Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Like all inhalation anesthetics, halothane (CF3CHBrCl) has a dose-dependent negative inotropic effect on cardiac muscle. The mechanism of the action has not been determined, although effects on glycolysis, mitochondrial respiration and calcium kinetics, and sarcoplasmic reticulum ATPase activity have been suggested. Previous studies of the effect of halothane on the ATPase of contractile protein suffered from design and dosing defects. We have measured ATP splitting by canine cardiac natural actomyosin using extraction and equilibration procedures described previously (Honig, C. R. and Reddy, Y. C. 1973, J. Pharmacol. 184: 330-338). Drug dosing calculations were facilitated by measurement of the partition coefficient of halothane in protein. Halothane shifted the Ca++ concentration effect curve for actomyosin ATPase activity to the right. The maximum depression occurred at pCa 7.0 or 6.5. The effect was dose dependent with less than 10 percent depression at threshold and 50-60 percent depression at peak. Enzyme inhibition was antagonized by high Ca++ concentration, and was reversed by removing halothane from the reaction mixture. We suggest that inhibition of ATP utilization by the contractile system may be a mechanism of the in vivo myocardial depression produced by halothane.
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PMID:Halothane decreases actomyosin ATPase activity: a possible mechanism of the negative inotropic effect. 12 60

The calcium pump of liver microsomes is sensitive to CCl4 metabolism in vitro and in vivo. Treatment of rats with alcohol might involve an enhancement of the action of low doses of CCl4 on rat liver microsomal calcium pump. It was found that treatment of fasted rats with isopropanol or ethanol potentiated the increase of serum glutamic oxaloacetic transaminase elicited by CCl4. Alcohol pretreatment alone had no effect on calcium pump activity. After CCl4 alone, the calcium pump was 50% inhibited at 20 min, and 85% inhibited at 1 hr. Pretreatment with either alcohol had no effect on either rate of decline or extent of CCl4-dependent depression of the liver microsomal calcium pump. The mechanism of alcohol potentiation of CCl4-induced hepatotoxicity probably resides in alteration of processes developing after the initial events of CCl4 metabolism.
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PMID:Failure of ethanol or isopropanol pretreatment to affect carbon tetrachloride-induced inhibition of hepatic microsomal calcium pump activity. 627 82

Cyclic nucleotide modulation of the sarcoplasmic reticulum calcium pump has been recognized for some time. Little is known, however, of cyclic nucleotide effects on the sarcolemmal Ca2+-pump. In sarcolemmal vesicles prepared from ventricular muscle by a recent technique (Jones, L.R., Maddock, S.W. and Besch, H.R. (1980) J. Biol. Chem. 255, 9971-9980) we have demonstrated via Millipore filtration that 10(-8) M and 10(-9) M cyclic GMP depressed the rate of ATP- and Mg2+-dependent 45Ca2+ uptake by 34% and 52%, respectively. Only at millimolar levels did cyclic AMP have any effect and the respective 5'-nucleotides had no effect at all. Parallel measurement of the associated (Ca2+ + Mg2+)-ATPase in the presence of either cyclic or 5'-nucleotides, however, revealed no concomitant depression in ATP hydrolysis. In another series of experiments, the cyclic GMP effect on 45Ca2+ uptake was associated with a significant decrease in the pump Vmax, and at the most effective concentration of cyclic GMP increased the apparent Km for Ca2+. These results suggest that cyclic GMP may depress ventricular Ca2+ efflux by decreasing the enzyme turnover and to a limited extent, decreasing pump affinity for Ca2+. This supports a hypothesis whereby cyclic GMP might modulate both local biochemical and electrophysiological events by an effect on a discrete, regional pool of intracellular Ca2+.
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PMID:Regulation of canine heart sarcolemmal Ca2+-pumping ATPase by cyclic GMP. 629 42

The nonspecific interaction of the beta-adrenergic blocking drugs, propranolol and timolol, with model and biological membranes has been investigated. Radioisotope measurements of the association of these drugs with dimyristoyl lecithin (DMPC) bilayers showed that both propranolol and timolol had a significantly greater molar association (mole of drug per mole of lipid) with DMPC above its phase transition temperature than below. Timolol had a much lower molar association with DMPC as compared with propranolol both above and below the phase transition temperature. For the DMPC model membrane system, the molar association of propranolol as measured by radioisotope and inferred from calorimetric studies was similar. Neutron diffraction utilizing propranolol deuterated in the naphthalene moiety showed that the naphthalene moiety of propranolol partitions into the hydrocarbon core of the DMPC lipid bilayer, and that the charged amine side chain is most likely positioned in the aqueous phospholipid head group region. For timolol, the association as measured by radioisotope methods was apparently greater than the partitioning inferred from calorimetric studies using freezing point depression analysis, suggesting a more complex interaction of timolol as compared with propranolol with the DMPC lipid bilayer. The association of propranolol and timolol with sarcoplasmic reticulum vesicles (SR) was similar to that with highly purified protein-depleted SR lipids, and DMPC above its phase transition. The association of propranolol with the SR membrane (mole of propranolol per mole of SR phospholipid) correlated with its ability to inhibit calcium uptake, whereas only a fraction of the total association of timolol with the SR membrane appeared to lead to inhibition of calcium uptake. These results suggest that the major nonspecific interactions of propranolol and timolol are with the SR membrane lipids, and that the magnitude of their interactions depends on both the lipid solubility of the drug and the physical state of the fatty acyl chains of the membrane. Both propranolol and timolol appear to perturb the functional properties of the calcium pump protein in the SR membrane (inhibition of ATP-induced calcium uptake) indirectly by partitioning into the bulk lipid matrix of the SR lipid bilayer, although other sites of interaction cannot be excluded.
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PMID:Comparisons of the interaction of propranolol and timolol with model and biological membrane systems. 688 69

The underlying mechanism of Ca2+ uptake function of cardiac sarcoplasmic reticulum (SR) was investigated in the rat septic shock model produced by cecal ligation and puncture (CLP). The results are as follows. During the early phase of sepsis, the initial rate of ATP-dependent Ca2+ uptake by SR was decreased, while both the capacity of Ca2+ uptake and the activity of Ca(2+)-ATPase were unaffected. In the late sepsis, the impairment in SR function was even greater as the initial rate and the capacity of Ca2+ uptake by SR were significantly decreased, and this was paralleled by a reduction in Ca(2+)-ATPase activity. Although Ca2+ affinity (Km value) to calcium pump and the A0.5 values for Mg2+ and ATP activation on the Ca2+ uptake rate were unchanged, during sepsis the phosphorylation of SR vesicles by adding of catalytic subunit of the cAMP-dependent protein kinase (PKA), calmodulin, or the fragment of PKC into Ca2+ uptake buffer, failed to stimulate Ca2+ uptake activities of SR isolated from early or late septic rats. These data suggest that depression of cardiac SR function is aggravated as sepsis develops, the impairment of SR Ca2+ uptake is possibly based on a mechanism of defective phosphorylation of SR rather than the ionic and energic regulatory actions of Ca2+, Mg2+, ATP on cardiac SR.
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PMID:[Impaired calcium uptake by cardiac sarcoplasmic reticulum and its underlying mechanism during rat septic shock]. 748 74

We investigated the role of creatine kinase bound to sarcoplasmic reticulum membranes of fast skeletal muscle in the local regeneration of ATP and the possible physiological significance of this regeneration for calcium pump function. Our results indicate that ADP produced by sarcoplasmic reticulum Ca(2+)-ATPase is effectively phosphorylated by creatine kinase in the presence of creatine phosphate. This phosphorylation is an important function of the membrane-bound creatine kinase because accumulation of ADP has a depressive effect on Ca(2+)-uptake by sarcoplasmic reticulum vesicles. The concentration-dependent depression of Ca(2+)-uptake by ADP was especially pronounced when there was strong back inhibition by high intravesicular [Ca2+]. ATP regenerated by endogenous creatine kinase was not in free equilibrium with the ATP in the surrounding medium, but was used preferentially by Ca(2+)-ATPase for Ca(2+)-uptake. Efficient translocation of ATP from creatine kinase to Ca(2+)-ATPase, despite the presence of an ATP trap in the surrounding medium, can be explained by close localization of creatine kinase and Ca(2+)-ATPase on the sarcoplasmic reticulum membranes. These results suggest the existence of functional coupling between creatine kinase and Ca(2+)-ATPase on skeletal muscle sarcoplasmic reticulum membranes. Several factors (amount of membrane-bound creatine kinase, oxidation of SH groups of creatine kinase, decrease in [phosphocreatine]) can influence the ability of creatine kinase/phosphocreatine system to support a low ADP/ATP ratio and fuel the Ca(2+)-pump with ATP. These factors may become operative in the living cells, influencing functional coupling between creatine kinase and Ca(2+)-ATPase and may have an indirect effect on Ca(2+)-pump function before Ca(2+)-ATPase itself is affected.
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PMID:Functional coupling between sarcoplasmic-reticulum-bound creatine kinase and Ca(2+)-ATPase. 850 36

Since the contractile status of the myocardium depends on tight regulation of calcium concentrations by the sarcoplasmic reticulum (SR), we investigated the possibility that acute ethanol-induced alterations in the calcium pump function of the SR could contribute to the myocardial depression seen after acute ethanol exposure. In this study, LV function (Langendorff preparation) was significantly reduced after ethanol (ETOH, 2.0 ml/kg, iv) in adult guinea pigs. Compared to control hearts (N = 10), hearts from ethanol-treated animals (N = 10) had significantly lower peak systolic LVP (84 +/- 2 vs 67 +/- 4 mmHg, P < 0.005), +dP/dt max (1175 +/- 54 vs 967 +/- 54 mmHg/sec, P < 0.02), and -dP/dt max (1087 +/- 42 vs 892 +/-52 mmHg/sec, P < 0.02) and at a maximal isoproterenol dose of 30 ng/ml, had lower LVP (150 +/- 5 vs 90 +/- 6 mmHg, P < 0.02), +dP/dt max (3400 +/- 120 vs 180 +/- 40 mmHg/sec, P = 0.001), and - dP/dtmax (2500 +/- 50 vs 1520 +/- 40 mmHg/sec, P < 0.002) than control hearts. SR calcium ATPase activity was not altered by ethanol (control: 70.6 +/- 2.6 micromol/mg protein/hr, N = 10; ETOH: 81.3 +/- 6.9, N = 8). Maximal calcium uptake, however, was decreased by 25% in SR vesicles isolated from ethanol-treated (3.8 +/- 0.27 micromol/mg, N = 10) compared to control hearts (5.1 +/- 0.20, N = 10, P < 0.01). Our data confirm that moderate doses of ethanol depress cardiac contractile function, and our finding that acute ethanol exposure decreased calcium uptake by the SR in the face of no change in calcium ATPase activity suggests that ethanol uncoupled ATP hydrolysis and calcium transport.
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PMID:Cardiac contractile and sarcoplasmic reticulum function after acute ethanol consumption. 881 24

Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.
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PMID:Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation. 1116 76

One of the prominent markers of end-stage heart failure at the molecular level is a decrease in function and/or expression of the sarcoplasmic reticulum ATPase protein [sarco(endo)plasmic reticulum calcium-ATPase, SERCA]. It has been often postulated that a decrease in SERCA pump activity can contribute in a major way to decreased cardiac function. To establish a functional relationship, we assessed how alterations in SERCA activity level affect basic contractile function in healthy myocardium devoid of other significant molecular changes. We investigated baseline contractile function, frequency-dependent activation, and beta-adrenergic response in ultrathin trabeculae isolated from hearts of mice overexpressing SERCA (transgenic, TG), underexpressing SERCA2a (heterozygous knockout, Het), and their respective wild-type (WT) littermates. At physiological temperature and frequency, compared with their respective WT littermates, SERCA1a mice displayed increased developed force at frequencies of 4-8 Hz ( approximately 90% increase at 4 Hz) and force equal to WT mice at 10-14 Hz. Force development at 4 Hz in presence of 1 muM isoproterenol was similar in TG and WT mice. In Het mice, developed force was nearly identical at the lower end of the frequency range (4-8 Hz) but slightly depressed at higher frequency (P < 0.05 at 14 Hz). In presence of 1 muM isoproterenol, developed force at 4 Hz was equal to that in WT mice. Compared with normal levels, increased SERCA activity enhanced force development only at subphysiological frequencies. A reduction in SERCA activity only showed a depression of force at the higher frequency range. Thus generalizations regarding the correlation between SERCA activity and contractility can be highly ambiguous, because this relationship is critically dependent on other factors including stimulation frequency.
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PMID:Frequency-dependent contractile strength in mice over- and underexpressing the sarco(endo)plasmic reticulum calcium-ATPase. 1725 13

Although Na+-H+ exchange (NHE) inhibitors such as methyl-N-isobutyl amiloride (MIA) are known to depress the cardiac function, the mechanisms of their negative inotropic effect are not completely understood. In this study, isolated rat hearts were perfused with MIA to study its action on cardiac performance, whereas isolated subcellular organelles such as sarcolemma, myofibrils, sarcoplasmic reticulum, and mitochondria were treated with MIA to determine its effect on their function. The effect of MIA on intracellular Ca2+ mobilization was examined in fura-2-AM-loaded cardiomyocytes. MIA was observed to depress cardiac function in a concentration-dependent manner in HCO3- -free buffer. On the other hand, MIA had an initial positive inotropic effect followed by a negative inotropic effect in HCO3-containing buffer. MIA increased the basal concentration of intracellular Ca2+ ([Ca2+]i) and augmented the KCl-mediated increase in [Ca2+]i. MIA did not show any direct effect on myofibrils, sarcolemma, and sarcoplasmic reticulum ATPase activities; however, this agent was found to decrease the intracellular pH, which reduced the myofibrils Ca2+-stimulated ATPase activity. MIA also increased Ca2+ uptake by mitochondria without having any direct effect on sarcoplasmic reticulum Ca2+ uptake. In addition, MIA did not protect the hearts subjected to mild Ca2+ paradox as well as ischemia-reperfusion-mediated injury. These results suggest that the increase in [Ca2+]i in cardiomyocytes may be responsible for the initial positive inotropic effect of MIA, but its negative inotropic action may be due to mitochondrial Ca2+ overloading as well as indirect depression of myofibrillar Ca2+ ATPase activity. Thus the accumulation of [H+]i as well as occurrence of intracellular and mitochondrial Ca2+ overload may explain the lack of beneficial effects of MIA in preventing the ischemia-reperfusion-induced myocardial injury.
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PMID:Mechanisms of cardiodepression by an Na+-H+ exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia-reperfusion injury. 1748 46


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