Biological implications from the stability of ternary complexes in solution.1 Mixed-ligand complexes with manganese (II) and other 3d ions.
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Biomedical subjects
Publications and source records attributed to H Sigel.
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Cyclic precordial variations of radiation after i.v. administration of 15 mCi 99mTc-HSA correspond to cyclic volume changes of ventricular volumes of the heart. The "gated blood pool procedure" yields reliable data. Extensive analysis of these data results in subsequent information concerning left ventricular myocardial behaviour: 1. extent of the regional myocardial contraction 2. homogeneity of the contraction 3. regional contraction velocity 4. regional relaxation velocity. Four parametric scans present the distribution of each one of those parameters within the heart. Gated blood pool data have been compared with angiographic data. Reliability of those parameters obtained by extensive analysis of the gated blood pool data could be proven.
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The clinical diagnosis of mitral-valve prolapse was made in ten patients on the basis of a late systolic murmur with or without a click. In each case the echocardiogram confirmed the diagnosis. In five it was further confirmed by angiocardiography. The late systolic murmur, with or without click, accentuated after nitroglycerin, is characteristic for mitral-valve prolapse.
The dependence of the rate of dephosphorylation of ATP, ITP, GTP and CTP (= NTP), expressed as first-order rate constants (50 degrees C; I = 0.1 M, NaClO4), on pH (2 to 10), in the absence and presence of Mn2+, Ni2+, and Zn2+, was investigated. The reaction is accelerated by Zn2+ and passes through a pH optimum at about 8 for the system Zn2+-ATP or 9 for Zn2+-ITP and Zn2+-GTP; this is analogous to observations made earlier with the corresponding Cu2+ systems. By computing the pH dependence of the distribution of the several species present in these systems it is shown that the highest rates are observed in the pH regions where the concentration of Zn(ATP)2-, Zn(ITP-H)3-, or Zn(GTP-H)3- dominates. By evaluating the pH dependence evidence is given that the attacking nucleophile is OH- or H2O for Zn (ATP)2- and H2O for Zn (ITP-H)3- or Zn(GTP-H)3-. For all these complexes metal-ion/nucleic-base interactions are known, leading to the formation of macrochelates. These metal-ion/nucleic-base interactions are crucial for the observation of a metal-ion-promoted dephosphorylation; in agreement with this, and the small tendency of the cytosine moiety to coordinate, the CTP systems are rather stable towards dephosphorylation. It should be noted that these experimental results do not necessarily mean that the macrochelates usually described are the reactive complexes, but only that the active complex must be closely related to them (e.g. isomers, etc). Although for the Ni2+ systems with ATP, ITP, and GTP, and for the Mn2+-ATP system a metal-ion/nucleic-base interaction is also known, these systems are not very sensitive to hydrolytic cleavage of the terminal P-O-P bond. The only known significant structural difference between the Ni2+-NTP or the Mn2+-ATP complexes and those of Cu2+ or Zn2+ is that Ni2+ Mn2+ coordinate to all three phsophate groups, whereas Cu2+ and Zn2+ involve only the beta and gamma ones. This structure-reactivity relationship is rationalized by the suggestion that in the active species the metal ion should be coordinated to the alpha,beta-phosphate groups leaving the gamma-group open to nucleophilic attack. Obviously, an initial beta,gamma-coordination is suitable for a shift of the metal ion along the phosphate back-bone into the reactive alpha-beta-position, while for an alpha,beta,gamma-coordination only the less favorable removal of the coordinated gamma-group remains. The metal-ion/nucleic-base interaction is considered as being important for achieving this reactive structure. The connection between trans-phosphorylation in vitro and in vivo is discussed. It is also shown that the formation of mixed-ligand or ternary complexes inhibits the dephosphorylation process. This is on the one hand of interest with regard to the transport of hydrolysis-sensitive phosphates in nature, while on the other it casts doubts on conclusions based on experiments carried out in the presence of buffers, because these contain weak bases and hence potential ligands.
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Camera-Kinematography is a nearly noninvasive method to investigate regional motion of the myocard, and allows evaluation of the function of the heart. About 20 min after injection of 15-20 mCi of 99mTC-Human-Serum-Albumin, when the tracer is distributed homogenously within the bloodpool, data acquisition starts. Myocardial wall motion is represented in an appropriate quasi three-dimensional form. In this representation scars can be revealed as "silent" (akinetic) regions, aneurysms by asynchronic motion. Time activity curves for arbitrarily chosen regions can be calculated and give an equivalent for regional volume changes. 16 patients with an old infarction have been investigated. In fourteen cases the location and extent of regions with abnormal motion could be evaluated. Only two cases of a small posterior wall infarction did not show deviations from normal contraction pattern.
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The dephosphorylation of CTP, GTP, ITP, ATP, CDP, GDP, IDP and ADP was characterized by measuring the first-order rate constant (50 degrees; I = 0.1, NaClO4) in dependence on pH (2 to 10). Except with CTP and CDP, the reactions are significantly accelerated by Cu2+ and pass through pH optima. By computing the pH dependence of the distribution of the several species present in the nucleotide (NP) systems, it is shown that the most reactive species is Cu(NP). Cu(NP-H), where N(1) is deprotonated, is somewhat less reactive. In both types of complexes, a metal ion-nucleic base interaction, which is responsible for the increased reactivity, occurs, i.e., macrochelates involving the phosphate chains and the base moieties are formed. In accord herewith, CTP and CDP are rather stable as the coordination tendency of the cytosine moiety is small. Furthermore, in the ternary complexes Cu(2,2'-bipyridyl)(NP) and Cu-(2,2'-bipyridyl)(NP-H), where the formation of a macrochelate is inhibited, the nucleotides are protected. The structure-reactivity relationship is also evident with Cu(ITP)2- and Cu(IDP)- which exist only in part as macrochelates; hence, they are less reactive than for example Cu(ATP)2- or Cu(ADP)-. With the aid of the initial rate, vo = d[PO4(3-)]/dt, the rate laws of the ascending side of the pH optima were determined: vo = k[Cu(NP)]/[H+]. A reaction mechanism that includes an intermolecular attack of OH- at the terminal phosphate group is proposed. The descending side of the pH optimum is attributed to the formation of CU(NP)(OH) or Cu(NP-H)(OH), where the Cu2+-base interaction is insignificant. However, these hydroxy complexes are still somewhat faster dephosphorylated than the free nucleotides. This is attributed to an intramolecular attack of the bound OH- at the terminal phosphate group.
As shown in previous investigations overdoses of isoproterenol produce an abundant myocardial Ca uptake, followed by high energy phosphate breakdown, mitochondrial damage and, eventually, cardiac fibre necrotization. Conversely Ca antagonistic compounds such as verapamil, D 600 or prenylamine which reduce the transmembrane Ca influx into the heart muscle cells, can prevent high energy phosphate deficiency and cardiac lesions. Ethyl-4-(3,4,5-trimethoxycinnamoyl) poperazinyl acetate (Vascoril) is another compound which, according to our tracer studies, interferes with transmembrane Ca uptake into the myocardium. As expected the rat hearts were also protected by Vascoril against isoproterenol-induced metabolic disorders and structural alterations. Equiprotective subcutaneous doses, as studied on the right ventricular myocardium of rats, were 600 mg/kg Vascoril, 250 mg/kg prenylamine, 17 mg/kg verapamil or 10 mg/kg D 600.
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The crucial point in the pathogenesis of isoproterenol-induced myocardial necrotization is an abundant intracellular Ca accumulation leading to high energy phosphate exhaustion. Accordingly, in the early stage of the isoproterenol-induced necrotization process, the onset of ATP and creatine phosphate breakdown strictly parallels the acute Ca gain. In this type of necrosis, the Mg losses from the myocardium appear as a concomitant phenomenon. The hearts can be protected against the deleterious Ca overload and necrotization by increasing the plasma concentration of Mg, K, or H ions in order to counterbalance Ca according to the ration (see article). On the other hand, if Mg, K, or H ion concentrations are too low, isoproterenol-induced Ca uptake and myocardial lesions are potentiated.
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