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At least 19 recordsLinked to original sources

PubMed1976

Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (IV). Influence of functional antagonism by spasmogens.

A new theory is presented to describe the effect of functional antagonism on the competitive antagonism between adrenergic beta-mimetics and beta-blockers. According to this theory the shape of the log (dose ratio-1) vs.--log [B] curve and the apparent pA2 value in competitive antagonism should be affected by functional antagonism when the agonist is taken up by the saturable uptake process, and this was experimentally confirmed. The competitive antagonism between isoproterenol (ISO) and propranolol (Prop) was influenced by the functional antagonism between ISO and spasmogens (histamine and carbachol). The log (dose ratio-1) vs. --log [B] curve is ISO-Prop competitive antagonism was shifted variously depending on the concentration of a spasmogen used. Theoretical predictions and experimental results were in good parallel.

Adrenergic beta-Agonists↗

PubMed1976

Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (III). Functional antagonism between beta-mimetics and spasmogens.

New equations which can explain the following characteristic phenomena in the functional antagonism between isoproterenol (ISO) and spasmogens in guinea-pig trachea are proposed: (1) The amplitude of relaxation of the muscle induced by ISO varied depending on the concentration of a spasmogen used (histamine or carbachol). (2) The dose-response curves for the relaxation by ISO shifted to the right in a parallel manner as the concentration of the spasmogen increased, and became stationary at high concentrations of the spasmogen. (3) The slope of the dose-response curve became steeper with increasing concentrations of the spasmogen. When the saturable uptake process of ISO was taken into consideration, a satisfactory parallel was seen between the theoretical dose-response curves and the present experimental results.

Adrenergic beta-Agonists↗

PubMed1978

2,6-Methano-3-benzazocine-11-ropanols. Lack of antagonism between optical antipodes and observation of potent narcotic antagonism by two n-methyl derivatives.

Resolution of a 2,6-methano-3-benzazocine-11-propanol analogue of buprenorphine showed that the biological activity resides in the levo antipode. An attempt to enhance agonist activity by preparation of N-methyl derivatives resulted in two compounds three and five times as potent as nalorphine as antagonists of phenazocine. These compounds are the most potent N-methyl narcotic antagonists reported to date.

Animals↗

PubMed1979

The use of Reuber hepatoma cells for the study of a lipopolysaccharide-induced macrophage factor: glucocorticoid-antagonizing factor.

Endotoxin-stimulated glucocorticoid-antagonizing factor (GAF) was assayed by its specific inhibition of hydrocortisone-induced synthesis of phosphoenolpyruvate carboxykinase. Defined induction of phosphoenolpyruvate carboxykinase synthesis in hydrocortisone-treated rat hepatoma cells permitted reliable quantitation of GAF and analysis of the mechanism of cortisol antagonism. GAF was present maximally in serum 2 hours after endotoxin challenge in mice; however, GAF production could be suppressed by pretreating mice with indomethacin or cortisol. Endotoxin-tolerant mice were also nonresponsive to endotoxin-stimulated GAF production. Gel filtration on Sephadex G-200 resolved four regions of glucocorticoid-antagonizing activity in serum from endotoxin-poisoned mice, two of which were not present in normal serum. Cortisol antagonism by GAF resembled that of insulin; however, insulin differed from GAF in its ability to antagonize dibutyryl cyclic AMP. Unlike insulin, endotoxin-induced serum glucocorticoid-antagonizing activity was heat-labile at 70 degrees C. GAF antagonism of hydrocortisone was partially reversible but did not act in a competitive manner. Production of hepatoma growth inhibitory activity and glucocorticoid-antagonizing activity in serum were closely associated, indicating a common methanism for their generation.

Animals↗

PubMedDate not supplied

Antagonism of pancuronium and its metabolites by neostigmine in cats.

Antagonism by neostigmine of neuromuscular blockade produced by pancuronium or its metabolites was studied in the cat anterior or tibialis muscle-peroneal nerve preparation using constant infusions of muscle relaxants. The ED50 of neostigmine (dose which caused a 50% antagonism) was 16, 11, 29, and 26 micrograms/kg for pancuronium, 3-hydroxypancuronium, 17-hydroxypancuronium, and 3, 17-hydroxypancuronium, respectively. Times of onset of neostigmine action were shorter when antagonizing 17-hydroxypancuronium neuromuscular blockade. Duration of neostigmine action when antagonizing 17- or 3, 17-hydroxypancuronium blockade was shorter than with pancuronium or 3-hydroxypancuronium. We conclude that more neostigmine is required to antagonize 17- or 3,17-hydroxypancuronium neuromuscular blockade than is required to antagonize pancuronium. Conversely, less neostigmine was required to antagonize 3-hydroxypancuronium blockade.

Animals↗

PubMed1975

Antagonism of the antibacterial action of some penicillins by other penicillins and cephalosporins.

There are many examples of two penicillins acting synergistically, usually by one competitively inhibiting beta-lactamase, thus protecting the other from inactivation. There are few reports on penicillins antagonizing each other. Eight strains of three genera (Proteus, Escherichia, Pseudomonas) isolated at Boston City Hospital or Institut Pasteur, Paris, showed antagonism of carbenicillin or ampicillin by cephaloridine, cloxacillin, or 6-aminopenicillanic acid. Broth dilution tests showed that with seven of the eight strains the minimum inhibiting concentration (MIC) of the more active antibiotic was increased by 800-6,400% by low concentrations (often one-tenth the MIC) of the antagonist, whereas higher concentrations of "antagonist" were not as antagonistic, This suggested that two or more receptor sites of action for penicillins were present; the antagonist thus blocks the antibacterial action at the more sensitive site but acts additively with the antagonized antibiotic at the less sensitive site. The possibility that the mechanism of antagonism was induction of inactivating enzymes (beta-lactamase, penicillin acylase) was studied in two strains(one Escherichia coli and one Proteus rettgeri), and two antagonists were studied in detail. With E. coli cephaloridine was a poorer inducer of beta-lactamase than were the antagonized antibiotic and 6-aminopenicillanic acid. From these organisms, the good inducers of a beta-lactamase that acted on benzylpenicillin did not induce enzymes that inactivated carbenicillin. Thus, the mechanism of antagonism was not due to beta-lactamase induction.

Ampicillin↗

PubMed1976

Studies on the mode of antagonism between adrenergic beta-mimetics and beta-blocking agents (II). Analysis by the uptake saturation model.

Curves of experimentally plotted log (dose ratio-1) vs.-log [B] for the antagonism between adrenergic beta-mimetics, isoproterenol (ISO) and trimetoquinol (TMQ), and various beta-antagonists in relaxation of guinea-pig trachea could not be reasonably fitted to Schild's equation which has been commonly used in the analysis of drug-antagonism. Taking into consideration the saturable uptake process of the drug used herein, the equation presented in this paper fitted fairly well to the experimental curves and explains the following results: 1, TMQ was more strongly antagonized than ISO by all the blocking agents tested, that is, the apparent modes of antagonism were different between ISO and TMQ although they are considered to interact with the same receptor site. 2, The slope of the curve for a given antagonist markedly differed between ISO and TMQ. It is hypothesized that ISO is more easily taken up than TMQ. This was experimentally confirmed: i.e., ISO was potentiated about 8 fold by inhibiting the uptake process with dibenamine while TMQ was not. By pretreatment with dibenamine, the log (dose ratio-1) vs.-log [B] curve for the ISO-propranolol antagonism was shifted upward and superimposed with the theoretical curve of antagonism in which uptake of the agonist was neglected.

Adrenergic beta-Agonists↗

PubMed2026

Implications of proteome allocation constraints for understanding interbacterial antagonism.

Bacteria live in dense communities where competition influences the composition and, therefore, the function of these communities. Beyond competing for resources, bacteria engage in antagonism by deploying a range of molecular weapon systems to inhibit and kill other bacteria. Investing in antagonism is expected to incur a fitness trade-off, but the nature of this trade-off at the level of molecular physiology remains underexplained. Applying recent advances about the physiological constraints faced by bacterial cells may help us better understand existing studies and design new investigations into interbacterial antagonism. Bacterial cells face two important constraints: a finite amount of protein and a maximum translation speed for ribosomes. As a result, the only way for a cell to grow faster is to allocate more of its finite proteome to synthesizing ribosomes. A cell choosing to attack competitors must therefore allocate some of its limited proteome budget to antagonistic proteins instead of other functions. Conversely, being attacked and resisting the effects of such attacks also require an investment of proteomic resources. The extent to which proteome allocation constraints influence bacterial physiology is not fully understood; consequently, how these constraints influence interbacterial antagonism has not been investigated. Here, I will discuss how proteome allocation constraints can re-contextualize our existing understanding of the costs of both deploying and resisting attacks and how investigation of these constraints may further our understanding of interbacterial antagonism.

Proteome↗

PubMed1976

The antagonism of nicotine-induced cardiovascular responses by DMAE and DEO analogs.

A series of quaternary ammonium compounds cinsisting of 4, 4'-bis-[N-(2, 2-diethoxyethyl)-N, N-dimethylammonioacetyl]-biphenyl dibromide (DMAE) and 4, 4'-bis-[N, N-di(2-ethoxyethyl)-N-methylammonioacetyl]-biphenyl dibromide (DEO) analogs was investigated for selective nicotine antagonism. Each series of compounds contained the monophenyl (MPh.DMAE, MPh.DEO); biphenyl (DMAE, DEO); terphenyl (TPh,DMAE, TPh.DEO); half-molecule (1/2DMAE, 1/2DEO); p-phenyl half-molecule (p-Ph.-1/2DMAE, p-Ph.-1/2DEO) and biphenyl half-molecule (p-BPh.-1/2DMAE, p-BPh.-1/2DEO) analogs. Studies were conducted on isolated spontaneously beating guinea pig atria and anesthetized dogs. Relative potencies of the DMAE and DEO series to antagonize the nicotine (20 mug/ml) induced positive chronotropic effect of the guinea pig atria were determined as follows: DMAE (1.0); TPh.DMAE (0.82); P-Ph.1/2DMAE (0.59); DEO (0.54); MPh.DMAE (0.27); TPh.DEO (0.26); MPh.DEO (0.18); p-Ph.-1/2DEO (0.16); 1/2DMAE (0.03); 1/2DEO (0.02); p-BPh.-1/2DMAE (less than 0.01); p-BPh.-1/2DEO (less than 0.01) and C-6 (0.85). The I50 to antagonize nicotine induced responses by DMAE was 0.13 muM (0.10 mu/ml). Several of the above analogs were studied in the dog and their ability to antagonize nicotine (100 mug/kg) induced positive chronotropic effects were compared with their ability to inhibit transmission through the stellate or the superior cervical ganglia. The I50 doses of the drugs antagonizing nicotine, impairing superior cervical ganglionic transmission and the corresponding fold shifts in the dose--response curves follow: DMAE (120 mug/kg, 3.0 mg/kg, 25); TPh.DMAE (40 mug/kg, 1.10 mg/kg, 30), DEO (45 mug/kg, 1.30 mg/kg, 25) and C-6 (140 mug/kg, 0.42 mg/kg, 0.42 mg/kg, 3.0). These findings are suggestive of the hypothesis that receptors normally activated by endogenously released ACh in the stellate or superior cervical ganglia of the dog may be dissociated from those receptors activated by nicotine which results in an increase in blood pressure or heart rate. Clinical implications are that TPh.DMAE as well as other DMAE analogs may pose less of a problem with hypotension than hexamethonium as a nicotine antagonist.

Animals↗

PubMed1975

The effect of acid-base balance on neostigmine antagonism of d-tubocurarine-induced neuromuscular blockade.

d-Tubocurarine (dTc) was infused intravenously into 35 cats anesthetized with chloralose and urethane at a constant continuous rate to produce and maintain 90 per cent depression of twitch height of the anterior tibial muscle following supramaximal stimulation of the peroneal nerve. The mean infusion rates that produced 90 per cent depression were not significantly altered by respiratory acid-base changes. Metabolic alkalosis decreased (32.5 per cent) and metabolic acidosis increased (27.7 per cent) the required infusion rate of dTc. When pH and Paco2 were maintained at 7.37 and 38 torr, respectively, the addition of a bolus of neostigmine, 10.5 mug/kg, intravenously, to the continuing infusion of dTc produced 50 per cent antagonism of the dTc-depressed twitch. Respiratory alkalosis and metabolic acidosis did not alter the dose of neostigmine needed to produce 50 per cent antagonism. However, during respiratory acidosis (pH 7.13, Paco2 66 torr) and metabolic alkalosis (pH 7.59, Paco2 36 torr) 20.0 and 18.0 mug/kg neostigmine, respectively, were needed to produce 50 per cent antagonism. Still larger doses of neostigmine (75 mug/kg) could not completely antagonize the block unless pH and Paco2 were returned to 7.30-7.50 and 35-45 torr, respectively. It is concluded that respiratory acidosis and metabolic alkalosis limit and oppose antagonism of dTc by neostigmine.

Acid-Base Equilibrium↗

PubMedDate not supplied

Neostigmine and 4-aminopyridine antagonism of lincomycin-pancuronium neuromuscular blockade in man.

Seven anesthetized patients were studied to determine the interaction between pancuronium and lincomycin and the ability of neostigmine and 4-aminopyridine to antagonize the block. Lincomycin 600 mg given IV alone did not decrease twitch tension. An 8 to 10% decrease in twitch tension occurred when lincomycin was given after neostigmine antagonism of pancuronium. Lincomycin augmented a partial pancuronium neuromuscular blockade. The combined lincomycin-pancuronium neuromuscular blockade was effectively antagonized by both neostigmine and 4-aminopyridine although the latter produced a slower rate of antagonism. The authros conclude that lincomycin, 600 mg IV, augments a pancuronium neurovascular blockade. 4-Aminopyridine offers no advantage over neostigmine and, in fact, may offer a disadvantage because of a slower rate of antagonism.

Adolescent↗

PubMed1979

Differential antagonism of antiavoidance, cataleptic and ptotic effects of neuroleptics by biperiden.

The interaction between neuroleptics and an anticholinergic, biperiden, in the antiavoidance, catalepsy and ptosis tests was investigated in mice for the purpose of predicting the extrapyramidal side-effects of neuroleptics. The cataleptic effect of most neuroleptics used was antagonized to some extent by biperiden, while the ptotic effect was hardly influenced. The antiavoidance effect of haloperidol, trifluperidol and perphenazine was markedly antagonized and that of chlorpromazine moderately. However, the effect of thioridazine, chlorprothixene, levomepromazine and clozapine was little antagonized. In neuropharmacological tests, haloperidol, trifluperidol and perphenazine exhibited a selective antidopaminergic activity, while chlorprothixene, levomepromazine and clozapine showed antidopaminergic, antiadrenergic and also anticholinergic activities when similar doses were given. These results indicate that biperiden antagonism may be marked in the tests related to the extrapyramidal symptoms and in drugs liable to induce extrapyramidal side effects, however, there would be little or no antagonism in drugs possessing the anticholinergic property and eliciting few extrapyramidal side-effects.

Animals↗

PubMed1978

Deoxyadenosine antagonism of the antiviral activity of 9-beta-D-arabinofuranosyladenine and 9-beta-D-arabinofuranosylhypoxanthine.

Deoxyadenosine but not adenosine reversed the antiviral activity of 9-beta-D-arabinofuranosyladenine (ara-A) and 9-beta-D-arabinofuranosylhypoxanthine (ara-H) when used in the presence of coformycin, an inhibitor of adenosine deaminase. In suspension cultures of KB cells, 10 muM ara-A inhibited the replication of herpes simplex virus type 1 by 80%. Concomitant addition of 50 muM deoxyadenosine reduced the antiviral activity of 10 muM ara-A to only 40% inhibition. Adenosine failed to antagonize the antiviral activity. In monolayer cultures of KB cells, the 50% inhibitory concentration of ara-A was increased from 1.5 to 2.9 muM by 2 muM deoxyadenosine and to 8.5 muM by 10 muM deoxyadenosine. Analysis of the dose-response data by a double reciprocal plot method indicated that the antagonism was competitive. The antiviral activity of ara-H also was antagonized by deoxyadenosine. The 50% inhibitory concentration of ara-H was increased from 42 muM to 70, 91, or 121 muM by the concurrent addition of 5, 10, or 20 muM deoxyadenosine. Competitive antagonism could not be demonstrated. In the absence of the adenosine deaminase inhibitor, neither ara-A nor ara-H was antagonized by deoxyadenosine. Since such inhibitors were not available unitl recently, previous investigators were unable to observe the antagonistic capacity of deoxyadenosine.

Adenosine↗

PubMedDate not supplied

Train-of-four fade and edrophonium antagonism of neuromuscular block by succinylcholine in man.

Thumb twitch in response to train-of-four stimulation (2 Hz for 2 sec) of the ulnar nerve was measured in 36 patients anesthetized with halothane and N2O and paralyzed with succinylcholine chloride (SCC). Train-of-four fade was detected whenever a block was produced. The train-of-four ratio decreased with continued exposure to SCC. Edrophonium effect was predictable by the train-of-four ratio in a semiquantitative manner, a high ratio predicting block enhancement and a low ratio, antagonism. When calculated at 30 to 50 percent recovery (from complete block), a train-of-four ratio of 0.4 or less reliably predicts antagonism. The magnitude of antagonism is also predictable in a semiquantitative manner, although complete antagonism cannot be ascertained. The lower the ratio, the more effective the antagonism becomes. Train-of-four fade, therefore, appears to be a consistent and sensitive quantitative sign of phase II neuromuscular block by SCC in man.

Adult↗

PubMed1978

Antagonism of morphine action on brain acetylcholine release by methylxanthines and calcium.

The inhibitory effect of morphine on the release of acetylcholine (ACh) from the rat cerebral cortex was antagonized by theophylline, caffeine and 3-isobutyl-1-methylxanthine (IBMX). Theophylline antagonism of morphine action was dose related and this agent failed to influence a comparable action of chlorpromazine on the release of ACh. Intraventricular injection of calcium also antagonized the anti-release effect of morphine. Neither methylxanthines nor calcium modified the spontaneous release of ACh in the absence of morphine. It is suggested that methylxanthine antagonism of morphine action is selective and that it could be related to the ability of methylxanthines to mobilize bound calcium.

Acetylcholine↗

PubMed1978

Antagonism by mianserin and classical alpha-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine.

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

Adrenergic alpha-Antagonists↗

PubMed1976

Antagonism of the prostaglandin endoperoxide imhibition of hormone-stimulated adenylate cyclase by guanosine triphosphate and 5'-guanylyl-imidodiphosphate.

The prostaglandin endoperoxide prostaglandin H2 (15-hydroxy-9alpha, 11alpha-peroxidoprosta-5,13-dienoic acid) inhibits basal and hormone-stimulated adenylate cyclase in fat cell ghosts. This inhibition by prostaglandin H2 has been found to be antagonized by GTP and Gpp(NH)p. Dose response studies have shown GTP and Gpp(nh)p to be maximally effective at 3.3 muM, the lowest concentration tested. Although the system is exceedingly sensitive to modulation by GTP or Gpp(NH)p UTP, CTP, GMP, and cyclic GMP did not antagonize the antihormone activity of prostaglandin H2. Kinetic studies indicate that the GTP or Gpp(NH)p antagonism of prostaglandin H2 is observable on initial rates of cyclic AMP synthesis, and persists throughout the adenylate cyclase measurements. Preincubation of fat cell ghosts with GTP followed by washing and resuspension results in a prostaglandin H2-sensitive adenylate cyclase system. However, the same preincubation experiment with Gpp(NH)p produces an irreversible antagonism of the prostaglandin H2 inhibition of hormone-stimulated adenylate cyclase. It is suggested that prostaglandin H2 stabilizes the fat cell adenylate cyclase system in a state that is resistant to hormone stimulation, and GTP or Gpp(NH)p overcome this stabilization.

Adenylyl Cyclases↗

PubMed1977

Mitogen-stimulated glucose transport in thymocytes. Possible role of Ca++ and antagonism by adenosine 3':5'-monophosphate.

The plant lectin, concanavalin A (Con-A), and the ionophore, A-23187 (specific for divalent cations), stimulated glucose transport in rat thymocytes. Con-A stimulation developed more slowly and was somewhat less extensive than that of stimulation developed more slowly and was somewhat less extensive than that of A-23187. Both responses showed saturation dose dependencies. The two responses were poorly additive, suggesting that A-23187 may saturate regulatory processes shared by the two stimulatory mechanisms. Doses of methylisobutylxanthine (MIX) and prostaglandin E2 which raised adenosine 3':5'-monophosphate (cAMP) levels in these cells also antagonized the Con-A stimulation of glucose transport but did not inhibit basal glucose transport or the A-23187 stimulation. Dibutyryl-cAMP and 8-bromo-cAMP also natagonized Con-A stimulation without inhibiting basal glucose transport. MIX antagonized high Con-A doses about as strongly as it did low Con-A doses, suggesting that MIX did not compete in the Con-A binding step or other process saturable by Con-A. [3H-A1Con-A binding was not affected by MIX. The stimulatory effects of Con-A and A-23187 were reduced by reduction of Ca++ in the medium. Both Con-A and A-23187 enhanced 45Ca++ influx and cellular Ca++ content. The A-23187 dose, which was saturating for glucose transport stimulation, enhanced Ca++ influx and cellular Ca++ content more than did the Con-A dose which was saturating for glucose transport stimulation. The dose fo MIX which specifically antagonized Con-A stimulation of glucose transport proved also to reduce Ca++ influx and cellular Ca++ in the presence of Con-A but not in the presence of A-23187. Thus, glucose transport correlates rather well with cellular Ca++. These results are compatible with the view that Ca++ in a cellular compartment can promote glucose transport, the Con-A's enhancement of Ca++ entry contributes to its stimulation of glucose transport, and the MIX antagonized Con-A action at least partly by reducing Ca++ entry. The action of MIX is apparently mediated by cAMP.

Animals↗