The reaction of Pt-antitumor drugs with selected nucleophiles. I. The reaction of cis-[Pt(NH3)2Cl2] with glycine

Various Pt(II)-glycine coordination compounds were characterized by 1H and 13C NMR spectroscopy, some of them also by electrophoretic and chromatographic behavior. The results were applied to the analysis of the reaction mixtures of cis-[Pt(NH3)2Cl2] and glycine obtained under various conditions. Cis-[Pt(NH3)2Cl2] reacts with glycine to give cis-diammine-(glycine-N,O)-Pt(II) and cis-diammine-bis(glycine-N-)Pt(II). Their ratio depends primarily on the pH of the reaction medium. Conformation of these compounds is discussed based on the observed Pt-C and Pt-H NMR coupling constants.     

The effect of 5-fluorouracil on experimental acute pancreatitis

The present study was undertaken to elucidate the effects of different doses of 5-fluorouracil on experimental acute pancreatitis. Twelve mongrel dogs were used. Acute pancreatitis was induced by intraductal injection of sunflower-oil. Two groups of animals were treated with intravenous 5-fluorouracil: 1 mg/kg body weight for the first group of 5 animals, and 5 mg/kg body weight for the second one of 7 animals in subsequent three postoperative days. All the animals in the first group died within 24 to 36 hours due to acute haemorrhagic pancreatitis. All the animals in the second one survived longer than 36 hours. A statistically significant increase of serum amylase and lipase levels was found in pancreatitis with significant decrease of them during treatment. Three to 8 weeks later signs of chronic pancreatitis could be detected in surviving dogs.     

Na+/K(+)-ATPase regulation by neurotransmitters.

A long period of experimental work has led to the conclusion that Na+/K(+)-ATPase is the enzymatic version of the Na+/K+ pump. This enzymatic system is in charge of various important cell functions. Among them cationic equilibrium and recovering of resting membrane potential in neurons is relevant. A tetrameric ensemble of peptides conform the system known as alpha and beta subunits. The alpha subunit is subdivided in alpha 1, alpha 2 and alpha 3, according to different location and properties. Regulatory factors intrinsic to the Na+/K(+)-ATPase system are: ATP, Na+ and Mg2+ concentrations inside the cell, and K+ outside. The enzyme activity is also regulated by extrinsic factors like some hormones (insulin and thyroxine). Induction of gene expression or post-translational modifications of the preexisting pool of the enzyme are the basic mechanisms of regulation proposed. Other extrinsic factors that seem to regulate the enzyme activity are some neurotransmitters. Among them the most extensively studied are catecholamines, mainly norepinephrine (NE) and lately serotonin (5-HT). The mechanism suggested for NE activation of the enzyme seems to involve specific receptors or a non-specific chelating action related to the catechol group that would relieve the inhibition by divalent cations. Another possibility is that NE removes an endogenous inhibitory factor present in the cytoplasm. The Na+/K(+)-ATPase is activated also by 5-HT. In vivo pharmacological and nutriological manipulations of brain 5-HT are accompanied by parallel responses of Na+/K(+)-ATPase activity. Serotonin agonists do activate the enzyme and antagonists neutralize the activation. In vitro there is a different dose dependent activation, according to the brain region. The mechanism involved seems to implicate a specific receptor system. Serotonin-Na+/K(+)-ATPase interaction in the rat brain is probably of functional relevance because it disappears in amygdaloid kindling. Also it seems to influence the ionic regulation of the pigment transport mechanism in crayfish photoreceptors. In relation to other neurotransmitters, a weak response to histamine was observed with acetylcholine, GABA and glutamic acid, the results were negative.     

A microcomputer method for recording and analysing behavioural elements

The trend in ethology, psychopharmacology and behaviour genetics is to get increasingly higher resolution of the behaviour of animals, since it increases the sensitivity of the tests used. Consequently the higher resolution requires an increased data-logging efficiency, and a decreased time-investment for data handling. In this paper a method for inexpensive microcomputers is presented, which enables an individual experimenter to obtain frequency, relative duration and its variance from as many behavioural elements as desired.     

Presence of covalently bound energy-rich phosphates in human tracheal smooth muscle myosin

In a preliminary report, the tracheal NaCl-myosin prepared from an old and a young subject was discussed. In the present paper, the total bound phosphate (P) content and its distribution is described in two parallel preparations of human muscle myosin. It was shown that a considerable amount of covalently bound P was present not only in NaCl, but in the fresh preparations of tracheal KCl-myosin. Analysing this phosphate fraction in the alkaline hydrolysate of RNA- and lipid-free preparations of myosin it was confirmed that phosphate was linked to the basic amino acid residues and their hydrolytic derivatives. As the phosphoryl binding sites are partly saturated, the phosphate concentration can be enhanced nearly three-fold compared to the fresh preparation. Phosphate incorporation is an autophosphorylation process depending on the ATP and Mg2+ concentration. Studying the actomyosin fraction in the presence of ATP it was found that its phosphate content can also be increased to a certain degree. It is supposed that the changes in phosphate content of myosin are associated with the formation of crossbridges between the actin and myosin filaments in the processes of muscle contraction and relaxation. The process can be influenced directly and indirectly by some natural factors and drugs resulting in the concentration or relaxation of bronchial muscles.     

The effect of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides and arrhythmogenic activity due to myocardial ischaemia

The effects of different sulphonylureas on the electrical cardiac activity were studied in 145 rabbits and in 103 rats as well as in 278 digitalis-treated, non-smoker non-insulin-dependent diabetics on the same therapy at least during the previous three months. In rabbits and rats glibenclamide (0.0032-100 mumol. kg-1) decreased, while tolbutamide and carbutamide (0.008-1000 mumol. kg-1) increased strophantidin toxicity and myocardial ischaemia induced transitory ventricular fibrillation dose-dependently. The differences between the dose-response curve of glibenclamide and those of tolbutamide or carbutamide were significant. In digitalized non-insulin-dependent diabetics, multifocal ectopic ventricular beats could be observed in none among the 80 glibenclamide-treated diabetics, while in 12 cases of the 71 tolbutamide and in 10 cases of the 61 carbutamide treated diabetics. Two of the 66 non-insulin-dependent diabetics receiving only diet and 7 of the 278 age and sex matched, non-smoker, metabolically healthy patients had multifocal ectopic ventricular beats. No significant difference could be found between the therapeutical groups. It was concluded that instead of tolbutamide, glibenclamide must be preferred in digitalis-treated diabetics, when metabolic control is not satisfactorily achieved by diet and regime alone.     

Voltage dependence of depolarization-contraction coupling processes in skeletal muscle cells

Changes of contraction and optical anisotropy of isolated skeletal muscle cells from Rana temporaria and Astacus fluviatilis were compared under voltage clamp conditions. The time course of the optical signal from frog muscle was shown to consist of two components which could be attributed to calcium binding both on the sarcoplasmic reticulum Ca-ATPase and troponin C. The optical signal from the crayfish muscle has no distinguishable components, and its onset probably reflects the start of Ca-ATPase activity. This hypothesis is supported by the analysis of effects of some pharmacological agents and conditioning depolarization on tension and optical signal.     

Vasopressin analog delays extinction of classically conditioned bradycardia

Albino rabbits were subjected to Pavlovian (classical) conditioning and extinction of concomitant heart rate and eyeblink responses. Sixty minutes before each of three extinction sessions animals were treated with 5 or 20 μg/kg of deamino-dicarba-arginine-8-vasopressin or saline. Vasopressin treatment delayed extinction of bradycardiac conditioned responses but did not affect concomitant eyeblink conditioned responses. It was concluded that classically conditioned autonomic responses may be useful tools for studying the effects of peptides on learning.