Physiological Antagonism Research Articles

SIMULTANEOUS EFFECTS OF DIETARY MOLYBDENUM AND COPPER ON THE ACCUMULATION OF COPPER IN THE LIVER AND KIDNEY OF COPPER POISONED RATS. A HISTOCHEMICAL STUDY

The present investigation reports on the accumulation and damage caused by copper in the liver and kidney of albino rats. Simultaneous treatment with copper and molybdenum shows that no traces of copper are retained in these tissues. Thus these observations lead to the conclusion that copper is ineffective in the presence of molybdenum exhibiting physiological antagonism. Several hypothesises have been considered for their antagonistic behaviour. Present authors suggest that molybdenum may act on copper as a chelating agent binding with it and forming either cupric molybdate or copper thiomolybdate which is ultimately excreted. Intake of molybdenum with the diet has also been suggested for the occupational victims of copper.

Renal prostaglandins and the regulation of blood pressure and sodium and water homeostasis

In addition to its well known prohypertensive role in various states of experimental and human hypertension, the kidney has also been shown to exert an antihypertensive “endocrine” function. According to this hypothesis, certain forms of experimental and human hypertension might not solely be the result of an excess in the activity of such renal pressor systems as the reninangiotensin system and the sympathetic nervous system, but might also result from an absolute or relative deficiency of intrarenal vasodilator antihypertensive factors which might allow pressor systems to act unopposed to produce peripheral arteriolar vasoconstriction and sustained hypertension. At least four factors have been characterized in the kidney of various animal species and man which might be responsible for such an antihypertensive function. These are (1) the renomedullary prostaglandins (PGs), (2) the renomedullary antihypertensive neutral lipid, (3) antirenin phospholipid and (4) the renal kinins. This review is restricted to an examination of the possibility that the vasodepressor renomedullary prostaglandins (PGA and/or PGE) may, at least in part, mediate the so-called antihypertensive function of the kidney and participate in the regulation of renal blood flow and natriuresis by physiologic antagonism of various renal vasoconstrictor stimuli such as the renal renin-angiotensin and the sympathetic nervous systems.

The interaction between prostaglandin E1 and delta 9-tetrahydrocannabinol on intestinal motility and on the abdominal constriction response in the mouse.

The interaction between delta9-tetrahydrocannabinol (THC) and PGE1 was studied using two pharmacological parameters-the rate of passage of a charcoal meal through mouse small intestine and the abdominal constriction response in the mouse. PGE1 administered intraperitoneally produced a dose-dependent decrease in intestinal motility, and this effect was antagonized by low (0.25 mg/kg) doses of THC and potentiated by higher doses of THC (1 mg/kg). Kinetic analysis suggested that the interaction was of a mixed but predominantly competitive type. PGF2alpha produced an increase in intestinal motility but this was not dose-dependent. THC antagonized the effect of PGF2alpha in a dose-dependent manner suggestive of a physiological antagonism. THC (0.25-2 mg/kg) antagonized the dose-dependent PGE1 abdominal constriction response in a fashion which suggested a mixed (though mainly competitive) antagonism. It would ssem, therefore, that on the two pharmacological parameters studied THC appears to be interacting with PGE1 at the same receptor site. Although the doses of THC used are within the range of those used in man, it is not implied that these results are necessarily implicated in the psychoactivity of the drug.

Effect of prostaglandins E 1 , E 2 and A 2 on vascular resistance and responses to noradrenaline, nerve stimulation and angiotensin in the dog hindlimb.

1. The relationship between the vasodilator and inhibitory effects of prostaglandin E(1) (PGE(1)), E(2) and A(2) on responses to nerve stimulation, noradrenaline and angiotensin was evaluated in the dog hindlimb preparation.2. PGE(1) and PGE(2) were equipotent as vasodilators in the hindlimb; however, PGE(1) was much more potent as an inhibitor of vasoconstrictor responses to nerve stimulation, noradrenaline and angiotensin.3. PGA(2) and PGE(2) were approximately equal as inhibitors of vasoconstrictor responses to noradrenaline, nerve stimulation and angiotensin; however, PGE(2) was far more potent as a vasodilator.4. Since there is no relationship between the vasodilator and inhibitory effects of PGE(1), E(2) and A(2), and since the inhibitory effect of PGA(2) was present at a time when hindlimb perfusion pressure had returned to control value, it is concluded that the inhibitory action is probably not the result of a physiological antagonism.5. Since each prostaglandin inhibited responses to nerve stimulation and noradrenaline to approximately the same extent and responses to angiotensin were also inhibited, it is suggested that these agents antagonize vasoconstrictor responses by a nonspecific depressant effect on smooth muscle cells.

Sleep produced by clonidine (2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride).

1. The dose of clonidine (given intravenously) required to elicit sleep in the young chick is 1/25th to 1/50th of an equiactive dose of noradrenaline. The approximate ED50 is 0.01 mumol/kg. Phentolamine (10-15 mg/kg, but not 5 mg/kg) antagonizes the action of both clonidine and noradrenaline.2. Intensive treatment with p-chlorophenylalnine (700 mg/kg for 3-4 days) does not prevent the hypnotic effect of clonidine in the chick, although brain 5-HT is reduced to 15% of normal. Neither is natural sleep modified.3. Sleep after clonidine is not affected by methysergide (0.1-1 mumol/kg, i.m.), but prevented by LSD (0.1-0.3 mumol/kg). The effect of LSD is interpreted as a physiological antagonism.4. Clonidine (50 mg/kg) injected intravenously into adult rats causes sleep which is not abolished by phentolamine (5 mg/kg) or by p-chlorophenylalanine in doses which interfere with natural sleep.5. When, per kg body weight, the same dose of clonidine is injected into the lateral cerebral ventricle of rats, sleep ensues in more than half the animals, and persistent eating in about a third; only one of seventeen rats showed no change in behaviour. Eating and sleeping remained unaltered after p-chlorophenylalanine. The actual dose of clonidine injected into the lateral ventricle was 0.037 mumol, amounting to about 0.15 mumol/kg or 15 times the dose required intravenously in the chick. Noradrenaline 0.15 mumol per (intraventricular) injection caused eating but no sleep, whereas higher doses produced ataxia and paresis.6. The work suggests that clonidine does not elicit sleep by an action requiring the integrity of the 5-HT-containing neurones arising in the raphé nuclei, and that its action is not on tryptamine receptors. In the chick, sleep appears to be produced by a central sympathomimetic effect; it is possible, but not certain, that this also holds for the rat.7. The intravenous hypnotic dose of clonidine for the cat is about the same as that for the rat, but injection is not accompanied by signs of peripheral sympathetic stimulation.

Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by L-tryptophan or 5-methoxy-N,N-dimethyltryptamine in rats treated with a monoamine oxidase inhibitor.

1. The hyperactivity and hyperpyrexia produced by L-tryptophan in rats treated with a monoamine oxidase inhibitor was inhibited by chlorpromazine.2. Chlorpromazine did not inhibit the increased rate of synthesis of brain 5-hydroxytryptamine (5-HT) produced by tryptophan loading.3. Hyperactivity and hyperpyrexia were also produced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) in rats. Pretreatment with a monoamine oxidase inhibitor potentiated the hyperactivity response. Pretreatment of rats with p-chlorophenylalanine did not inhibit hyperactivity produced by 5-MeODMT.4. Chlorpromazine inhibits hyperactivity caused by tryptophan or 5-MeODMT after monoamine oxidase inhibition either by competition with 5-HT or 5-MeODMT, respectively, at receptor sites or by physiological antagonism.

Relation of magnesium ions to calcium and phosphate absorption.

CHEMICALLY, magnesium and calcium are related since both elements are members of Group II of the Periodic Table. Physiologically, however, in plants1 or in animals2 their actions are often antagonistic. It has been shown that magnesium-deficient rats absorb more calcium from the gastrointestinal tract than do control rats3 and the active transport of calcium ions across the intestinal wall of several species is depressed by magnesium ions4. These experiments indicate again a physiological antagonism between these ions and also suggest the possibility of a common absorptive pathway. However, the experimental conditions in the former study3 are abnormal since magnesium is an integral part of normal diets and magnesium deficiency may have caused changes in the intestinal mucosa which allowed more calcium to be absorbed. In vitro type experiments4 are, by their nature, unphysiological and extrapolations from such isolated systems to interpretations concerning overall calcium absorption in vivo may not be valid.

SOME BIOLOGICAL PROPERTIES OF SYNTHETIC 18-HYDROXYTESTOSTERONE.

18-Hydroxytestosterone inhibited the renal electrolyte effects of DC A and aldosterone in acute experiments with adrenalectomized rats. Comparative tests show that it is approximately as potent as spironolactone parenterally and considerably more potent than testosterone; orally, it is ineffective, not unlike testosterone. Available evidence indicates that 18-hydroxytestosterone is pharmacodynamically a specific antagonist of mineralocorticoids which competes reversibly with mineralocorticoids for target tissues. Androgenic and myotrophic properties were adversely affected with the 18-hydroxy modification. (Endocrinology 74: 999, 1964) A PRACTICAL method for synthesis of x x 18-oxygenated steroids from the alkaloid conessine was described by Pappo (1). This procedure made available supplies of 18hydroxylated derivatives of deoxycorticosterone, its acetate and progesterone for biological tests in the past (2). Recently, experience in the laboratory was extended to another derivative in the series of 18-oxygenated steroids, 17/3,18-dihydroxy-4-androsten3-one or 18-hydroxytestosterone (18-OHT), for which no data appear to exist. Results of our study, described herein, indicate the 18-hydroxy analog of testosterone is a mineralocorticoid antagonist, without important androgenic or myotrophic properties. Materials and Methods Renal electrolyte properties of 18-OH-T were investigated in acute experiments with salineloaded adrenalectomized rats weighing 150-200 g. In general, the test procedures involved the treatment subcutaneously or orally with corn oil solutions of the compound, followed by collection of a 4-hr urinary specimen in metabolism cages (4 animals/cage). Antimineralocorticoid effects were assessed by reversal of the urinary electrolyte manifestations of a standard dose of deoxycorticosterone acetate (DCA) or d-aldosterone-21-acetate. Pooled s values in these studies are 0.092, 0.074 and 0.084 per 4animal response for log Na, K and (Na X10) /K, respectively (degrees of freedom =60). Other details of the test procedures have been described elsewhere (3). Androgenic and myotrophic activities of 18-OH-T, injected in oil intramuscularly for 7 days, were determined in castrated male rats by examination of weights of the seminal vesicle, ventral prostate and levator ani (4). Statistical analyses for significance were done by Student's t test, relative potencies were computed by Irwin's method (5), and Received December 20, 1963. 1 The chemistry of 18-OH-T has been described in U. S. Patents 3,017,410 and 3,080,360. urinary Na and K were determined on the Beckman flame photometer. Results and Discussion Table 1 summarizes urinary electrolyte data of 2 replicate experiments, designed according to preliminary studies, with 18OH-T given alone and in various dosage combinations with mineralocorticoids in adrenalectomized rats. DCA at a 12 jug dose produced Na retention, K loss and a reduction of the ratio of Na/K in the urine relative to untreated controls, as expected of a mineralocorticoid; these manifestations of DCA were readily reversed with 1.2 and 4.8 mg of 18-OH-T. Similar inhibitory effects were noted with the testosterone derivative against d-aldosterone-21-acetate given at a dose equivalent in mineralocorticoid potency to that of DCA. In the absence of mineralocorticoids, 18-OH-T induced Na loss at the 4.8 mg dose (p<.05), but otherwise failed to demonstrate electrolyte effects that would oppose mineralocorticoid action. Pharmacodynamically, these data suggest that 18-OHT inhibits the renal effects of mineralocorticoids by specific antagonism rather than by physiological antagonism (6), to show thereby a characteristic in common with spironolactone (3) and testosterone (7). Noteworthy, furthermore, is the fact that blocking properties of the 18-hydroxy derivative were progressively reversed with increasing doses of a mineralocorticoid (cf responses obtained with combinations of 4.8 mg of 18-OH-T and 12, 60 and 300 Mg of DCA), which data strongly support the view of competitive interaction with the steroids, presumably at the kidney level. 18-OH-T was also tested comparatively 2 3 (3-Oxo-7a acetylthio -17/3 hydroxy 4 androsten-17a-yl)propanoic acid lactone.

THE EFFECTS OF PITRESSIN AND DESOXYCORTICOSTERONE IN LOW DOSAGE ON THE EXCRETION OF SODIUM, POTASSIUM, AND WATER BY THE NORMAL DOG1

In 1938, Silvette and Britton presented evidence that there exists a physiological antagonism between the diuretic action of adrenal cortical hormone and the antidiuretic action of posterior pituitary hormone. An antagonism between the sodium and chloride conserving effects of the former and the chloruretic and natriuretic effects of the latter has also been postulated—first by Silvette and Britton (1938), and more recently by Roemmelt, Sartorius and Pitts (1949). It has been suggested that the major disturbances in electrolyte and water metabolism of the adrenalectomized animal resemble an exaggerated effect of posterior pituitary antidiuretic hormone (Roemmelt et al., 1949, Birnie et al., 1949). As desoxycorticosterone is known to correct the disturbed electrolyte balance in Addison’s disease without significantly altering the disturbed water balance (Talbott et al., 1942; Reforzo-Membrives et al., 1945), it seemed reasonable to predict that desoxycorticosterone would reduce the natriuresis but have no ...

The Measurement of Individual Differences in Autonomic Balance

To summarize the report briefly, the Eppinger and Hess hypothesis has been slightly reworded as follows: A. The differential chemical reactivity and the physiological antagonism of of the adrenergic and cholinergic branches of the autonomic nervous system permit of a situation in which the action of one branch may predominate over that of the other. This predominance, or autonomic imbalance, may be phasic or chronic, and may obtain for either the adrenergic or the cholinergic system. B. Autonomic imbalance, when measured in an unselected population, will be distributed continuously about a central tendency which shall be defined as autonomic balance. The hypothesis has been tested by measuring the physiological status of 62 children 6 to 11 years of age, for twenty physiological variables, twelve of them supposedly mediated at least in part by the autonomic nervous system; and by intercorrelating the resulting data. Positive intercorrelation among most of the appropriately reflected autonomic functions, and further evidence of their communality from a factor analysis, lends support to the first portion of the hypothesis. For 48 of these children, scores for the autonomic factor are shown to be quite consistent over periods of at least a year, and best measured in terms of a multiple regression equation derived from the factor analysis. These regression scores are regarded as measures of autonomic balance and are found to distribute themselves symmetrically about a central tendency. Support is thus afforded the second portion of the hypothesis which defines the central tendency of the distribution as autonomic balance. The seven-test and its regression equation is offered as the first, though tentative, quantitative, weighted scale for the measurement of individual differences in the autonomic nervous system.

THE ADDITIVE EFFECT OF CALCIUM AND DIGITALIS

The specific therapeutic action of most drugs is generally well established and their action may be predicted with a fair degree of certainty. The use of drugs in combination has also led to recognition of the fact that certain drugs enhance the action of others—a synergistic effect. That certain drugs counteract the action of others, i. e., physiologic antagonism, is also common knowledge. However, the administration of one drug may produce a sensitization of the tissues, which so modifies the functional response of the tissues that a second drug exerts an effect diametrically opposed to its customary and expected action. This alteration of the functional activity of the cells may be produced by physical-chemical forces, by disease or by drugs.1There are many examples of drugs exhibiting this reversal of action under varying conditions. Calcium may produce a varying cardiac response, depending on existing circumstances. Its action is affected not only by the state of the cardiac musculature but by the earlier administration of other drugs. Furthermore, when calcium is employed beforehand, the action of other drugs may be modified.

副腎皮質越幾斯ノ「モルフィン」ニ對スル解毒作用ニ就テ

In the previous paper, the author stated that the cortical extract of the adrenal body decreases the toxicity of certain poisons and most markedly that of morphine.The author's further experiments about the antitoxic action of the cortical extract. upon morphine, brought about the following results : 1. he antitoxic action of the cortical extract upon morphine can appear either by injecting it in the same place as morphine or in different places.2. The cortical extract is still effective after boiling for 3 hours at 100°C.3. The alcoholic extract of the cortex as well as the watery extract exerts the same antitoxic action upon morphine.4. The cortical extract is effective in raising the sensibility of the respiratory centre, and is capable of removing the respiratory paralysis caused by morphine.5. Cholin is likely to decrease the toxicity of morphine but is less effective than the cortical extract.6. Cholesterin decreases the toxicity of morphine.7. Protein and cholesterin are not proved to be in the cortical extract which was used by the author, but it seems probable that cholin is present in it.8. Muscle and brain extract have the effect of decreasing the toxicity of morphine, but to a much less degree than the cortical extract.From the data mentioned above it can be concluded that : 1. The physiological antagonism between the cortical extract and morphine on. the respiratory centre is considered to be one of the chief mechanisms of the antito xic process.2. The active principle of the cortical extract is a substance soluble in alcohol and in water, and not destructible by heating to 100°C.3. The antitoxic action upon morphine is not a specific of the cortical extract, but it is the most effective of the extracts obtained from venous organs.

Societies and Academies

LONDON. Royal Society, March 12.—Sir Charles Sherring-ton: Remarks on some aspects of reflex inhibition. Attempt is made to schematise in a diagram certain features of the interaction of central inhibition and excitation. Assumption is made of an inhibitory agent liberated centrally which neutralises chemically an excitatory agent when this latter is present, but the liberation of which is not dependent on pre-existence of the excitatory agent. Tetanic inhibition is dealt with as due to iterate production of the inhibitory agent, with exhibition of temporal summation and "recruitment."Central after-action, both inhibitory and excitatory, is attributed to temporary persistence of a residuum of the liberated inhibitory or excitatory agent. The schema is designed to meet in particular the experimental data furnished by the knee-extensor under crossed excitation and ipsilateral exhibition. It does not attempt to deal with late successive effects such as successive induction and rebound.-E. G. T. Liddell and Sir Charles Sherrington: Recruitment and some other features of reflex inhibition. Under mere prolongation of an otherwise unaltered stimulus of the inhibitory afferent nerve, the central inhibitory process recruits more motoneurones as it proceeds. The "stimulation-plateau"of the reflex contraction is more easily inhibited than the "after-discharge plateau."Experiments suggest that a reflex maintains maximal responf e of the individual "motor-unit "by a degree of central excitation which is commonly “supramaximal”, i.e. of intensity above the lower limit required for evoking the unit's maximal response. In the excitatory reflex a mechanism proximal to the motoneurone axon seems to react in an "all-or-none "manner when exposed to inhibition. -D. T. Harris: Studies on the biological action of light. Ultra-violet radiations exert a stimulant action on the gaseous metabolism of small animals, and on the movements of the frog's isolated stomach. This action is completely annulled by the presence of visible radiations, an action which seems to be physiological antagonism rather than physical interference. Exposure of an animal to mixed radiations of a powerful source of light depresses its heat production to an extent greater in pigmented animals than in albinos for the same rise of temperature in the surrounding medium. Thermo-electric measurements indicate that pigment, nevertheless, possesses high absorptive properties. Pigment appears to protect an animal against the lethal action of certain photo-dynamic substances.- H. Hartridge and F. J. W. Roughton: The kinetics of haemoglobin. III. Velocity with which oxygen combines with reduced haemoglobin. The reaction between oxygen and reduced haemoglobin is very rapid, the time required for half-completion being o-oi to o-ooi sec. The velocity-constants obtained at PH 7 and PH10, with different concentrations of haemoglobin and oxygen, agreed in showing that the reaction is bi-molecular. The dissociation curve for dilute haemoglobin solutipns is approximately hyperbolic. The quotient of the two velocity-constants, oxidation and reduction, is practically equal to the equilibrium constant. The presence of haemoglobin aggregates would not be expected to affect the velocity of oxidation, so long as the part of the molecule with which the oxygen combines is sharply localised and far removed from the aggregate-forming portion. This affords an explanation of the low-temperature coefficient obtained.-S. B. Schryver, H. W. Buston and D. H. Mukherjee: The isolation of a product of hydrolysis of the proteins hitherto undescribed. By means of the "carbamate "method, a base C6H14O3N2 has been isolated from isinglass. It differs from the other basic products of hydrolysis of the proteins in that it yields a barium carbamate insoluble in water. It gives a tri-benzoyl derivative C6H11O3N2(C6H5CO)3 m.p. 68–69°, and it is assigned the formula CH2. (NH2). CH2. CH2. CH(OH)CH2. (NH2). CO2H. It has been found after hydrolysis of fish gelatin, isinglass and three vegetable proteins of very diverse origin. It is absent from, or present only in very small traces in, the hydrolysis products of gelatin of mammalian origin, of casein, fibrin, and egg-white.-D. Keilin: On cytochrome: a respiratory pigment common to animals and yeast. Under names myohaematin and cytohsematin, McMunn described a respiratory pigment, here named cytochrome. Cytochrome, in reduced form, shows a very characteristic spectrum, with four bands (a, b, c, d), with positions of maximum intensity: a, 603; b, 565; c, 550; d, 523. In the oxidised form no absorption bands can be seen. In different concentrations cytochrome exists in tissues of all animals, e.g., worms, molluscs, arthropods and vertebrates. It is also present in cells of ordinary baker's yeast, a thin layer of which shows well the above four bands. The highest concentration of cytochrome is found in thoracic wing-muscles of insects, striated muscles of mammals, and yeast-cells. It yields various derivatives similar to hsemochromo-gen and its oxy- and CO-compounds, and porphyrin. Cytochrome may co-exist with other respiratory pigments, and may be considered an intracellular respiratory pigment, generally distributed, forming part of a complicated system of respiratory catalysts.

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

The Physiological Antagonism between Medicines and between Remedies and Diseases

Art. IV.—The Efficacy of the Physiological Antagonism of Opium and Belladonna in the Treatment of Poisoning, as shown by an Analysis of 370 Cases.

Art. IV.—The Efficacy of the Physiological Antagonism of Opium and Belladonna in the Treatment of Poisoning, as shown by an Analysis of 370 Cases.