Biomedical subjects

N S Dhalla

Publications and source records attributed to N S Dhalla.

At least 325 records · Page 18Linked to original sources

PubMed1975

Defective membrane systems in dystrophic skeletal muscle of the UM-X7.1 strain of genetically myopathic hamster.

1. The function of mitochondria, sarcotubular membranes (heavy microsomes), sarcolemma and myofibrils from the hind-leg skeletal muscle of about 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters was examined. 2. The mitochondrial calcium uptake as well as mitochondrial phosphorylation and respiratory rates were lower in 60-day-old myopathic skeletal muscle, unlike 150-day-old myopathic animals, when pyruvate-malate and glutamate-malate were used as substrates. However, mitochondria from 150-day-old myopathic animals showed depressed glutamate-dependent respiratory and phosphorylation rates and succinate-supported initial rate of calcium uptake. 3. The microsomal calcium-uptake, but not calcium-binding, and Ca2+-stimulated adenosine triphosphatase (ATPase) activity of the 150-day-old myopathic skeletal muscle were lower than the control values. Although microsomal calcium-binding, calcium-uptake and ATPase activities of the 60-day-old myopathic muscle were not depressed significantly, the initial rate of calcium uptake was less than the control. 4. The sarcolemmal Ca2+-ATPase, but not Mg2+-ATPase or Na+ +K+-ATPase, activity was higher in 60-day-old myopathic muscle whereas the activities of all these enzymes from 150-day-old myopathic animals were higher than the control. On the other hand, the Na+ +K+-ATPase activities from 60- and 150-day-old myopathic animals were inhibited by ouabain to a lesser extent in comparison with the respective control values. 5. The myofibrillar Ca2+-ATPase and Mg2+-ATPase activities as well as inhibition of Mg2+-ATPase due to Na+ and K+ in myopathic muscle were no different from the control values. 6. The results reported here give further support to the view that different membrane systems of the dystrophic muscle are defective.

Adenosine Triphosphatases↗

PubMed1975

Studies on adenylate cyclase-cyclic AMP system of the myopathic hamster (UM-X7.1) skeletal and cardiac muscles.

Cyclic AMP content, adenylate cyclase (EC 4.6.1.1) activity and phosphodiesterase I (EC 3.1.4.1) activity of the hind leg skeletal muscle and cardiac muscle in 60- and 150-day-old normal and myopathic (UM-X7.1) hamsters were examined. In 60-day-old myopathic animals, cardiac cyclic AMP levels were higher and phosphodiesterase I activity was lower, without any changes in the basal adenylate cyclase activity, whereas in 150-day-old myopathic hamsters, cardiac cyclic AMP and basal adenylate cyclase activity were lower, without any changes in the homogenate phosphodiesterase I activity. On the other hand, basal adenylate cyclase and phosphodiesterase I activities in the skeletal muscle homogenate from 60- and 150-day-old myopathic animals were not different from the normal values but the skeletal muscle cyclic AMP levels were significantly less in 60-day-old myopathic hamsters only. The plasma cyclic AMP levels in 60-day-old myopathic hamsters, unlike 150-day-old myopathic animals, were higher than the normal. Although these results reveal differences in myopathic cardiac and skeletal muscles, it is concluded that changes in adenylate cyclase-cyclic AMP system in myopathy are dependent upon the degree of disease.

Adenylyl Cyclases↗

PubMed1975

Subcellular and functional effects of quinidine, procaine amide, and lidocaine on rat myocardium.

Different antiarrhythmic agents such as quinidine, procaine amide, and lodocaine at 1 mM concentrations were found to depress the ability of an isolated perfused rat heart to generate contractile force. Quinidine, but not procaine amide or lidocaine, decreased calcium uptake by both mitochondrial and microsomal fractions at different concentrations of calcium. The mitochondrial phosphorylation rate, respiratory control index, and state 3 oxygen consumption, but not ADP:O ratio and state 4 oxygen consumption, were depressed by only quinidine. None of these agents had any effect on myofibrillar Mg2+-ATPase or Ca2+-stimulated ATPase activities. On the other hand, sarcolemmal Mg2+-ATPase and Ca2+-ATPase activities, but not Na+-K+-ATPase activity, were increased by all these drugs. The sarcolemmal adenylate cyclase (EC 4.6.1.1) activity was decreased by quinidine only. These results suggest some similarities and differences in the sites of action of quinidine, procaine amide, and lidocaine within the myocardium.

Adenosine Triphosphatases↗

PubMed1975

Alterations in energy metabolism and ultrastructure upon reperfusion of the ischemic myocardium after coronary occlusion.

The effects on myocardial function, metabolism and ultrastructure of 60 minutes of reperfusion, instituted after 30, 60 and 90 minutes of occlusion of the left anterior descending coronary artery, were studied in 48 dogs. Twelve sham-operated dogs served as controls. Coronary occlusion for 60 or 90 minutes caused significant depression in the first derivative of left ventricular pressure (dP/dt) (P less than 0.05) that could not be reversed by reperfusion. Upon reperfusion, creatine phosphate stores in myocardium made ischemic for 30 and 60 minutes, but not for 90 minutes, returned toward control levels, but stores of adenosine triphosphate (ATP) and total nucleotides and the ATP/adenosine diphosphate ratio of myocardium subjected to 60 and 90 minutes of ischemia were further decreased. After 60 and 90 minutes of ischemia, swelling of the sarcoplasmic reticulum and mitochondrial damage (swelling, decreased matrix density and partial loss of cristae) were seen. Myofibrils were relaxed in all these groups. Reperfusion produced gross contraction of myofibrils and aggravated these changes in mitochondria and sarcoplasmic reticulum. In the hearts subjected to 90 minutes of ischemia these changes were gross. The levels of creatine phosphokinase, glutamic oxaloacetic transaminase and lactic dehydrogenase in the coronary sinus blood increased dramatically (P less than 0.05) upon reperfusion after 60 or 90 minutes of occlusion, indicating severe impairment of cell membranes. This secondary rise in serum enzyme activity during reperfusion should be taken into consideration when estimating the size of a myocardial infarct from enzyme changes alone. It appears that 60 and 90 minutes of ischemia cause severe myocardial damage that is not reversed by reperfusion maintained for 1 hour although longer periods of reperfusion may be beneficial.

Animals↗

PubMed1975

Myocardial cell damage during experimental infective endocarditis.

Infective endocarditis was induced in 15 catheterized rabbits by a single intravenous injection of Streptococcus viridans and the papillary muscles from the left ventricle were examined for histologic and ultrastructural changes at 3 and 6 days of infection. Papillary muscles from 10 normal and 12 catheterized uninfected animals were used for comparison. Catheterized animals, infected and uninfected, had cardiac hypertrophy and papillary muscles which showed an increase in myofiber size and some interstitial edema. The muscle from infected hearts had areas of focal necrosis, diffuse monocytic infiltration, and loss of normal myocardial architecture. The papillary muscles from catheterized uninfected animals showed some degree of mitochondrial and sarcotubular swelling as well as contracture of myofibrils; the infected myocardium exhibited dramatic changes in ultrastructure such as mitochondrial swelling and destruction, sarcotubular swelling, separation of the intercalated disc, and myofibrillar contracture and disruption. These histopathologic and ultrastructural changes in papillary muscles from rabbits with bacterial endocarditis are indicative of the presence of myocardial cell damage.

Animals↗

PubMed1975

Membrane alteration in failing hearts of cardiomyopathic hamsters.

Cardiomyopathic hamsters (UM-X7.1) show clinical signs of congestive heart failure and an abnormal EKG pattern. The sarcolemmal fraction obtained from the failing hearts at advanced stages of myopathy exhibited no change in the basal adenylate cyclase activity; however, the activity of this enzyme in the presence of catecholamines or NaF was lower in the failing heart sarcolemma than that in the control. The activities of Ca2+-ATPase, Mg2+-ATPase, and Na+-K+-ATPase in the failing heart sarcolemma were also less than the control values. These results suggest an association of membrane defect with heart failure.

Adenosine Triphosphatases↗

PubMed1975

Adenylate cyclase activation in lymphoid tissues during graft-versus-host reaction.

Graft-versus-host reactions were induced in adult F1 hybrid animals by injecting parental spleen cells. Adenylate cyclase activity was determined in the washed cell particles of the lymphoid tissues. During a time course study of the regional GVH reaction an increase in lymph node weight was apparent at day 2, whereas the adenylate cyclase activity increased at day 4 after the injection. Maximal lymph node hypertrophy and adenylate cyclase activation were observed 8 to 10 days after initiation of the GVH response. Adenylate cyclase stimulation by epinephrine of the GVH response. Adenylate cyclase stimulation by epinephrine and glucagon in experimental preparations was less than in the control. NaF was stimulatory only in the control preparations. Ca-2+ in concentrations up to 8 mM had no inhibitory effects on the control or experimental preparations. The pattern of responses of the experimental preparations to Zn-2+ and Cu-2+ was different than the control; however, in high concentrations both of these cations had marked inhibitory effects. An increase in the adenylate cyclase activity was also direct relationship between the adenylate cyclase activity and the cytolytic activity of spleen cells from mice undergoing systemic GVH reaction. These results can be explained on the basis of alterations in the cell membranes, and it is suggested that such changes play an important role in the pathogenesis of GVH disease.

Adenosine Triphosphate↗

PubMed1975

Role of mitochondrial calcium transport in failing heart.

Mitochondrial calcium uptake, but not binding, like microsomal calcium uptake in failing human hearts, was less than the control values for dog, rabbit, and hamster hearts. Decrease in mitochondrial calcium binding and uptake was observed in genetically myopathic hamsters (BIO 14.6) at early, moderate, and late stages of congestive heart failure. Inhibitors of mitochondrial calcium transport, Dicumarol, dinitrophenol, and sodium azide, were found to produce a rapid fall in contractility of the isolated rat heart. Inability of rat hearts to generate contractile force on perfusion with Na+- or K+-free medium was associated with an increase in mitochondrial calcium uptake. A dramatic increase in mitochondrial calcium uptake was observed on perfusing rat hearts with control medium after CA++-free medium. No change in mitochondrial calcium uptake was noted in acute ischemic dog myocardium or hypoxic rat heart in which contractile force was severely depressed. Both mitochondrial calcium transport and contractility were decreased on perfusing rat hearts with substrate-free medium; however, the change in calcium uptake was secondary to the fall in contractile force. Decrease in pH, ATP:ADP ratio, ATP6AMP ratio, and K+:Na+ ratio were found to reduce the dog heart mitochondrial calcium uptake. It is likely that various factors such as pH, ATP:ADP ration, ATP:AMP ratio, and K+ :Na+ ration, in addition to damage in mitochondrial structure, play an important role in inhibiting mitochondrial calcium transport in failing hearts. The results also suggest that alterations in mitochondrial calcium transport are dependent upon the degree and type of heart failure.

Adenine Nucleotides↗

PubMed1975

Alterations in norepinephrine pattern in the damaged myocardium in the rat.

In the albino rat, the evolvement of myocardial necrosis induced by a single injection of ISO was accompanied by a fall in total NE. Pretreatment with propranolol and pargyline protected against ISO-induced necrosis and myocardial hypertrophy, but did not influence the ISO-induced depletion of NE stores. The depletion of NE stores is not due to impairment in synthesis or increased intraneuronal metabolism of NE since, in ISO-treated rats, neither cardiac tyrosine hydroxylase activity nor MAO activity was altered. The decrease in endogenous NE is not due to a defect in the storage of NE. The ability of myocardium to take up and store NE returned to normal within 48 hours, whereas endogenous levels returned to normal within 5 days, even in the presence of demonstrable necrosis. Thus, there is lack of correlation between chemical and morphological changes, since catecholamine depletion occurred in the absence of morphologically demonstrable tissue injury, and the function of the adrenergic neuron returns to normal in the presence of demonstrable necrosis.

Animals↗

PubMed1974