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Biomedical subjects

B F Becker

Publications and source records attributed to B F Becker.

At least 91 records · Page 5Linked to original sources
PubMed1989

Inhibition of platelet aggregation following chronic in vivo treatment of rats with nicotine: prevention by simultaneous application of propranolol.

Platelet aggregability is known to be enhanced and platelet-survival time shortened in smokers when compared with nonsmokers. Up to now it is unknown which of the substances in tobacco smoke are responsible for these effects. To evaluate a possible role of nicotine, rats were chronically treated with the alkaloid (10 mg/kg/day), continuously released from subcutaneously implanted osmotic minipumps. Surprisingly, after 8 weeks, platelet sensitivity toward the aggregating stimulus adenosine 5'-diphosphate (ADP) was markedly reduced. The mean ADP concentration required to induce half the maximum rate of aggregation (EC50) was 0.88 mumol/L in nicotine-treated animals, as compared with 0.67 mumol/L in controls (p less than 0.002). Platelet aggregability remained normal when the rats were treated simultaneously with nicotine and the beta blocker propranolol (3.5 mg/kg/day); for these animals, the mean EC50 for ADP was 0.73 mumol/L. These results are suggestive of a catecholamine-mediated action of nicotine. However, neither the basal levels of cAMP in platelet-rich plasma, nor the cAMP levels attained after stimulation of platelet adenylate cyclase with prostaglandin E1 (PGE1), were affected by 8 weeks of treatment with nicotine or nicotine plus propranolol. No effect on platelet aggregation was observed when the rats were treated with nicotine for only 2 weeks, or when nicotine or nicotine plus cotinine were added to platelet-rich plasma in vitro in concentrations equal to those attained in vivo after 8 weeks. Thus, prolonged application of nicotine in vivo caused an inhibition of ADP-induced rat platelet aggregation presumably mediated by beta-catecholaminergic stimulation of platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1989

Antibodies to the ADP/ATP carrier, an autoantigen in myocarditis and dilated cardiomyopathy, penetrate into myocardial cells and disturb energy metabolism in vivo.

We identified the ADP/ATP carrier, located within the inner mitochondrial membrane, to be an organ- and conformation-specific autoantigen in myocarditis and dilated cardiomyopathy. We also showed that autoantibodies to the ADP/ATP carrier inhibit the nucleotide transport in vitro. Specific binding of the autoantibodies to the carrier was demonstrated by radioimmunoassay and the immunoblot technique; the inhibition of the nucleotide transport was determined by the inhibitor stop method. To establish if these autoantibodies might also affect cardiac energy metabolism in vivo, we measured whether they are capable of penetrating into myocytes and whether subcellular ATP/ADP ratios and phosphorylation potentials of ATP change in hearts of guinea pigs that have been immunized with the isolated ADP/ATP carrier. An intracellular deposition of autoantibodies was observed by direct immunofluorescence and by immunoperoxidase staining on cryosections of the myocardial tissue of animals immunized with the ADP/ATP carrier. Furthermore, binding of autoantibodies to mitochondrial membrane structures was shown by immunoelectron-microscopic methods. The cytosolic and intramitochondrial distribution of adenine nucleotides in stimulated, isolated perfused hearts of guinea pigs immunized with the ADP/ATP carrier was measured by nonaqueous fractionation. Compared with controls performing equal external heart work, the cytosolic ATP decreased in the immunized animals, whereas the mitochondrial ATP increased strongly; ADP concentrations showed an opposite change. Thus, a resultant cytosolic decrease and a marked mitochondrial increase of the ATP/ADP ratio was established. As a consequence, the cytosolic-mitochondrial phosphorylation potential of ATP was diminished. These findings demonstrate that antibodies against intracellular antigens are able to penetrate into living cells, and that autoimmunity to the ADP/ATP carrier may contribute to the pathophysiology of myocarditis and dilated cardiomyopathy by causing an autoantibody-mediated imbalance between intracellular energy delivery and demand.

Adenosine Diphosphate↗
PubMed1988

Endothelium-mediated coronary dilatation by adenosine does not depend on endothelial adenylate cyclase activation: studies in isolated guinea pig hearts.

Adenosine, applied to the coronary system of guinea pigs at up to 10(-6) M, elicits dilatation solely via an endothelium-mediated process. We investigated the role of coronary A2 receptors in this dilation, since the coronary endothelium possesses adenosine A2-receptors with a stimulatory action on the adenylate cyclase. In situ, A2 receptor stimulation can be assessed by prelabeling the coronary endothelial adenine nucleotide pool with 3H-adenosine and subsequently determining the rate of release of radiolabeled cAMP induced by A2 agonists. Thus, perfusion of isolated hearts with 5'-N-ethylcarboxamidoadenosine (NECA) dose-dependently increased coronary flow and the release of 3H-cAMP from the endothelium. In the presence of 50 microM 2',5'-dideoxyadenosine (ddA), a P-site agonist which inhibits the catalytic activity of adenylate cyclase, coronary flow increases induced by both adenosine and NECA were unaffected. In contrast, ddA reduced the release of labeled cAMP in response to NECA by about 60%. In cultured endothelial cells, ddA likewise inhibited cAMP accumulation due to NECA by about 70%. Moreover, ddA antagonized the adenylate cyclase mediated flow response due to the PGI2 analogue, iloprost, as well as the positive chronotropic and inotropic actions of isoproterenol. The dissociation elicited by ddA between the coronary flow response and the release of cAMP strongly indicates that the endothelial A2 receptors which are linked to adenylate cyclase are not causally involved in endothelium-dependent coronary dilatation induced by adenosine.

Adenosine↗
PubMed1988

Blood platelet function after chronic treatment of rats and guinea pigs with nicotine.

To establish whether long-term application of nicotine can at all alter thrombocyte function, the alkaloid was administered to rats and guinea pigs for up to 8 weeks, using subcutaneously implanted ALZET minipumps. These two species were examined, since rat platelets are known to possess both alpha 2- and beta 2-adrenoceptors, whereas guinea pig platelets have practically none of either type. Platelet activity was assessed ex vivo by determining rates of ADP-induced aggregation and by applying a new in vitro technique giving a measure of primary hemostasis. Nicotine in doses of 2 mg/kg/day (rats) and 10 mg/kg/day (guinea pigs), continuously applied over 8 weeks, yielded alkaloid plasma levels in the respective species in the same range as found for smokers. This chronic in vivo pretreatment had no discernible effect on platelet function. However, platelets from rats having received the higher dose of 10 mg nicotine/kg/day for 8 weeks required a significantly higher concentration of ADP to induce the half-maximal rate of aggregation. Concomitantly, the in vitro determined bleeding time doubled. The nicotine-induced decrease in platelet sensitivity towards ADP could be prevented by simultaneously treating the rats with the beta-blocker propranolol. Adrenaline applied chronically to rats for 8 weeks stimulated platelet response instead of mimicking nicotine effects. The unexpected inhibition of rat platelet function at higher alkaloid-dosage thus seems to be an indirect nicotine action, mediated via platelet beta-adrenoceptors. Since chronic treatment with adrenaline did not exert such an effect, the action of nicotine may, rather, be attributed to increases in endogenous noradrenaline. These results could explain varying responses of human blood platelets in smokers.

Animals↗
PubMed1986

Increasing platelet aggregability after venepuncture is platelet, not plasma derived.

The time course of ADP induced aggregation of human platelets was determined in aliquots of stored platelet rich plasma 3.5, 10, 30 and 100 minutes after venepuncture. The maximal rate of aggregation was found to increase throughout this entire period, even though pH (7.4), CO2 (7 volume per cent) and temperature (35 degrees C) of the samples were kept constant. The mean acceleration (+/- SEM) between 3.5 and 100 minutes was 41.7 +/- 6.9 per cent (n = 67) at an ADP-concentration of 1 mumol/l and 18.3 +/- 6.2 per cent (n = 23) at 2 mumol/l ADP. The effect did not result from changes of any platelet regulatory factors putatively present alone in the plasma. Acceleration of aggregability was only found when the platelets themselves underwent storage, but not when freshly prepared plasma was given to prestored platelets. The change in aggregability was not diminished after inhibition of platelet cyclooxygenase by oral administration of acetylsalicylic acid.

Adenosine Diphosphate↗
PubMed1985

[Recent knowledge about the metabolic regulation of coronary circulation, with a contribution on adenine nucleotide metabolism of coronary endothelial cells].

The adenosine hypothesis in its original form neglects other myocardial tissues besides the predominant cardiomyocyte compartment. We could, however, demonstrate that the coronary endothelium comprises a metabolically very active adenosine and adenine nucleotide compartment of the heart, and functions as an impermeable metabolic barrier for interstitially or intravascularly accumulating adenosine if the vasoactive nucleoside is present at concentrations less than 10(-6) M. As a consequence, the vasodilatory action of intracoronarily applied adenosine cannot result from a direct action on the smooth muscle cells of the arterioles, but must be mediated by the endothelium. Since high molecular weight derivatives of adenosine, which are clearly confined to the coronary system, can also induce a very prompt coronary flow increase when applied intravascularly, smooth muscle relaxation must be triggered by an extracellular adenosine receptor at the luminal surface of the endothelium. According to preliminary pharmacological studies, this receptor belongs to the A2-type and thus stimulates the endothelial adenylate cyclase system. On the basis of our findings it is evident that with respect to the vasodilating effect of adenosine one has to distinguish between its action from the interstitial space directly via the putative receptor at the surface of the arteriolar smooth muscle cells, and its action from the intravascular space via the newly detected endothelial A2-receptor. It is a matter of further experimentation to determine to what extent both receptor populations actually participate in the metabolic regulation of coronary flow under physiological and pathophysiological conditions.

Adenine Nucleotides↗
PubMed1984

Acute effects of nicotine on hemodynamic and metabolic parameters of isolated, perfused hearts of guinea pigs and rats.

Nicotine infused in concentrations greater than 10(-6) M exerted a dose-dependent negative inotropic effect on isolated, perfused hearts of guinea pigs (Langendorff and working heart preparations). This effect became manifest after an initial positive inotropic and positive chronotropic response had subsided. Furthermore, the stimulation of cardiac contractility by norepinephrine (concentration less than 10(-7) M) was attenuated by nicotine in the guinea pig heart, but not in isolated, perfused hearts of Sprague-Dawley rats. Nicotine inhibited the positive inotropic effect of catecholamines according to the order norepinephrine greater than epinephrine greater than isoproterenol. In no case did nicotine have a marked negative chronotropic action. Changes in coronary flow, oxygen consumption, and the release of lactate and adenosine were in keeping with the state of myocardial activity in the presence of nicotine. The drug did not significantly alter myocardial uptake or release of norepinephrine during expression of its negative inotropic action. Prazosin, phentolamine, cocaine, and hexamethonium suppressed both the nicotine-induced transient stimulatory response and the negative inotropic effect in norepinephrine-stimulated hearts. In the presence of theophylline and at high perfusate calcium levels (7.5 mEqu/l) the negative inotropic effect was alleviated. The cardiodepressive action of nicotine may possibly evolve from a weak blockade of beta 1-adrenoceptors. Direct modifications of myocardial Ca2+-transport could not be observed.

Animals↗
PubMed1984

Compartmentation and hemodynamic effects of nicotine in isolated, perfused guinea pig hearts.

Tachyphylaxis with respect to the positive inotropic and positive chronotropic effects of nicotine in isolated perfused hearts of guinea pigs was found to persist for 3 and 10 min, respectively, after discontinuation of intracoronary infusion of nicotine (5 X 10(-5) M). The longer duration of chronotropic tachyphylaxis correlated with a slower release of nicotine from the tissue of the right atrium in comparison to the washout from the ventricular myocardium. A similar disparity in washout between atrial and ventricular tissue was found for inulin. Thus, greater perfusion of the ventricular tissue, not a difference in affinity for nicotine, seems to account for the more rapid recovery of the inotropic response to nicotine. The apparent volume of distribution of nicotine in both atrial and ventricular myocardium was about 2 ml/g wet weight; uptake and release of nicotine was rapid. Kinetic analyses of coronary venous washout yielded four components, indicating that nicotine is distributed in at least four (kinetically defined) compartments within the ventricular myocardium. Washout from the largest tissue compartment was controlled by the rate of perfusion of the vascular space, as demonstrated by comparison with washout of erythrocytes, inulin, sucrose, and urea from the heart. Hexamethonium reduced the nicotine content of this fast-emptying compartment from 85-57 nmol/g (prelabeling concentration of nicotine 5 X 10(-5) M), giving an upper estimate for the number of specific nicotine binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Studies on lithium transport across the red cell membrane. V. On the nature of the Na+-dependent Li+ countertransport system of mammalian erythrocytes.

Ouabain-resistant Na+-Li+ countertransport was studied on erythrocytes of man, sheep, rabbit, and beef. A transport system, exchanging Li+ for Na+ in a ratio of 1:1, was present in all four species. Li+ uptake by the exchange system increased 30-fold in the order man less than HK-sheep less than LK-sheep less than rabbit less than LK-beef. This order is identical to that of ouabain-resistant Na+-Na+ exchange in these species, but bears no relation to the Na+-K+ pump activity. The activity of the Na+-Li+ exchange system varied up to 7 and 16-fold among individual red cell specimens from man and beef, the variability being much smaller in sheep and rabbit erythrocytes. The affinities of the system for Li+ and Na+ were similar among the species and individuals (half saturation of the external site at about 1 mM Li+ and 50 mM Na+, respectively). 50-60% of Na+-Li+ exchange was blocked by N-ethylmaleimide in all species. p-Chloromercuribenzene sulfonate inhibited the exchange only in beef and sheep erythrocytes (60-80%). The two SH-reagents act by decreasing the maximum activity of the system, whilst leaving its affinity for Li+ unaltered. Phloretin was a potent inhibitor in all species. 1 mM each of furosemide, ethacrynic acid, and quinidine induced only a slight inhibition. The Na+-Li+ exchange of human and beef erythrocytes increased 3.5-fold upon elevation of the extracellular pH from 6 to 8.5, the pH-dependence arising from a change in affinity of the system for the cations and being similar to that reported for ouabain-resistant Na+-Na+ exchange in beef erythrocytes. It is concluded that a transport system exists in the red cell membranes of the four species which can mediate ouabain-resistant exchange of either Na+ for Na+, Na+ for Li+, or Li+ for Li+. The exchange system exhibits essentially identical transport characteristics in the four species, but shows a marked inter- and intra-species variability in maximum transport capacity and some differences in susceptibility towards inhibitors. A similar transport system is probably present also in other tissues. The exchange system seems to be distinct from the conventional Na+-K+ pump and shows no clear relation to one of the furosemide-sensitive, ouabain-resistant Na+ transport systems described in the literature.

4-Chloromercuribenzenesulfonate↗
PubMed1979

Studies on lithium transport across the red cell membrane. VI. Properties of a sulfhydryl group involved in ouabain-resistant Na+-Li+ (and Na+-Na+) exchange in human and bovine erythrocytes.

The reactivity of the SH-group essential for ouabain-resistant Na+-Li+ (and Na+-Na+) exchange and its location within the membrane are studied on human and beef erythrocytes and beef red cell ghosts. N-ethylmaleimide (NEM), 1,6-hexane dimaleimide, and iodoacetamide can induce an irreversible, partial inhibition of Na+-Li+ exchange in erythrocytes of the two species. The development of the inhibition due to the alkylating agents is greatly accelerated by external Na+ and Li+. The inhibition takes 3 min (NEM) and 60 min (iodoacetamide) to come to completion in isotonic Na+ media, but is hardly detectable in choline+, K+ or Mg2+ media. The transport site of the exchange system and the site promoting NEM binding exhibit similar affinities for external Na+. The impermeable, monofunctional glutathione derivative of 1,6-hexane dimaleimide does not inhibit Na+-Li+ exchange. The mercurials PCMBS, PCMB, and Hg2+ inhibit Na+-Li+ exchange in beef, but not in human erythrocytes. The inhibitory action of PCMBS, being slightly accelerated by external Na+, is fully reversed by penetrating thiols such as 2-mercaptoethanol, whilst glutathione, an impermeable thiol, is ineffective. Pretreatment with PCMBS affords partial protection from the irreversible inhibition caused by NEM. Oxidation with copper orthophenanthroline inhibits Na+-Li+ exchange only when performed in the presence of penetrating thiols such as 2-mercaptoethanol. It is concluded that the SH-reagents studied inhibit Na+-Li+ exchange by modifying an essential SH-group of a membrane protein in such a way that the turnover number of the exchange system is reduced. This SH-group is separated from both the red cell exterior and interior by a penetration barrier and seems to be distinct from the cation binding site. The action of external Na+ and Li+ in promoting the reaction of alkylating inhibitors is interpreted to result from a conformational change of the transport protein induced by the binding of external Na+ or Li+.

4-Chloromercuribenzenesulfonate↗
PubMed1979

Benefits of self-insured hospitalization programs.

As part of hospitals' continuing efforts to control costs, many have begun to consider implementing self-insured hospitalization programs for their employees. Not only can self-insurance provide cash flow savings and actual cost savings but it can also promote prevention among hospital employees.

Accounts Payable and Receivable↗
PubMed1978

Evidence for anionic cation transport of lithium, sodium and potassium across the human erythrocyte membrane induced by divalent anions.

1. The passive net transport of Li+ and Na+ across the human red cell membrane was accelerated by the divalent anions carbonate, sulphite, oxalate, phosphite and malonate. Phthalate, maleate, sulphate and succinate were found additionally to stimulate downhill transport of K+. Marked differences in anion efficacy and selectivity were observed. 2. The effects of these 'carbonate type' anions were reversible and fully blocked by SITS, dipyridamole and other inhibitors of anion transfer. 3. Cation transport acceleration induced by the monovalent anions salicylate, benzoate, thiocyanate and 2,4-dinitrophenol were inhibited by dipyridamole, but not affected by SITS. A great number of mono- and polyvalent anions were without detectable influence on Li+ transport. 4. Li+ net uptake induced by oxalate exhibited a pH dependence similar to that reported for halide self exchange. 5. Transport acceleration by carbonate type anions displayed a linear, 1:1 dependence on the concentrations of both the anion and the cation and was symmetric with respect to the two sides of the membrane. 6. It is concluded that the divalent carbonate type anions form singly charged, negative 1:1 ion pairs with the respective alkali metal cations, the ion pairs traversing the red cell membrane via the anion exchange pathway. This concept of anionic formation of some of the ion pairs considered. The relative efficacies and cation selectivities of polyvalent anions can largely be explained on the basis of electrostatic interactions governing ion pair formation. However, the chelating properties, structural flexibility, polarizability of the anions and the accessibility of the ion pairs to the anion exchange pathway need also be considered. 7. An exchange of NaCO-3 ion pairs for internal HCO-3 or Cl- is discussed as a possible mode of cellular pH regulation.

Anions↗
PubMed1977

Studies on the lithium transport across the red cell membrane. III. Factors contributing to the intraindividual variability of the in vitro Li+ distribution across the human red cell membrane.

1. Extracellular potassium bicarbonate, ouabain, dipyridamole and the Na+ distribution between red cells and plasma influence Li+ transport across the human red cell membrane. The significance of these parameters for the intraindividual variability of the steady-state ratio of external to internal Li+ was studied in vitro. 2. Elevation of external K+ in the physiological concentration range increases the steady-state distribution ratio Lie+/Lii+ indirectly by increasing the ratio Nae+/Nai+ through activation of the Na+-K+ pump, and directly by inhibiting ouabain-sensitive Li+ uptake. 3. A rise in bicarbonate concentration decreases the Li+ ratio directly by accelerating Li+ uptake through a leak, and indirectly by increasing the Na+ leak, thus reducing the Na+ ratio. 4. Dipyridamole blocks both bicarbonate effects. 5. Ouabain decreases the Na+ ratio and inhibits Li+ uptake by the Na+-K+ pump, thereby exerting two opposite effects on the Li+ distribution ratio. 6. The results confirm the previous observation that the steady-state Li+ distribution depends strongly on the Na+ distribution ratio, i-e., the driving force for Na+-dependent Li+ uphill countertransport. It is concluded that the Na+ distribution between red cells and plasma and the concentrations of K+ and bicarbonate in plasma need to be considered as factors influencing the in vivo Li+ distribution. However, the considerable interindividual differences of Li+ distribution cannot be ascribed to variations in these parameters.

Bicarbonates↗