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Dose of theophylline and caffeine which do not produce aortic arch anomalies in embryonic chicks have been shown to potentiate catecholamine-induced aortic arch malformations in that experimental animal. Theophylline (2.1 X 10(-5) mole per milliliter isotonic saline solution) potentiated the effective dose of norepinephrine more than 100 times. The greatest potentiation observed with epinephrine (2.5 X) was induced by 2.6 X 10(-5) mole caffeine. This study also demonstrated that both methylxanthines specifically induce aneurysms of the ascending aorta and complete absence (or nearly complete constriction) of the right ductus arteriosus. The incidences of these types of cardiovascular malformations proved to be dose dependent with theophylline a more potent teratogen than caffeine. The mobilization of calcium and/or cyclic nucleotide phosphodiesterase inhibition by the methylxanthines are suggested as significant actions in the potentiation of catecholamine-induced aortic arch anomalies.
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PMID:The effects of methylxanthines on catecholamine-stimulated and normal chick embryos. 19 58

Glycogen phosphorylase isolated from bovine skeletal muscles was found to be homogeneous during polyacrylamide gel electrophoresis. The enzyme phosphorylation by phosphorylase kinase is accompanied by the incorporation of one mole of labeled phosphate per protein dimer; therefore the enzyme is represented by a partly phosphorylated form. The presence of a phosphate group prevents the removal of the protein-bound pyridoxal phosphate. The partly phosphorylated bovine phosphorylase possesses a low affinity for AMP and is inactive in the presence of IMP. Bovine phosphorylase a obtained from the partly phosphorylated enzyme has a molecular mass corresponding to a dimer. Both forms of bovine phosphorylase exhibit high cooperativity towards the substrate. The mechanism of phosphorylase a activation by AMP and IMP is identical: the nucleotides increase the enzyme affinity for the substrate as well as the maximal rate of the enzymatic reaction. Study of the enzyme inhibition by caffeine revealed the cooperativity of caffeine-binding centers. The equilibrium between the active and inactive enzyme conformations in the presence of caffeine is markedly shifted towards the inactive (T) form of glycogen phosphorylase.
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PMID:[Purification and properties of glycogen phosphorylase isolated from bovine skeletal muscles]. 312 32

The concentration-dependent effects of ouabain on the contractility of postnatally developing rat heart ventricles were studied. Ouabain caused a positive inotropic effect in right ventricular strips of neonatal rats up to the age of about 30 days but a negative inotropic effect in the adult cardiac tissue. When extracellular Ca concentration was lowered from 2.5 to 1.0 mmol/l and the rate of stimulation was simultaneously elevated from 0.2 to 1.0 Hz a clear positive inotropic effect was also generated in the adult rat heart. The positive inotropic effect of ouabain showed a biphasic developmental pattern: the contractile force first grew from birth to about 15 days of age but steeply declined near to the adult level during the 3rd postnatal week. The force response to ouabain occurred within two distinct dose-ranges. In the newborn only the high-dose (above 3 X 10(-6) mol/l) effect was seen but in rats older than 5 days a mixed low-dose (below 3 X 10(-6) mole/l)/high-dose effect was apparent. In both ranges the positive inotropic effect of ouabain seemed to be dependent on caffeine sensitive Ca store, perhaps the sarcoplasmic reticulum. It is suggested that during the 3rd postnatal week a transition from extracellular to intracellular Ca stores occurs in the rat heart, which is reflected as a changing inotropic effect of ouabain on the developing cardiac tissue.
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PMID:Postnatal changes in the inotropic effect of ouabain on the rat heart ventricle. 359 85

1. In the large single muscle fibres from the barnacle Balanus nubilus, the total fibre Mg concentration was estimated as 15.1 m-mole/kg wet wt., of which about 3-3.5 m-mole/kg wet wt. was extracellular. The diffusible Mg, measured by internal sampling, was 11.5 m-mole/kg wet wt., of which at least half may be complexed to larger diffusible molecules. The free ionized Mg level was estimated as < 5 m-mole/kg wet wt.2. The loss of [(28)Mg]MgCl(2) from both Maia and Balanus muscle fibres following axial micro-injection approximated to first-order kinetics. The maximum rate constant for the loss was 1.51 +/- 0.20 (S.E.) x 10(-5) sec(-1) for Balanus (sixty-seven fibres) and 1.06 +/- 0.46 (S.E.) x 10(-5) sec(-1) for Maia (seven fibres) at 20-25 degrees C.3. The calculated Mg efflux was in the range 6-12 p-mole/cm(2).sec based on this rate constant, assuming isotopic equilibration internally and that the surface area of the fibres approximated to that of a simple cylinder. If account was taken of the area of the cleft system the efflux was reduced by about fifteen times.4. The diffusion coefficient for injected (28)Mg was estimated as 2-3 x 10(-6) cm(2) sec(-1), about half the value in free solution. Injections of 2 M-MgCl(2) or 200 mM-EDTA subsequent to the injection of the isotope caused about a 30% reduction in the tracer efflux.5. External application of salines containing 100 mM-Ca or Mg caused a rapid but reversible inhibition of the magnesium efflux. Similar effects were observed with salines containing 32 mM-Co or Mn chlorides or 1-2 mM-La or Gd chlorides. Polyarginine (200 mug/ml.) had no effect.6. The Mg efflux had a Q(10) of 3-4 over the temperature range of about 5-20 degrees C. It was irreversibly inhibited by the sulphydryl reagent NEM (1 mM), but PCMBS (0.2-2 mM) had no effect. Contractile agents (5 mM caffeine or 200 mM-K salines) and a variety of inhibitors of ion movement or active transport had no appreciable effect on the Mg efflux. Lowering the pH of the saline from 7 to 5 produced a 70% reduction in the efflux which was reversible over short periods of application.7. Replacement of external Na, but not Ca or Mg, with Li, choline or sucrose caused a rapid and partially reversible reduction of the Mg efflux, but increasing the internal Na by micro-injection in zero Na salines had no consistent effect. It is suggested that the extrusion of Mg from these muscle cells is largely dependent upon the inward movement of Na.
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PMID:The efflux of magnesium from single crustacean muscle fibres. 462 63

1. The efflux of calcium, as the isotope (45)Ca, has been investigated from single muscle fibres from the barnacle Balanus nubilus and from the crab Maia squinado.2. If the isotope was initially injected with sufficient calcium (5-65 mM) to cause a contraction, the efflux did not follow first order kinetics. There was an early rapid phase which reached a peak after 5-10 min and then declined slowly over a period of 50-150 min to a low residual value.3. Injection of the isotope with the calcium-binding agent EGTA, so that the injected free calcium concentration was ca. 2 x 10(-8)M, abolished the initial rapid loss of calcium. The efflux rose to give a steady value after 10-15 min and its magnitude was similar to the value of the residual efflux.4. The rate constant for the low residual loss was ca. 7 x 10(-4) min(-1) for Maia and ca. 17 x 10(-4) min(-1) for Balanus. The rate constant predicted a calcium efflux of 0.4 p-mole/cm(2).sec for Maia and 1-2 p-mole/cm(2).sec for Balanus at 16-25 degrees C based on the total fibre calcium concentration.5. The residual calcium efflux was not affected by 0.5 mM ouabain or 0 potassium salines applied externally. It was stimulated, some 10-15 times in Maia and to a lesser extent in Balanus, by salines containing 600 mM potassium or 2-5 mM caffeine. The increased efflux was associated with a brisk contraction.6. External application of salines containing 20, 40 or 60 mM potassium or 0.5 mM caffeine in Maia produced some stimulation of the residual efflux but no visible contraction.7. Pre-treatment of Maia fibres with 40 mM potassium or 0.5 mM caffeine salines abolished the ability of the fibres to respond to higher concentrations of these agents. A depletion of a releasable calcium fraction by these subthreshold stimuli could explain this phenomenon.8. Electrical stimulation, the injection of 50 mM calcium chloride or 50 mM caffeine produced an elevated calcium efflux which was associated with a contraction.9. Intracellular injections of EGTA only lowered the residual efflux by up to half its initial value. This suggests that calcium can be released rapidly within these muscle fibres and that the sarcoplasmic calcium concentration is not much altered from its normal value by the injection.10. The experiments suggest that in Maia, changes in the calcium efflux reflect in magnitude, but not in time course, the internal calcium changes which can be observed with the calcium-sensitive protein, aequorin.
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PMID:The efflux of calcium from single crab and barnacle muscle fibres. 504 39

Doxorubicin (adriamycin) forms molecular associations with other aromatic and planar molecules (hetero-association) and with other doxorubicin molecules (self-association) in aqueous solution. The ability of doxorubicin to form complexes was demonstrated in a nonbiological system by measuring the doxorubicin partition coefficient. A decreased apparent doxorubicin activity coefficient in the presence of complex formation was also demonstrated in a biological system by measuring the transmembranous doxorubicin transport and the doxorubicin distribution at equilibrium in human red blood cells and their suspending medium. Doxorubicin formed complexes in aqueous solution at 37 degrees (pH 7.3) with (a) DNA-derived bases, nucleosides, and nucleotides; (b) amino acids such as tryptophan; (c) proteins such as human serum albumin and hemoglobin; and (d) a broad range of biologically active compounds such as NAD, propanthelline, caffeine, chloroquine, imipramine, and propranolol. The apparent thermodynamic quantities of the complex formation with adenosine 5'-triphosphate were delta H0, -9.5 kcal . mole-1; delta S0, -19 eu . mole-1; and delta G0 (310 degrees K), -3.6 kcal . mole-1. The binding forces of the molecular associations were probably hydrophobic (short-range force), sometimes supported by electrostatic interaction (long-range force).
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PMID:Molecular association between doxorubicin (adriamycin) and DNA-derived bases, nucleosides, nucleotides, other aromatic compounds, and proteins in aqueous solution. 712 47

The solubility of caffeine in various dioxane-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of the Hildebrand treatment for regular solutions. The solubility equation employs a term (W) to replace the geometric mean (c1c2)1/2, where c1 and c2 are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in delta 1 of the binary mixture. A quartic expression of W in terms of the solvent solubility parameter was found for predicting the solubility of caffeine in dioxane-water mixtures. The expression yields an error in mole fraction solubility of less than 3%, a value approximating that of the experimentally determined solubility. The one exception to a good fit is near the maximum solubility, where a depression or valley occurs between the two peaks in solubility data; at this point, the theoretical equation predicts the solubility within approximately 9%. The new model also may be used to estimate the solubility of drug molecules employing the volume fraction of water in the solvent mixture instead of the composite solubility parameter, delta 1. The method has potential usefulness in preformulation and formulation studies during which solubility determination is important for drug design.
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PMID:Extended Hildebrand approach: solubility of caffeine in dioxane-water mixtures. 720 77

The solubility profiles of theobromine, theophylline, and caffeine at 25 degrees were examined in binary solvent systems including dioxane-formamide, water-polyethylene glycol 400, and glycerin-propylene glycol. Theobromine solubility was studied in dioxane-water mixtures, a solvent system that was investigated earlier for the solubility of theophylline and caffeine. Solubilities were calculated in these polar systems by a regression method, based on an extension of the Hildebrand-Scatchard equation of regular solution theory. A linear relationship between the mixed solvent solubility parameter, and dielectric constant, epsilon, was introduced earlier and was confirmed in the present study. In addition, it was observed that a regression of log (activity coefficient) on epsilon in a second or higher degree polynomial provides reasonable solubility values for the methylxanthines in mixed solvents. A direct regression of molal or mole fraction (but not molar) solubility against delta 1, epsilon, or against volume percent of one or the other solvent in a binary solvent mixture provided a suitable measure of solubility for these crystalline drugs in mixed polar solvents. The drug's solubility parameter as determined from peak solubility in mixed polar solvents varied somewhat, depending on the specific solvent system employed. It is suggested that a drug may exhibit one (or more) solubility parameters in nonpolar solutions and multiple solubility parameters in polar systems. The extended solubility approach serves for the back-calculation of solubilities in mixed solvent systems, even though the solubility parameter of the solute may vary from one solvent system to the next.
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PMID:Extended Hildebrand Solubility Approach: methylxanthines in mixed solvents. 729 44

A novel purine, (N6-2-(4-chlorophenyl)-bicyclo 2.2.2.-octyl-(3)-adenosine) EMD 28422 increases the binding of (3H) diazepam to benzodiazepine receptors in vivo within 10 min after intraperitoneal administration. This increase in (3H) diazepam binding is due to an increase in the number of benzodiazepine receptors (Bmax) rather than an altered affinity of the radioligand for receptor (Kd), EMD 28422 protects mice against pentylenetetrazole and caffeine-induced seizures and potentiates the anticonvulsant action of subeffective doses of diazepam in a dose-dependent fashion. Furthermore, EMD 28422 also produces a significant increase in punished responding in a conflict situation (rats), and a long-lasting, dose-dependent decrease in spontaneous motor activity (mice). In contrast, neither EMD 39011 nor adenosine (the two component molecules of EMD 28422) possess anticonvulsant properties at doses up to five mole-equivalents of EMD 28422. These data indicate that the purine EMD 28422 produces a spectrum of pharmacologic effects similar to the benzodiazepines, yet in contrast to the benzodiazepines (and other purines), increases benzodiazepine receptor number. Thus, EMD 28422 may represent the prototype of a class of synthetic purines exerting a unique neurochemical effect on benzodiazepine receptors and possessing several therapeutic actions of the benzodiazepines.
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PMID:Pharmacologic and behavioral effects of EMD 28422: a novel purine which enhances (3H) diazepam binding to brain benzodiazepine receptors. 739 62

This study examined the effects of caffeine (Caf) ingestion on muscle glycogen use and the regulation of muscle glycogen phosphorylase (Phos) activity during intense aerobic exercise. In two separate trials, 12 untrained males ingested either placebo (Pl) or Caf (9 mg/kg body wt) 1 h before cycling at 80% maximum O2 consumption (VO2 max) for 15 min. Muscle biopsies were obtained from the vastus lateralis at 0, 3, and 15 min of exercise. In this study, glycogen "sparing" was defined as a 10% or greater reduction in muscle glycogen use during exercise after Caf ingestion compared with Pl. Muscle glycogen use decreased by 28% (Pl 255 +/- 38 vs. Caf 184 +/- 24 mmol/kg dry muscle) after Caf in six subjects [glycogen sparers (Sp)] but was unaffected by Caf in six other subjects [nonsparers (NSp), Pl 210 +/- 35 vs. Caf 214 +/- 37 mmol/kg dry muscle]. In both groups, Caf significantly increased resting free fatty acid concentration, significantly increased epinephrine concentration by twofold during exercise, and increased the Phos a mole fraction at 3 min of exercise compared with Pl, although not significantly. Caf improved the energy status of the muscle during exercise in the Sp group: muscle phosphocreatine (PCr) degradation was significantly reduced (Pl 47.9 +/- 3.6 vs. Caf 40.4 +/- 6.7 mmol/kg dry muscle at 3 min) and the accumulations of free ADP and free AMP (Pl 6.8 +/- 1.3 vs. Caf 3.1 +/- 1.4 micromol/kg dry muscle at 3 min; Pl 8.7 +/- 0.8 vs. Caf 4.7 +/- 1.1 micromol/kg dry muscle at 15 min) were significantly reduced. Caf had no effect on these measurements in the NSp group. It is concluded that the Caf-induced decrease in flux through Phos (glycogen-sparing effect) is mediated via an improved energy status of the muscle in the early stages of intense aerobic exercise. This may be related to an increased availability of fat and/or ability of mitochondria to oxidize fat during exercise preceded by Caf ingestion. It is presently unknown why the glycogen-sparing effect of Caf does not occur in all untrained individuals during intense aerobic exercise.
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PMID:Regulation of muscle glycogenolytic flux during intense aerobic exercise after caffeine ingestion. 968 98


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