Action Of Salicylate Research Articles

Effects of intravenous injection of salicylate on the cochlear nerve action potentials

It is not yet well understood the actions of salicylate on the auditory system. Our previous study has shown that injections of salicylate increases the spontaneous discharge rate of cochlear nerve fibers. This study was aimed to elucidate the effects of various doses of salicylate on the cochlear nerve by recording the compound action potentials (CAPs) which were evoked by electrical pulse applied to the cochlea through the round window membrane before and after intravenous injection of salicylate.After injection of 100mg/kg, 200mg/kg and 400mg/kg of salicylate, the amplitude of CAPs was decreased significantly, while their latency was increased significantly only after injection of 400mg/kg of salicylate. These results suggest that intravenous injection of salicylate acts directly on the cochlear nerve and causes increase of its excitability and that the amplitude changes of CAPs are better indicaters than the latency changes of CAPs.

Molecular mechanisms of drug-induced hearing loss.

Although the ototoxic actions of a variety of drugs have long been documented, the biochemical mechanisms underlying such toxicity largely remain to be established. For example, recent advances have provided us with information about the actions of salicylates (aspirin) and diuretics (furosemide) but we are not yet able to specify the mechanisms by which these drugs damage the cochlea. On the other hand, the considerable amount of biochemical and pharmacological data on the effects of aminoglycosides (streptomycin, neomycin, gentamicin and related compounds) has enabled us to formulate a rational hypothesis of their mechanism of action. We have previously presented evidence for an involvement of polyphosphoinositides in the ototoxic actions of aminoglycosides. Recent electrophysiological and pharmacokinetic studies have shown in addition that aminoglycosides occupy at least two distinct compartments in the course of their actions. Further studies of drug uptake in vitro and of drug toxicity in cochlear perfusions suggested the involvement of an active (energy-requiring) aminoglycoside transport system. These and other data are compatible with the following multi-step model of aminoglycoside toxicity: The initial step in the reaction sequence is an electrostatic interaction of aminoglycosides with the plasma membrane. The resulting displacement of calcium accounts for acute effects but the action is reversible and antagonized by divalent cations. An energy-dependent uptake process is required for the expression of toxicity. It can be prevented by select metabolic blockers. A crucial step in subsequent intracellular drug actions is the binding of aminoglycosides to phosphatidylinositol bisphosphate inhibiting its hydrolysis and preventing its physiological function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of sodium ion on the adjuvant action of sodium salicylate in enhancing rectal ampicillin absorption in rats

Sodium chloride facilitated the adjuvant action of sodium salicylate in enhancing rectal ampicillin absorption in rats. This action of sodium chloride involves facilitated absorption of salicylate by sodium ion. That is, enhancement of ampicillin absorption in the presence of salicylate correlated well with the increase of salicylate absortion with increasing concentration of sodium ion. The effect of sodium ion on the action of salicylate was confirmed using the sodium salts of ascorbate instead of sodium chloride. Since a mixture of sodium ascorbate and sodium salicylate showed less disruption of the rectal mucosal surface compared to a mixture of sodium chloride and sodium salicylate, sodium ascorbate seems to be suitable additive for inclusion with sodium salicylate for the formulation of rectal dosage forms of ampicillin.

The action of salicylates on bile flow in man.

Following oral administration of 1.5 g of sodium salicylate or acetylsalicylate to five patients with indwelling T-tubes there was an approximately 50% increase in bile flow. The increase appeared to be in the bile-acid independent fraction of canalicular flow and was not accompanied by a change in lithogenicity. Neither agent would be of use in the medical treatment of cholesterol gallstones.

Effect of salicylate poisoning on insulin secretion. Studies on its mechanism of action.

Sodium salicylate poisoning increased glucose-induced insulin secretion by slices of rat pancreas. The alpha adrenergic blocker phentolamine, but not salicylate poisoning, overcame the inhibitory effect of epinephrine on insulin secretion. Theophylline (5, 10 and 15 mM) significantly increased the insulin secretion induced by 11 mM glucose. The highest insulin response was obtained when theophylline was used at a 10 mM concentration. However, when pancreas slices from salicylate poisoned rats were used, a 5 mM concentration was sufficient to achieve maximal insulin response. Salicylate poisoning diminished the free tubulin pool, an action that was impaired by imidazole; however, imidazole did not modify the effect of the ionophore A23187. The results suggest that: a) sodium salicylate poisoning increases B-cell response to glucose; b) changes in alpha adrenergic activity are not related to the mechanism of action of salicylate; c) an increment in the cAMP concentration may mediate the stimulatory effect of salicylate poisoning on insulin secretion; d) the effect of salicylate on the microtubular system is indirect and probably mediated through an increment in pancreatic cAMP.

Further studies on the actions of salicylates on nerve membranes

The effects of sodium salicylate, sodium benzoate and 5-bromo salicylate on nerve fibres of the rabbit cervical vagus and of the frog sciatic nerve ‘in vitro’ were studied using the single sucrose gap technique. The application of 5-bromo salicylate in concentrations between 2 × 10 −3 to 5 × 10 −3 M induced a slow fall in spike height accompanied by a small hyperpolarization (0.5−2.0 mV). Higher concentrations (1 × 10 −2 − 2 × 10 −2 M) produced depolarization and a rapid block of nervous conduction. Concentrations of 1 × 10 −2−2 × 10 −2 M of sodium salicylate were needed to induce the same hyperpolarizing and slow blocking effects in non-myelinated nerve fibres. Myelinated fibres of the frog sciatic nerve were also blocked by concentrations greater than 1 × 10 −2 M of 5-bromo salicylate, but showed an increase in the amplitude of the compound action potential and a prolonged falling phase when superfused with concentrations around 5 × 10 −3 M. A frequency-dependent decrease in the action potential amplitude was observed with sodium salicylate and 5-bromo salicylate and was shown to be more easily induced in non-myelinated than in myelinated fibres. 5-Bromo salicylate (2 × 10 −2 M) and 2,4-dinitrophenol (1 × 10 −4 M) reduced the amplitude and the rate constant of decay of the hyperpolarization produced by tetanic stimulation of non-myelinated nerve fibres. Sodium salicylate (2 × 10 −2 M) increased the time constant of decay of the hyperpolarization of the potassium-activated response and slightly decreased its amplitude. Sodium salicylate was 3–5 times less potent than 5-bromo salicylate; while sodium benzoate was practically ineffective in producing the phenomena under study.

Rebound rise in renin concentrations after cessation of salicylates.

SALICYLATES are widely used in the treatment of rheumatic disorders, and they have been shown to induce minor changes in renal function.1 2 3 One of the major mechanisms of action of salicylates is...

Salicylates: Molecular Mechanism of Therapeutic Action

This chapter presents the analysis of the molecular mechanism of action of salicylates with the aim of interpreting the therapeutic effects of these drugs in terms of their interactions with biochemical processes in cells or tissues. It is expected that such interactions might result from the binding of the drug molecule with one or more types of macromolecule that conducts such processes. Such binding might be expected to occur—for example, at the active site of an enzyme, at the receptor for a neurohumoral transmitter, or at some comparable point. The primary task, however, was to identify the biochemical process or processes whose modification by salicylates led to the therapeutic effects of these drugs and to examine how these effects occurred. This task was pursued along two main lines, emerging from the questions: (1) what is the character of the therapeutic actions of salicylates and (2) what potent effect(s) of salicylates at a molecular level might give rise to actions of this character? Inhibition of the cyclooxygenase of prostaglandin synthetase explains those actions of salicylates in which aspirin is more potent than sodium salicylate, including certain forms of analgesia, inhibition of platelet aggregation, antagonism of bradykinin-induced bronchoconstriction in the guinea pig, and possibly antipyresis.

The action of salicylate ions on the frog node of Ranvier.

1. The effects of salicylate on the membrane currents in the frog node of Ranvier were investigated. 2. External salicylate slows the falling phase of the action potential, with little effect on the action potential amplitude. 3. External salicylate has no effect on the leak current. 4. Most of the actions of external salicylate can be attributed to a simple incorporation of negative charge into the membrane surface. The h infinity, tau h, tau m and m infinity curves for the sodium current are shifted to more negative potentials, as are the n infinity and k infinity curves for the potassium current. Potassium ion accumulation prevented analysis of the action of salicylate on the time constant of the potassium current kinetics. 5. In addition to the h infinity and tau h curves being shifted to more negative potentials, the shapes of the curves are also changed by salicylate. These shape changes cannot be explained by conventional homogeneous surface charge theory. Possible explanations for these changes are discussed. 6. Internal salicylate has similar effects to external salicylate: the gating variable curves for the sodium current are shifted in the negative direction on the voltage axis, rather than in the positive direction expected if negative charge were added to the inner surface of the nodal membrane. This may be due to salicylate crossing the membrane and binding preferentially to a receptor at the external surface, or might be due to a rise in intracellular calcium concentration following inhibition of oxidative phosphorylation.

Gastric mucosal defense mechanisms: Effects of salicylate and histamine

Some of the recent concepts about the gastric mucosal defense mechanisms against damage by luminal acid and the effects of histamine and salicylate on these mechanisms are reviewed. The mucosal barrier to acid appears to consist of at least two physiologic components: a permeability mechanism and a metabolic mechanism related to cellular bicarbonate production as a result of acid secretion. In the absence of salicylate, histamine appears to exert some protection by affecting both mechanisms, but in the presence of salicylate, histamine's protective effect is limited to altering mucosal permeability. The actions of salicylate on the gastric mucosa are complex, related in part to the concentration of salicylate and the pH of the luminal fluid. The damaging effects of salicylate appear to be related more to the concentration of acid in the lumen than to the lipid solubility of the drug. Salicylate increases permeability regardless of pH; the increase is initially selective for cations and subsequently becomes nonselective, involving both cations and anions. Although both low and high concentrations of salicylate increase mucosal permeability to hydrogen ions, only high concentrations of salicylate affect cellular bicarbonate production.

Inhibitory Action of Sodium Salicylate on the Growth of Upper Jaw and Tibia in Rats

The inhibitory effect of sodium salicylate on the growing upper jaw and tibia was examined by the morphological measurement by radiography at different dose levels. The longitudinal growth of the tibia was greater than the sagittal growth of the upper jaw in young normal rats. The increment in length was approximately 10 mm a month in the former and 3 mm a month in the latter. Growth of these bones was reduced by successive subcutaneous injections of sodium salicylate, and the reduction of growth increased with increase of the dose administered. Sagittal growth of the upper jaw was much more sensitive to the action of salicylate, and was significantly reduced by the drug even at a dose of 100 mg/kg (P<0.01 ).

Effect of salicylates on histamine and L-histidine metabolism. Inhibition of imidazoleacetate phosphoribosyl transferase.

In man and other animals, urinary excretion of the histidine and histamine metabolite, imidazoleacetate, is increased and that of its conjugated metabolite, ribosylimidazoleacetate, decreased by salicylates. Imidazoleacetate has been reported to produce analgesia and narcosis. Its accumulation as a result of transferase inhibition could play a part in the therapeutic effects of salicylates. To determine the locus of salicylate action, we have investigated the effect of anti-inflammatory drugs on imidazoleacetate phosphoribosyl transferase, the enzyme that catalyzes the ATP-dependent conjugation of imidazoleacetate with phosphoribosylpyrophosphate. As little as 0.2 mM aspirin produced 50% inhibition of the rat liver transferase. In vivo, a 30% decrease in the urinary excretion of ribosylimidazoleacetate has been observed with plasma salicylate concentrations of 0.4 mM. The enzyme was also inhibited by sodium salicylate but not by salicylamide, sodium gentisate, aminopyrine, phenacetin, phenylbutazone, or indomethacin. The last four drugs have been shown previously not to alter the excretion of ribosylimidazoleacetate when administered in vivo. Since both the drug specificity and inhibitory concentrations are similar in vivo and in vitro, it seems probable that the effect of salicylates on imidazoleacetate conjugation results from inhibition of imidazoleacetate phosphoribosyl transferase.

Depression of taste responses by local or intravascular administration of salicylates in the rat.

The effects of aspirin and sodium salicylate on the taste response in the chorda tympani proper nerve have been studied during stimulation of the taste receptors in rats with salty, sweet, sour and bitter-tasting solutions. Three methods of administering the drugs were used: locally on the tongue, intravenously into one femoral vein and intraarterially close to the branching of the lingual artery. It was observed that salicylates, given in any of these three ways, depressed the response to taste stimuli. This is discussed in relation to present views on the action of salicylates.

Blockage of pyrogen induced fever by intrahypothalamic injections of salicylate in the rat

Changes in body temperature following intraperitoneal injections of Pseudomonas polysaccharide (Piromen) were measured in rats. Fever consistently occurred with higher doses (45–90 μg/kg). Indwelling cannulae were implanted in either the anterior or posterior hypothalamus. Microinjection of 5 μg of salicylate into the anterior hypothalamus blocked pyrogen-induced fever; whereas salicylate injected into the posterior hypothalamus did not. In the control, salicylate did not affect the body temperature of afebrile rats. These results support a central nervous system mechanism of the antipyretic action of salicylate, probably involving the anterior hypothalamic neurohumours.

Metal-salt potentiation of salicylate-induced teratogenesis and behavioral changes in rats.

AbstractThe effects of parenteral metal supplements on salicylate teratogenicity were studied in rats. Ferrous gluconate (16 mg/kg), manganous sulfate (10 mg/kg), cuprous sulfate (6 mg/kg), or deionized water were given ip on days 8, 9, and 10 of gestation, Sodium salicylate (250 or 500 mg/kg) or deionized water was administered po on day 9, l h after the metal‐salt treatment. Mn significantly enhanced the teratogenic effects of salicylate, Fe potentiated the salicylate effect but to a lesser extent than Mn, and Cu had little or no effect on salicylate teratogenicity. Mn and Fe significantly increased total salicylate concentration in both embryos and maternal plasma at 6 h after salicylate treatment, with Mn having the greater effect. No interference with plasma‐protem binding of salicylate could be detected. Posrnatal effects of possible salicylatemetal interactions were studied in 40‐day‐old offspring of animals treated with 125 mg/kg aspirin po and 16 mg/kg ferrous gluconate ip on days 8, 9, and 10. Increased exploratory activity and mean body weight were observed in both the aspirin‐Fe and aspirin groups relative to vehicle controls, but maze learning was impaired only in animals exposed to both aspirin and Fe. The potentiation of the pre‐ and postnatal effects of salicylate by parenteral metal‐salt treatment implies a salicylate‐metal interaction in the maternal circulation and suggests chelation as a mechanism of the teratogenic action of salicylate.

Sodium Salicylate

<i>To the Editor</i>.—I read with interest the article by Mitchell et al, "Electrophysiological Study of the Effect of Sodium Salicylate Upon the Cochlea" in the November 1973 issue of theArchives(98:297) that showed that a single subcutaneous dose of sodium salicylate interferes with the cochlea's ability to generate a nerveevoked potential (N_,) without a simultaneous change in the cochlea's ability to generate the alternating current cochlear potential. Recent work in my laboratory has a bearing on this study and may be of interest to readers concerned with the pathogenesis of salicylate ototoxicity. Under the hypothesis that the toxic action of salicylates occurs in the spiral ganglion and auditory nerve, an ultrastructural study of these tissues was performed in salicylate-treated animals. Six young adult albino guinea pigs received daily subcutaneous doses of 200 mg sodium salicylate per kilogram of body weight for five days from a saline solution of

Action of salicylates.

Action of salicylates.

Action of Salicylates

IT is now almost 100 years since sodium salicylate was first introduced into medicine as an antipyretic and an anti-inflammatory agent for the treatment of rheumatic fever. The salicylates are now among the most widely used and abundantly consumed of all drugs. Many proprietary analgesic compounds also contain some salicylate perhaps to ensure a therapeutic effect. Despite their wide use and a better understanding of the metabolism of salicylates in man,1 the mechanisms whereby salicylates produce such diverse effects as analgesia, reduction of fever, increase in respiration and suppression of inflammation in connective tissue are not understood. Out of the . . .

The glucuronidation pathway

Salicylic acid (SA) and acetylsalicylic acid (ASA), unlike cortisone, promote the release of lysosomal enzymes rather than protecting rat liver lysosomal membrane. Salicylic acid inhibits the oxidation of uridine-5-diphosphoglucose (UDPG) competitively with nicotinamide adenosine dinucleotide (NAD) and noncompetitively with UDPG. It also competitively inhibits the transferring of glucuronyl group of uridine-5-phosphoglucuronic acid (UDPGA) to the phenolic acceptor. The wound-healing retardation action of salicylates is probably due mainly to its inhibitory action on mucopolysaccharide synthesis.

Action of salicylate and acetate on frog muscle action potentials

Action of salicylate and acetate on frog muscle action potentials