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Biomedical subjects

J Linden

Publications and source records attributed to J Linden.

At least 145 records · Page 8Linked to original sources
PubMed1986

Effect of atrial contraction frequency on atrial natriuretic peptide secretion.

Paroxysms of atrial tachycardia are oftentimes associated with polyuria. The plasma levels of the potent diuretic hormone, atrial natriuretic peptide (ANP), are elevated during episodes of atrial tachycardia, suggesting that ANP may play a role in mediating the diuresis. The mechanism of enhanced ANP secretion associated with atrial tachycardia is not known. We examined the effect of altering the pacing frequency of isolated left rat atria on ANP secretion. Atria were suspended between an electrode and hook connected to a force transducer and superfused with medium 199. The ANP content of the superfusate was measured by radioimmunoassay. Increasing the frequency of pacing from 2 to 4 Hz resulted in a 46 +/- 5% (means +/- SE, n = 9) rise in immunoreactive ANP secretion above base line (P less than 0.01). Lowering the frequency from 4 to 2 Hz lowered immunoreactive ANP secretion by 36 +/- 3% (n = 6) relative to base line (P less than 0.02). Incremental increases in the pacing frequency from 2 to 8 Hz resulted in a continual rise in immunoreactive ANP with a peak increase of 191 +/- 6% of base line (n = 8) at 8 Hz. To examine the possibility that release of norepinephrine or acetylcholine from endogenous nerves mediated this effect, the atria were superfused with the combination of 0.1 microM propranolol, 1.0 microM phentolamine, and 10 microM atropine. The concentrations of the antagonists were 125-fold or higher than the dissociation constant for binding to receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Modulation of guanylate cyclase by lipoxygenase inhibitors.

Drugs that inhibit endothelium-dependent relaxation were tested to determine their effect on soluble guanylate cyclase purified from dog aorta. Basal, arachidonic acid (10(-5) M)-stimulated, and nitroprusside (5 X 10(-5) M)-stimulated guanylate cyclase activities were inhibited by methylene blue and the lipoxygenase inhibitors nordihydroguaiaretic acid and eicosatetraynoic acid. The effective inhibitory doses were in the range of those that have been reported to inhibit endothelium-dependent relaxation. Other compounds known to inhibit endothelium-dependent relaxation had little or no effect on guanylate cyclase activity. Basal guanylate cyclase activity was more resistant to inhibition than were activated states of the enzyme. The data suggest that reported inhibition of endothelium-dependent relaxation by some lipoxygenase inhibitors may be the result, at least in part, of their direct effect on guanylate cyclase activity.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1986

The influence of resting tension on immunoreactive atrial natriuretic peptide secretion by rat atria superfused in vitro.

Atrial natriuretic peptide is a potent diuretic hormone secreted by the atria in response to volume expansion. We examined the effect of resting tension on atrial natriuretic peptide secretion by rat atria superfused in vitro. Left atria were hooked between an electrode and force transducer and superfused with medium 199. The atria were studied at a pacing frequency of 0 or 3 Hz. Atrial natriuretic peptide content of the superfusate was measured by radioimmunoassay. In nonpaced and paced atria, increasing resting tension three- to five-fold caused immunoreactive atrial natriuretic peptide secretion to increase by 35 +/- 5% (mean +/- SEM, n = 6, p less than 0.01) and 30 +/- 3% (n = 4, p less than 0.01), respectively. Lowering resting tension by 50% in nonpaced and paced atria lowered immunoreactive atrial natriuretic peptide secretion by 30 +/- 3% (n = 7, p less than 0.01) and 24 +/- 3% (n = 6, p less than 0.01), respectively. To exclude the possibility that release of norepinephrine or acetylcholine from endogenous nerve endings was mediating this effect, the atria were superfused with the combination of propranolol 0.1 microM, phentolamine 1.0 microM, and atropine 10 microM. These concentrations of the antagonists were 125-fold or higher than their Kd for binding to their respective receptors. The antagonists did not block the rise in immunoreactive atrial natriuretic peptide secretion; neither did they inhibit an established rise in immunoreactive atrial natriuretic peptide secretion induced by increasing the resting tension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Activity level and behavioral style in young children.

A portable microcomputer activity recorder was used to measure a 24-hour sample of activity level in 4-to 8-year-old children. Recorded activity level was not related to parental perception of activity level and did not differentiate children with differing behavioral styles. Parental perception of activity level, on the other hand, significantly differentiated children's behavioral style. Parents may be responding to a composite image of the child's behavioral style when they rate activity level. We urge caution in the use of the term 'activity level', which may have different meanings according to how it is measured.

Child↗
PubMed1985

[125I]Aminobenzyladenosine, a new radioligand with improved specific binding to adenosine receptors in heart.

The density of adenosine receptors in membranes derived from rat hearts in 25 times lower than the density of receptors in rat brain membranes. Consequently, adenosine radioligands which are useful in brain such as l-[3H]phenylisopropyladenosine, [3H]cyclohexyladenosine, [3H]-2-chloroadenosine and l-[125I]hydroxyphenylisopropyladenosine are of limited usefulness in heart, due to a high ratio of nonspecific to specific binding. We have synthesized a new radioligand, [125I]-N6-4-aminobenzyladenosine, which binds to rat heart membranes with one-sixth the nonspecific binding of the other radioligands. [125I]-N6-4-aminobenzyladenosine bound to rat ventricle membranes with a KD equivalent to that of l-[125I]hydroxyphenylisopropyladenosine and a Bmax of 15.2 fmol/mg protein. [125I]-N6-4-aminobenzyladenosine bound with a higher affinity to brain (KD = 1.93 nM) than to heart membranes (KD = 11.6 nM). At the radioligand KD, 60% of the total [125I]-N6-4-aminobenzyladenosine bound to heart membranes was specifically bound. Iodination of aminobenzyladenosine increased its affinity for the adenosine receptor by 22-fold, possibly due to a steric or hydrophobic effect of iodine. The new ligand was found to be a full adenosine agonist based on its ability to inhibit cyclic adenosinemonophosphate accumulation in isolated embryonic chick heart cells and rat adipocytes. [125I]-N6-4-Aminobenzyladenosine bound to a single affinity site and was displaced from cardiac and brain adenosine receptors by other adenosine analogues with a potency order of l-phenylisopropyladenosine greater than 5'-N-ethylcarboxamide adenosine. These characteristics suggest that the radioligand binds to an Ri adenosine receptor.

Adenosine↗
PubMed1985

The mechanism by which adenosine and cholinergic agents reduce contractility in rat myocardium. Correlation with cyclic adenosine monophosphate and receptor densities.

The adenosine analogue phenylisopropyladenosine decreased the basal and isoproterenol-stimulated contractile state of isolated rat left atria. The ED50 levels for both responses were similar, suggesting that direct and antiadrenergic effects may be mediated by the same receptor. Phenylisopropyladenosine decreased the cyclic adenosine monophosphate content of isolated atria and inhibited isoproterenol-stimulated adenylate cyclase activity in membranes prepared from atria and ventricles, but not as much as did methacholine. A maximally effective concentration of phenylisopropyladenosine or methacholine greatly reduced atrial contractility measured in the presence of either isoproterenol (1 microM) or Ro7-2956 (a phosphodiesterase inhibitor, 1 mM); however, in the presence of isoproterenol plus Ro7-2956, the contractile effects of phenylisopropyladenosine and methacholine were greatly attenuated. From the contractile data and cyclic adenosine monophosphate analyses, we conclude that direct and antiadrenergic contractile effects of both phenylisopropyladenosine and methacholine result primarily from their effects on cyclic adenosine monophosphate metabolism. The densities of adenosine, muscarinic, and beta-adrenergic receptors in rat atrial membranes were found to be 30, 551, and 24 fmol/mg protein, respectively, based on equilibrium-binding assays conducted with 125I-aminobenzyl-adenosine, [3H]quinuclidinyl benzilate, and 125I-labeled pindolol. The greater effectiveness of methacholine than phenylisopropyladenosine as a negative inotropic agent and an inhibitor of adenylate cyclase in atria may be related to the relative densities of muscarinic and adenosine receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1985

The relation between neonatal and later activity and temperament.

Evidence from several longitudinal studies suggests that individual activity characteristics tend to persist over time and to influence the development of temperamental style. The activity of 50 children whose motility had been monitored by an electronic activity monitor when they were neonates was again monitored by an ambulatory microcomputer when they were 4-8 years old. Additionally, the parents of these children filled out the Behavioral Style Questionnaire by McDevitt and Carey. The results showed that the level of the children's day and night activity was unrelated. The vigor of neonatal movements was later positively related to high daytime activity. Also, the least vigorous infants tended to become the most inactive children during the day. The results further showed that the most active neonates became children who, as perceived by their parents, tended to approach rather than withdraw from new experiences.

Affect↗
PubMed1984

Rapid agonist-induced decrease of 125I-pindolol binding to beta-adrenergic receptors. Relationship to desensitization of cyclic AMP accumulation in intact heart cells.

Cyclic AMP accumulation in embryonic chick heart cells and binding of the beta-adrenergic antagonist 125I-pindolol to intact cells has been examined during the first 30 min of (-)-isoproterenol-induced desensitization. Myocardial beta-adrenergic receptors exist in two states which bind agonists with high (KD congruent to 10 nM) and low (KD congruent to 10 microM) affinities. Both activation and desensitization of cyclic AMP accumulation were mediated by (-)-isoproterenol binding to high affinity receptors. (-)-Isoproterenol-induced desensitization of cyclic AMP accumulation occurred with a t1/2 of 3.8 min. Desensitization was accompanied by a decrease in the number of 125I-pindolol binding sites assessed by equilibrium radioligand binding assays conducted at 4 degrees C or short (80 s) binding assays conducted at 37 degrees C. There was an excellent temporal correlation between loss of binding and loss of (-)-isoproterenol-stimulated cyclic AMP accumulation. After (-)-isoproterenol-induced desensitization, most of the remaining receptors assayed at 4 degrees C bound (-)-isoproterenol with high affinity. A rapid (-)-isoproterenol-induced decrease in the number of 125I-pindolol binding sites also occurred in adult canine heart cells and rat adipocytes. The data suggest that agonists do not cause uncoupling of surface receptors. Receptors may be uncoupled as a consequence of rapid sequestration into a hydrophobic compartment.

Animals↗
PubMed1984

Purification and characterization of (-)[125I]hydroxyphenylisopropyladenosine, an adenosine R-site agonist radioligand and theoretical analysis of mixed stereoisomer radioligand binding.

(-)-N6-(R-4-Hydroxyphenylisopropyl)adenosine (HPIA) was iodinated with NaI and trace 125I. Mono- and diiodinated reaction products and the starting material were separated by high pressure liquid chromatography and the structures of the reaction products were verified by NMR. (-)-N6-(R-Phenylisopropyl)adenosine (PIA), IHPIA, and I2HPIA decreased rat atrial contractility with ED50 values of 24, 28, and 33 nM, respectively. The contractile effects of these compounds were competitively blocked by theophylline (KI = 7.9 microM), but were not affected by adenosine deaminase. IHPIA also inhibited (-)isoproterenol-stimulated cyclic AMP accumulation in adipocytes with an ED50 (10 nM) and to an extent (83%) nearly identical to PIA. [125I]HPIA prepared using carrier-free 125I bound to adenosine receptors on membranes from rat cerebral cortex, adipocyte ghosts, and heart ventricles. Binding was inhibited stereospecifically by PIA and by other adenosine analogues and alkylxanthines. The KD of [125I]HPIA determined kinetically using brain membranes at 21 degrees was 0.94 nM (K1 = 2.55 X 10(7) M-1 min-1; K-1 = 0.024 min-1) in good agreement with the equilibrium determination of 1.94 nM. The density of adenosine receptors in brain membranes was found to be 871 fmol/mg of protein. When normalized to protein, the density of receptors in heart membranes and adipocyte ghosts, respectively, was found to be 39- and 2.3-fold less than in brain membranes. We conclude that [125I]HPIA can be rapidly synthesized and purified, binds to adenosine R-sites and is an agonist radioligand resistant to adenosine deaminase. Computer modeling of the equilibrium binding resulting from the use of mixed stereoisomers of a radioligand indicates that the combined use of (-)[125I]HPIA and (+)[125I]HPIA would result in the generation of nonlinear Scatchard plots.

Adenosine↗
PubMed1982

Evidence for persistent activation of cardiac slow channels in low-calcium solutions.

Action potentials were recorded from frog ventricular strips superfused with calcium-free solutions. Very long action potentials (3-60 s) were induced by chelating residual calcium with 1-5 mM ethyleneglycol-bis(beta-aminoethylether)-N,N'-tetraacetic acid (EGTA). The kinetics of changes in action potential duration suggest that calcium influences action potential duration at an intracellular site. In low-calcium solutions isoproterenol was found to lengthen action potentials. The lengthening effect of isoproterenol became progressively greater as [Ca2+] was reduced by elevating [EGTA]. In the presence of 2 mM EGTA, 0.1 microM isoproterenol increased action potential duration from 4.3 +/- 0.4 to 43 +/- 14 s. Verapamil produced a greater than 90% reduction in the duration of very long action potentials (60 s) induced by EGTA, isoproterenol, or both. After rapid or prolonged depolarizations in low-calcium solutions the last 10-30 mV of repolarization took 10-15 s. We speculate that this slow phase of repolarization may be a manifestation of persistent slow channel activation. The data suggest that in low-calcium solutions slow channels can remain activated for many seconds.

Action Potentials↗
PubMed1982

Sensitivity of Ca-dependent slow action potentials to methacholine is induced by phosphodiesterase inhibitors in embryonic chick ventricles.

Choline esters fail to depress developed tension or the maximum upstroke velocity (Vmax) of slow action potentials in embryonic chick ventricles, but they inhibit the stimulatory effect of the phosphodiesterase inhibitor methylisobutylxanthine (MIX). The mechanism by which the choline ester methacholine (MCh) counteracts the effects of MIX was examined in ventricular myocardium obtained from 7-day-old embryonic chicks. Four possible hypotheses were 1) that the physiological response to MCh is mediated by cyclic GMP, the production of which is potentiated by MIX; 2) that MCh acts by a mechanism independent of cyclic nucleotides; 3) that the binding of MIX to adenosine receptors induces sensitivity to MCh; or 4) that MCh acts by depressing basal cyclic AMP levels. Interactions between MCh, Angiotensin II and a nonmethylxanthine phosphodiesterase inhibitor (Ro 7-2956) were assessed by measuring tissue levels of cyclic nucleotides and the Vmax of slow action potentials. MCh significantly reduced the basal cyclic AMP level of embryonic chick ventricles, despite having no physiological effect. The results favor the final hypothesis and imply that MCh effects are mediated by inhibition of adenylate cyclase activity. The physiological response of the myocardium to a reduction in basal adenylate cyclase activity appears to be dependent on the initial tissue level of cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Calculating the dissociation constant of an unlabeled compound from the concentration required to displace radiolabel binding by 50%.

In order to determine the binding dissociation constant (KI) of a nonradiolabeled compound, the method of Cheng and Prusoff (1973) (Biochem. Pharmacol. 22, 3099-3108) has been widely employed. The technique involves monitoring the competitive displacement from receptors of a radiolabeled compound with a known dissociation constant, KD, by a nonradiolabeled compound. The concentration of nonradiolabeled compound which displaces 50% of the radiolabel, the IC50, is used to estimate its KI with correction for competition with the radiolabel. The error of this method is small as long as the concentration of receptor is much less than KD and KI, constraints which are sometimes difficult to meet. In this report formulae are derived from which KI can be calculated from IC50 with no constraints on the receptor concentration.

Kinetics↗