development of neuropathy, primary cardiomyopathy, microangiopathy and atherosclerosis in the diabetic population. Each of these pathogenic processes, which are associated with insulin deficiency, alone or in combination with others, may result in cardiac dysfunction in chronic diabetes. Activation of the sympathetic nervous system and abnormalities in catecholamine metabolism have been identified in diabetes; their involvement in the genesis of cardiac pump failure as well as large and small vessel disease is likely. The membrane defects as indicated by changes in both plasma membrane and glycocalyx in diabetic cardiomyopathy appear to be complex and may involve alterations in the metabolism of lipids and pyrimidine nucleotides. It seems that intracellular calcium overload is intimately involved in the development of diabetic cardiomyopathy; however, a concentrated research effort is required to understand the primary biochemical lesion in the pathogenesis of cardiac dysfunction in diabetes. In the meantime, a heightened awareness on the part of clinicians concerning the susceptibility of diabetic patients to cardiovascular problems may help in reducing mortality and morbidity in the diabetic population.

Animals↗

PubMedDate not supplied

Alterations in the cardiac adenylate cyclase activity in hypothyroid rat.

Adenylate cyclase activity of the washed particles from the ventricles of rats made hypothyroid by propylthiouracil (P.T.U.) treatment was studied in the absence or presence of different concentrations of catecholamines, guanylimido-diphosphate (GppNHp) and NaF. The washed particles preparation of hypothyroid rat displayed higher basal adenylate cyclase activity in comparison to that in the euthyroid animal. Fluoride stimulation was unaltered but GppNHp stimulation was markedly depressed over a wide range of concentrations in the hypothyroid heart washed particles. Epinephrine stimulation in the presence of GppNHp was altered only at 10(-5) to 10(-4)M concentrations. Depressed responsiveness of cardiac adenylate cyclase to GppNHp and epinephrine was also found in washed particles of thyroidectomized rats. Depression of GppNHp or epinephrine response in hypothyroid animals was reversed 48 hours after T3 administration. In contrast to the washed particulate preparation, no depressions in the responses of adenylate cyclase to GppNHp or epinephrine were seen in the purified sarcolemmal membranes from P.T.U. induced hypothyroid or thyroidectomized rat hearts. It is proposed that altered guanine nucleotide binding or altered guanine nucleotide binding protein-catalytic subunit interaction in the adenylate cyclase system may be an underlying mechanism of depressed positive inotropic action of catecholamines in the hypothyroid state.

Adenylyl Cyclases↗

PubMedDate not supplied

Beta-adrenoceptor mediated signal transduction in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters.

In view of the lack of information regarding the status of beta-adrenoceptor mediated signal transduction mechanisms at severe stages of congestive heart failure, the status of beta-adrenoceptors, G-proteins and adenylyl cyclase activities was examined in 220-275 day old cardiomyopathic hamster hearts. Although no changes in the Kd values for beta 1- and beta 2-adrenoceptors were seen, the number of beta 1-adrenoceptors, unlike that of beta 2-adrenoceptors, was markedly decreased in cardiac membranes from failing hearts. The activation of adenylyl cyclase in the failing hearts by different concentrations of isoproterenol was also attenuated in comparison to the control preparations. The basal adenylyl cyclase activity in cardiac membranes from the failing hearts was not altered; however, the stimulated enzyme activities, when measured in the presence of forskolin, NaF or Gpp(NH)p were depressed significantly. The functional activity of Gs-proteins (measured by cholera toxin stimulation of adenylyl cyclase) was depressed whereas that of Gi-proteins (measured by pertussis toxin stimulation of adenylyl cyclase) was increased in the failing hearts. Not only were the Gs- and Gi-protein contents (measured by immunoblotting) increased, the bioactivities of these proteins as determined by ADP-ribosylations in the presence of cholera toxin and pertussis toxin, respectively, were also higher in failing hearts in comparison to the control values. Northern blot analysis revealed that the signals for Gs- and Gi-protein mRNAs were augmented at this stage of heart failure. These results indicate that the loss of adrenergic support at severe stages of congestive heart failure in cardiomyopathic hamsters may involve a reduction in the number of beta 1-adrenoceptors, and an increase in Gi-protein contents as well as bioactivities in addition to an uncoupling of Gs-proteins from the catalytic site of adenylyl cyclase in cardiac membrane.

Adenylate Cyclase Toxin↗