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2-Phenylsulfenyl- ( 1b ), 2-phenylselenenyl- ( 1c ) and 2-phenyltellurenyl-1-naphthol ( 1d ) were prepared and their antioxidative properties evaluated in comparison with 2-benzyl-1-naphthol ( 1a ; DuP 654). 2-Phenyltellurenyl-1-naphthol had a significantly lower (1.00 V versus SCE) oxidation potential than the other three compounds (1.24, 1.27 and 1.25 V, respectively, versus SCE for compounds 1a, 1b and 1c ) as determined by cyclic voltammetry. In contrast to the other materials, compound 1d was able to catalyze the reduction of hydrogen peroxide in the presence of thiols as stoichiometric reducing agents. The organotellurium compound was also the most efficient inhibitor of azo-initiated peroxidation of linoleic acid in a two-phase model system. Ab initio geometry optimization at the 3–21G( ∗ ) level revealed infinitesimal changes in the molecular conformations of the carbon, sulfur, selenium and tellurium analogues. As judged by their ability to inhibit stimulated LTB 4 biosynthesis in human neutrophils, compounds 1a-1d all turned out to be highly potent 5-lipoxygenase inhibitors with IC 50 -values ranging from 0.40 μM for 2-benzyl-1-naphthol ( 1a ) to 0.063 μM for 2-phenyltellurenyl-1-naphthol ( 1d ).

The effect of antioxidants on the oxidation of low density lipoproteins in relation to prosta-cyclin synthesis was investigated in the prescence of rabbit smooth muscle cells (SMC) and Fe-containing culture medium. The lipid peroxidation of low density lipoproteins (LDL) assayed as thiobarbituric acid reactive substances was increased from 0.5 to 1.4 nmol malondialdehyde mL by the presence of smooth muscle cells. Two potent antioxidants, nordihydroguairetic acid (NDGA) and butylated hydroxytoluene (BHT), inhibited lipoprotein oxidation by ic 50 values of 0.2 and 0.8 μM, respectively. Inhibition of lipoprotein oxidation was associated with an increased prostacyclin synthesis by the SMC, the effect being more pronounced with nordihydroguairetic acid than with butylated hydroxytoluene. The stable metabolite of the lipid hydroperoxide, 15-hydroxyeicosatetraenoic acid (15-HETE), formed in the 15-lipoxygenase pathway was measured following antioxidant treatment and found to be eliminated or greatly reduced by both antioxidants. The results presented show that lipid hydroperoxides, formed as a consequence of lipoprotein oxidation and promoted by the smooth muscle cells through a lipoxygenase reaction, may regulate prostacyclin synthase, a process which may be influenced by the addition of antioxidants.

We investigated the effect of H290/51, a novel, low-molecular-weight inhibitor of lipid peroxidation, on cardiac ischemia–reperfusion injury. Lactate dehydrogenase (LD) release from cultured cardiomyocytes exposed to 1 h hypoxia and 4 h reoxygenation was measured after pretreatment with different concentrations of H290/51. In another series, Langendorff-perfused rat hearts were exposed to 30 min global ischemia and 60 min reperfusion (n = minimum 10 in each group): 1. Control ischemia–reperfusion. 2. Vehicle throughout the experiment. 3. Vehicle during stabilization, and H290/51 (10−6 mol/l) during reperfusion. 4. H290/51 throughout the experiments. During reoxygenation of isolated cardiomyocytes, H290/51 dose dependently inhibited LD release with an pIC50 value of 7.2 ± 0.4 (mean ± SEM), with 10−6 mol/l as the lowest efficient concentration. In isolated hearts ischemia–reperfusion induced severe reperfusion arrhythmias, reduced left ventricular developed pressure (LVDP) and coronary flow (CF), and increased LV end-diastolic pressure (LVEDP). LD activity in the effluent increased. H290/51 throughout perfusion (group 4) reduced the occurrence of severe reperfusion arrhythmias (p < .0001), attenuated the decrease of LVDP (p < .008), and CF (p < .006), the increase of LVEDP (p < .008), and the release of LD (p < .002). Tissue contents of thiobarbituric acid-reactive substances did not increase during reperfusion in controls, but was reduced in group 4 (p < .004). H290/51 given only during reperfusion (group 3) tended to improve cardiac function, but significantly so only for increase of CF (p < .01). The lipid peroxidation inhibitor H290/51 attenuated cardiac injury induced by ischemia–reperfusion.

In the present investigation, a method of studying the maximal rate of superoxide anion (O2.-) production in immobilised human neutrophils using a microtiter plate technique has been developed. The rate of O2.- production was determined from the rate of reduction of cytochrome (III) C, studied as the increase in absorbance at 550 nm. The protein kinase C activator, phorbol 12-myristate 13-acetate, was used to stimulate O2.- production. Neutrophils were evenly immobilised as a monolayer to microtiter culture plates to provide a reproducible exposure to the medium. Phorbol ester stimulated O2.- production was inhibited by staurosporine, a well-known inhibitor of protein kinase C, and by diphenylene iodonium, a potent NADPH-oxidase inhibitor, with IC50-values in this assay of 20 and 220 nm, respectively. The extracellularly produced O2.- was removed by superoxide dismutase with a half maximal effect of 0.6 microgram/mL. The maximal production rate of O2.- could therefore be estimated by addition of 20 micrograms/mL superoxide dismutase. Several antioxidants, including butylated hydroxytoluene, nordihydroguairetic acid, probucol and alpha-tocopherol, were studied and showed neither an effect on O2.- production nor a scavenging effect. This new method was highly reproducible, and the continuous measurement of O2.- production was very useful for validating the effect of inhibitors. The developed microtiter technique using immobilised cells has a large capacity and allows different compounds to be tested under comparable conditions, since they are exposed to the cells in a similar way. This is also the first test model which describes O2.- production as the maximal rate of cytochrome (III) C reduction.

To study the role of chain-breaking antioxidants on reperfusion injury in the ischemic heart, cultured ventricular heart cells (myocytes) were subjected to hypoxia and reoxygenation. The myocytes were prepared from neonatal rats and cultured in F10 medium that was supplemented with serum. As a marker for cell damage, lactate dehydrogenase was analyzed in the medium. Cells subjected to hypoxia for 5 h showed a 1.9 fold increase in lactate dehydrogenase (LD) leakage, while cells subjected to 1 h hypoxia followed by 4 h reoxygenation showed a 5-fold increase in LD intake. Alpha-tocopherol, beta-carotene, nordihydroguairetic acid (NDGA), butylated hydroxyltoluene (BHT), and ICI211965 were added to the cell medium every 24 h for 6 d prior to reoxygenation. All compounds protected against reoxygenation-induced cell damage. In the presence of the 5-lipoxygenase inhibitor ICI211965, protection against LD leakage was found only at high concentrations, which corresponded to the antioxidative effect of ICI211965, and not to inhibition of 5-lipoxygenase. We conclude that cultured ventricular myocytes can be used to evaluate the protective effect of antioxidants on reoxygenation-induced cell damage, and that chain-breaking antioxidants protected well against reoxygenation-induced cell damage.

The radioligand binding technique was used to perform a systematic investigation of the beta 1- and beta 2-adrenoceptor affinity of atenolol and metoprolol in tissues from the rat, the guinea pig and man. Radioligands, [125I](+/-)hydroxybenzylpindolol, [125I](-)pindolol, [3H](-)dihydroalprenolol and [3H](-)CGP12177, with different degrees of lipophilicity were used in the binding experiments. In membrane preparations of rat ventricular myocardium and uterus, the number of specific binding sites was similar when comparing experiments performed with the different radioligands. The percentage of the beta 1- and beta 2-adrenoceptor subpopulations in the tissues studied was not dependent on the radioligand or displacing compound used. Furthermore, the affinity of metoprolol and atenolol for beta 1- and beta 2-adrenoceptors was independent of the radioligand used or the tissue studied. The beta 1-adrenoceptor affinity of metoprolol was about 6-7 times higher than that of atenolol, while the beta 1-adrenoceptor selectivity was similar (about 30-fold) for the two beta-blockers. It is concluded that the physical-chemical properties of the radioactive ligands and beta-blockers studied do not affect the results obtained from beta-adrenoceptor-binding experiments in cellular membrane fractions. The beta 1- and beta 2-adrenoceptor affinities did not change in any experiments performed in tissues from the rat, the guinea pig and man for either atenolol or metoprolol.

This paper discusses some mathematical difficulties in handling sharp momentum eigenvectors for a massless helicity representation of the Poincare group, related to the non‐nuclearity of the space of differentiable vectors, and to the existence of singularities in the Lorentz group generators. A simple characterization of the nuclear space of differentiable vectors of the extension of the representation to a representation of the conformal group is given in terms of functions on the space R4− {0}. Using a fibration of this space over the forward light cone (in momentum space), the singularity in the generators is shown to be related to the fact that the standard presentation of the helicity representations should be reformulated in terms of nontrivial sections over the light cone. The problem is partly identical with the one encountered in the study of an electron in a magnetic monopole field, the generator singularity taking the place of the Dirac string.

In this study we have examined how relatives of cancer patients change their social patterns when they are offered increased possibilities to take active part in the care of the patient. Relatives who were offered such an activation programme were compared with relatives who were offered the usual routine programme ('comparison group'). The instrument used for the present study was a modified version of the 'coping wheel' introduced by Shalit. Fifty relatives in the activation group and 45 in the comparison group were followed at repeated occasions approximately once a month during the patient's treatment. Twenty-two in the activation group and 19 in the comparison group were followed 1 and 2 month(s) after the patient's death. Relatives in the activation group reported a significantly higher proportion of activities concerning friends and relatives (P less than 0.04) during the treatment period. At the last observation occasion preceding death, relatives in the comparison group reported significantly more areas dealing with 'own feelings' (P less than 0.04). Relatives in the activation group reported a significantly greater increase in number of 'own activities' from the last observation preceding the patient's death to 1 month after death (P less than 0.04) compared to the comparison group.

A method to construct Euclidean covariant fields corresponding to a relativistic quantum field theory with arbitrary spins is presented. The constructed fields act on a state space with an indefinite inner product, they commute (or anticommute) totally and (except for hermitian Fermion fields) adjoint relativistic fields correspond to adjoint Euclidean fields. The cases where this method can be applied include all Garding-Wightman theories invariant under space inversion.

Inositol phospholipid hydrolysis induced by agonist-stimulation of muscarinic receptors has been examined in slices of guinea-pig cerebral cortex, parotid gland and ileal smooth muscle. An assay measuring 3H-inositol phosphate formation from prelabelled lipids in the presence of LiCl, allowed marked stimulation by agonists to be followed. The pD2-value of carbachol differed markedly, between tissues being more than 10-fold lower in cerebral cortex than in parotid gland. The partial agonist oxotremorine showed the largest relative maximal responsiveness in parotid gland, followed by ileum and cortex. Atropine suppressed the phosphoinositide response to carbachol with an almost similar affinity in each tissue, but pirenzepine was found to have a 20-fold higher affinity in cerebral cortex, pKi = 7.7 than in parotid gland, pKi = 6.3. Carbachol, even in the presence of guanosine triphosphate (GTP), displayed complex binding against 3H-AT-methylscopolamine (3H-NMS) in cortical and ileal membranes, though in membranes from the parotid gland a single homogeneous population was found. Atropine inhibition of 3H-NMS parallelled its suppression of the phosphoinositide response, the affinities in each tissue studied being similar. Pirenzepine inhibited binding from two components in cerebral cortex, the high affinity value being similar to that obtained in the phosphoinositide assay. In parotid gland, however, only low affinity pirenzepine binding sites were observed, closely resembling the affinity found for this antagonist in the functional assay. These experiments suggest (a) that there are differences between agonist occupation of muscarinic receptors and phosphoinositide hydrolysis within the different tissues, (b) that both high and low affinity pirenzepine binding sites appear to be linked to phosphoinositide metabolism, and (c) that low affinity pirenzepine sites may be more efficiently coupled to the hydrolysis of phosphoinositides.

The effects of felodipine on renal hemodynamics and excretion were evaluated in the anesthetized dog. Unilateral renal arterial infusion of felodipine produced ipsilateral increases in the absolute and fractional excretion of sodium and water which were greater than those of potassium; these effects occurred in the absence of changes in mean arterial pressure, renal blood flow, or glomerular filtration rate. There were no significant effects on renal hemodynamic or excretory function in the contralateral kidney. The unilateral renal arterial infusion of isotonic saline or vehicle produced no significant effects on renal hemodynamic or excretory function in either ipsilateral or contralateral kidney. Felodipine, a calcium antagonist with vasodilator antihypertensive properties, in doses which do not affect systemic or renal hemodynamics in the dog, increased urinary flow rate and sodium excretion by decreasing renal tubular water and sodium reabsorption. As a vasodilator antihypertensive agent, felodipine possesses potentially advantageous diuretic and natriuretic properties.

beta-Adrenoceptor agonists inhibit contractile activity in isolated colon strips. In order to demonstrate that beta-adrenoceptors are located at different functional levels within the colon wall, increasing concentrations of muscarinic agonists were used to interact functionally with the beta-adrenoceptor-mediated inhibition of spontaneous colon activity. The effects of the full agonists isoprenaline and terbutaline and of the partial agonist prenalterol were functionally antagonized by carbachol (0.03 and 0.3 mumol/l) and bethanechol (1.3 and 30 mumol/l). This functional antagonism was parallelled by an increase in baseline tension and spontaneous contractile activity of the isolated colon strip. At lower concentrations of carbachol (0.003 and 0.01 mumol/l) or bethanechol (0.03 and 0.3 mumol/l) no effect on the contractile status of the smooth muscle or on the pD2-values of the full agonists was seen. However, at these lower concentrations of muscarinic agonists a marked decrease in the maximal inhibitory response to the partial beta-adrenoceptor agonist prenalterol was demonstrated. The inhibitory response to prenalterol showed a biphasic concentration-response curve. The muscarinic antagonist atropine produced an increase in the maximal response of the high potency component of the concentration-response curve for prenalterol and an increase in the sensitivity to isoprenaline. These results demonstrate the presence of a high cholinergic tone in the colon preparation of a magnitude that clearly reduces the sensitivity to beta-adrenoceptor agonists. The different responses to full and partial beta-adrenoceptor agonists in the presence of increasing concentrations of muscarinic agonists may indicate that beta-adrenoceptors are located on two different functional units within the colon wall.