Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the early effects of hypothyroidism on cardiac function and tolerance to hypothermic ischemia. Hypothyroidism was induced by thyroidectomy. Five days after operation, sham-operated and thyroidectomized rats were anesthetized and cardiac function was assessed. At this time, the plasma levels of triiodothyronine and thyroxine had fallen by eightfold and threefold, respectively, in thyroidectomized rats compared with the values in sham-operated rats. In vivo pump function was assessed by measuring mean arterial pressure, cardiac index, and stroke volume index: all were reduced by thyroidectomy (respectively 95 +/- 5 mmHg, 22 +/- 2 ml/min/100 gm body weight and 67 +/- 7 microliters/beat/100 gm body weight versus 112 +/- 4 mm Hg, 35 +/- 1 ml/min/100 gm body weight and 85 +/- 4 microliters/beat/100 gm body weight in the sham-operated group; p < 0.05 in each instance). Systemic vascular resistance index was higher in thyroidectomized than in sham-operated rats (4.4 +/- 0.4 versus 3.1 +/- 0.2 mmHg/ml/min/100 gm body weight; p < 0.05). In vivo indices of contractile function were also reduced by thyroidectomy: maximum rate of left ventricular pressure development fell by almost 50% (5190 +/- 790 versus 9600 +/- 900 mmHg/sec; p < 0.05) and left ventricular developed pressure and heart rate also fell (respectively 92 +/- 8 mmHg and 340 beats/min versus 129 +/- 6 mmHg and 398 +/- 6 beats/min; p < 0.05 in each instance). After excision, hearts were blood-perfused and ex vivo function assessed with intraventricular balloons. Systolic and diastolic functions were significantly impaired in the thyroidectomized group and the myocardial Na(+)-K(+)-adenosinetriphosphatase activity was reduced from a control value of 8.3 +/- 0.3 to 5.8 +/- 0.4 mean integrated extinction x 100. The hearts were then subjected to 2 minutes of cardioplegic infusion, 6 hours of hypothermic (4 degrees C) ischemia, and 40 minutes of reperfusion. In control hearts, left ventricular developed pressure (at an end-diastolic pressure of 8 mm Hg) recovered to 76% of its preischemic value (131 +/- 8 versus 173 +/- 8 mmHg; p < 0.05); in hearts from thyroidectomized rats, left ventricular developed pressure recovered to 81% of its preischemic value (110 +/- 8 versus 136 +/- 12 mmHg; p = not significant), an absolute value that was not significantly different from that in the sham-operated group. Diastolic function recovered to the same extent in both groups.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Early effects of hypothyroidism on the contractile function of the rat heart and its tolerance to hypothermic ischemia. 812 12

The elementary events in energy transduction by the actomyosin motor, driven by ATP hydrolysis, were directly recorded from multiple and single molecules using a recently developed technique for nano-manipulation of single actin filaments by a microneedle. In order to avoid the effects of random orientation of myosin and association of myosin with an artificial substrate in the surface motility assay, we used single myosin-rod cofilaments with various ratios. Distinct actomyosin attachment, force generation (the power stroke) and detachment events were detected at a very low myosin: rod ratio. At high load, one power stroke generated 5-6 pN peak force and 2.3 pN force averaged over the cycle, which were compatible with those deduced from noise analysis of force fluctuations caused by multiple molecules. As the load was reduced, the length of the power stroke increased. At near zero load, the length of a power stroke was approximately 17 nm. The results suggested that an ATPase cycle produces one power stroke at high load and many ones at low load.
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PMID:Single-molecule analysis of the actomyosin motor using nano-manipulation. 813 79

Recent clinical, physiological, biochemical, and molecular biology studies strongly suggest that digitalis glycosides function in a complex manner through differential binding to and inactivation of multiple distinct Na+,K(+)-ATPase isoforms that are differentially expressed and regulated throughout the cardiovascular system. The alpha 1 isoform predominates in the ventricular: myocardium, whereas the alpha 2 and alpha 3 isoforms may localize to the conducting system structures. The peripheral vasculature also potentially expresses three digitalis receptors, as do neurons in the central nervous system. It is likely that similar heterogeneity exists in the autonomic nervous system as well as in the cardiopulmonary baroreceptor structures. Therefore, differential regulation of these isoforms, by either genetic predisposition or hormones, could dissociate contractile from conduction function and play a role in determining the degree, if any, of therapeutic response to digitalis glycosides. Similarly, genetic polymorphism of the alpha subunits has been observed in humans and rats and may play an important functional role in the ion transport function in a strain of hypertensive rats. Genetic differences in the regulation or structure and function of each isoform could confer allele-specific functional and pharmacological features such as predisposition to digitalis toxicity. Alterations in the degree and type of Na+,K(+)-ATPase isoforms expressed during cardiac hypertrophy and cardiac development may mediate increases or decreases in cardiac sensitivity to digitalis glycosides. This unexpected complexity of the digitalis receptor raises new questions about the role of digitalis glycosides in the treatment of congestive heart failure.
Heart Dis Stroke
PMID:Digitalis and the Na+,K(+)-ATPase. 813 34

1. Lipid peroxidation and membrane-related enzyme changes in the cerebral cortex of stroke-prone rats (SHRSP) and normotensive rats were examined at 5 and 20 weeks of age. 2. In vivo formation of thiobarbituric acid-reactant substances was higher in SHRSP at 20 weeks of age and in vitro generation of free malondialdehyde was greater in SHRSP brains, both at 5 and 20 weeks of age, as compared with those in WKY. 3. Membrane-associated enzymes such as Na/K-ATPase and 5'-nucleotidase activities were lower in 20-week-old SHRSP than in age-matched WKY. 4. These results indicate how very prone the SHRSP brain is toward lipid peroxidation and subsequent membrane-related enzyme changes.
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PMID:A comparative study on lipid peroxidation in cerebral cortex of stroke-prone spontaneously hypertensive and normotensive rats. 813 18

SHR (spontaneously hypertensive rat) is the most popular genetic hypertensive model rat. Using the F2 progeny obtained from SHR and normotensive rats, for example, WKY (Wistar-Kyoto rat), many cosegregation studies to find the genes responsible for blood pressure have been done. In this review, we present some studies using F2 rats concerning candidate genes, renin, kallikrein, sodium potassium-ATPase, heat shock protein 70, angiotensin converting enzyme, phospholipase C-delta 1 and SA gene to show whether these genes really associate with blood pressure. We discuss the signification of these genes in the process of producing SHR and stroke-prone SHR from WKY. We hope these studies will lead to identify the mechanism of human essential hypertension.
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PMID:[Cosegregation studies in spontaneously hypertensive rats]. 832 Aug 40

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

In an attempt to elucidate the effects of two major risk factors of heart failure in humans, high blood pressure and coronary artery disease, renal hypertension and coronary artery constriction were induced singularly and in combination in rats, and the functional, structural, and biochemical alterations of the myocardium were examined 12-13 wk later. Renal hypertension (RH), coronary narrowing (CN), and their association (NH) resulted in left ventricular failure demonstrated by a significant increase in left ventricular end-diastolic pressure, a decrease in +dP/dt and -dP/dt, and a reduction in stroke volume and cardiac output. Measurements of ventricular loading documented that RH was characterized by elevations in systolic and diastolic wall stress of 42 and 160%, respectively. Corresponding changes with NH were 80 and 315%. CN was accompanied by an augmentation of diastolic wall stress only (280%). The abnormalities in mural stress were coupled with reductions in systolic and diastolic wall thickness-to-chamber radius ratios of 39 and 29% after CN. These anatomic parameters were preserved with RH, whereas the systolic wall thickness-to-chamber radius ratio was reduced 31% with NH. Structurally, multiple foci of replacement fibrosis were found with each intervention. The sites of tissue injury and their volume percent in the myocardium were comparable with CN and RH but were significantly more numerous and occupied a larger fraction of the ventricular wall in the presence of NH. Biochemically, the calcium dose-response curve of myofibrillar Mg2+ adenosinetriphosphatase (ATPase) activity did not vary with CN, RH, and NH. In contrast, a marked decrease in Ca2+ myosin ATPase activity was found in NH rats in association with a shift in myosin isoenzymes from V1 to V3. In conclusion, multiple physiological, morphological, and biochemical factors may participate in the generation of the abnormalities in ventricular loading with hypertension and/or coronary artery stenosis.
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PMID:Effects of hypertension and coronary constriction on cardiac function, morphology, and contractile proteins in rats. 836 72

The ionic current underlying the upstroke of axonal action potentials is carried by rapidly activating, voltage-dependent Na+ channels. Termination of the action potential is mediated in part by the rapid inactivation of these Na+ channels. We previously demonstrated that an influx of Na+ plays a critical role in the cascade leading to irreversible anoxic injury in central nervous system white matter. We speculated that a noninactivating Na+ conductance mediates this pathological Na+ influx and persists at depolarized membrane potentials as seen in anoxic axons. In the present study we measured the resting compound membrane potential of rat optic nerves using a modified "grease-gap" technique. Application of tetrodotoxin (2 microM) to resting nerves ([K+]o = 3 mM) or to nerves depolarized by 15 or 40 mM K+ resulted in hyperpolarizing shifts of membrane potential. We interpret these shifts as evidence for a persistent, noninactivating Na+ conductance. This conductance is present at rest and persists in nerves depolarized sufficiently to abolish classical transient Na+ currents. PK/PNa ratios were estimated at 35.5, 23.2, and 88 in 3 mM, 15 mM, and 40 mM K+, respectively. We suggest that this noninactivating Na+ conductance may provide an inward pathway for Na+ ions, necessary for the operation of Na+, K(+)-ATPase. Under pathological conditions, such as anoxia, this conductance is the likely route of Na+ influx, which causes damaging Ca2+ entry through reverse operation of the Na(+)-Ca2+ exchanger. The presence of this conductance in white matter axons may provide a therapeutic opportunity for diseases such as stroke and spinal cord injury.
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PMID:Noninactivating, tetrodotoxin-sensitive Na+ conductance in rat optic nerve axons. 839 4

The transient behavior of muscle in double-or multiple-step length perturbations [Lombardi, V., Piazzesi, G. & Linari, M. (1992) Nature (London) 355, 638-641] is simulated with a "conventional" cross-bridge model, which has been reported [Eisenberg, E., Hill, T. L. & Chen, Y. (1980) Biophys. J. 29, 195-227] to account for many mechanical, as well as biochemical, muscle data. The quick recovery of tension after double- or multiple-length perturbations was calculated for the model without any readjustment of its original parameters. The regeneration rate of the quick tension recovery of the model is fast and comparable to that measured experimentally by Lombardi et al. For multiple-step "stair-case"-type length releases, the tension response reaches a steady-state shape after three or four steps, and the average ATP turnover is much slower than the regeneration of the quick tension recovery. Our simulation shows that the experimental findings of Lombardi et al. can easily be reproduced by this simple conventional cross-bridge model, in which the completion of one work-producing power stroke is coupled to the hydrolysis of one ATP molecule. Thus, to account for the data of Lombardi et al., there is no need to assume that cross-bridges can execute multiple power strokes per ATPase cycle, although cross-bridges may well be able to do so. The mechanism that underlies the fast regeneration of the quick tension recovery in the conventional model used here is discussed.
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PMID:On the regeneration of the actin-myosin power stroke in contracting muscle. 850 62

Based on the MHC isoform pattern, adult mammalian limb skeletal muscles contain two and, in some species, three types of fast fibers (Type IIa, IIx, and IIb), and one slow fiber (Type I). Slow muscles, such as the soleus, contain primarily the slow Type I fiber, whereas fast-twitch muscles are composed primarily of a mixture of the fast myosin isozymes. Force generation involves cross-bridge interaction and transition from a weakly bound, low-force state (AM-ADP-P(i)) to the strongly bound, high-force state (AM-ADP). This transition is thought to be rate limiting in terms of dP/dt, and the high-force state is the dominant cross-bridge form during a peak isometric contraction. Intact fast and slow skeletal muscles generate approximately the same amount of peak force (Po) of between 200 and 250 kN.m-2. However, the rate of transition from the low- to high-force state shows Ca2+ sensitivity and is 7-fold higher in fast-twitch, as compared to slow-twitch, skeletal muscle fibers. Fiber Vo or the maximal cross-bridge cycle rate is highly correlated with and thought to be dependent on the specific activity of the myosin or myofibrillar ATPase. The hierarchy for Vo is the Type IIb > IIx > IIa > I. This functional difference for the fast fiber types explains the higher Vo observed in the predominantly Type IIb SVL vs. the mixed fast Type IIa and IIb EDL muscle. A plot of Vo vs. species size demonstrates that an inverse relationship exists between Vo and body mass. From the standpoint of work capacity, the important property is power output. An analysis of individual muscles indicates that peak power is obtained at loads considerably below 50% of Po. Individuals with a high percentage of fast-twitch fibers generate a greater torque and higher power at a given velocity than those with predominantly slow-twitch fibers. In humans, mean peak power occurred in a ratio of 10:5:1 for the Type IIb, IIa, and I fibers. The in vivo measurement of the torque-velocity relationship and Vmax in human muscle is difficult because of limitations inherent in the equipment used and the inability to study the large limb muscles independently. Nevertheless, the in vivo torque-velocity relationships are similar to those measured in vitro in animals. This observation suggests that little central nervous system inhibition exists and that healthy subjects are able to achieve maximal activation of their muscles. Although peak isometric tension is not dependent on fiber type distribution, a positive correlation exists between the percentage of fast fibers and peak torque output at moderate-to-high angular isokinetic velocities. Consequently, peak power output is substantially greater in subjects possessing a predominance of fast fibers. The mechanical properties of slow and fast muscles do adapt to programs of regular exercise. Endurance exercise training has been shown to increase the Vo of the slow soleus by 20%. This increase could have been caused by either a small increase in all, or most, of the fibers, or to a conversion of a few fibers from slow to fast. Recently, the increase was shown to be caused by the former, as the individual slow Type I fibers of the soleus showed a 20% increase in Vo, but there was little or no change in the percentage of fast fibers. The increased Vo was correlated with, and likely caused by, an increased fiber ATPase. We hypothesize that the increased ATPase and cross-bridge cycling speed might be attributable to an increased expression of fast MLCs in the slow Type I fibers (Fig. 14.10). This hypothesis is based on the fact that light chains have been shown to be involved in the power stroke, and removal of light chains depresses force and velocity. Regular endurance exercise training had no effect on fiber size, but with prolonged durations of daily training it depressed Po and peak power. When the training is maintained over prolonged periods, it may even induce atrophy of the slow Type I and fast Type IIa fibers. (ABSTRACT TRUNCATED)
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PMID:Muscle mechanics: adaptations with exercise-training. 874 58


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