Effects of ranitidine on the enzyme cholinesterase and the rat anococcygeus muscle

Ranitidine in lower doses, (100 ng and 1 microgram) accelerated the rate of reaction of the enzyme acetylcholinesterase with the substrate acetylthiocholine. However, in higher doses (10 micrograms and 100 micrograms) it inhibited the enzyme activity. In rat anococcygeus muscle preparation, the responses to acetylcholine were significantly inhibited in lower doses whereas in higher doses there was a dose-dependent potentiation of the responses to acetylcholine by ranitidine. The responses to carbachol were however, not affected by ranitidine in the same preparation. Our data suggest cholinomimetic as well as cholinolytic activity of ranitidine.     

Effects of some mono- and bisquaternary ammonium compounds on the reactivatability of soman-inhibited human acetylcholinesterase in vitro

Acetylcholinesterase (AChE) inhibited by the organophosphate soman (1,2,2-trimethyl-propylmethylphosphonofluoridate) rapidly becomes resistant to reactivation by oximes due to dealkylation of the soman-enzyme complex. This reaction is called aging. The effect of the four mono- and bisquaternary ammonium compounds tetramethylammonium (TMA), hexamethonium, decamethonium and suxamethonium on the reactivatability of soman-inhibited, solubilized AChE from human erythrocytes was investigated in vitro. All compounds were reversible inhibitors of AChE; the respective dissociation constants and the type of inhibition exhibited considerable differences. The affinities to both the active and the allosteric site were considerably higher for suxamethonium (Kii 81.3 microM; Ki 15.9 microM) and decamethonium (Kii 15.4 microM; Ki 4.4 microM) than for TMA (Kii 1 mM; Ki 289.6 microM) and hexamethonium (Kii 4.5 mM; Ki 331.8 microM). The reactivation experiments were performed in a four-step procedure (soman-inhibition at 0 degree and pH 10, aging at 37 degrees and pH 7.3, reactivation by the oxime HI 6 at 37 degrees and pH 7.3 followed by AChE assay). After these four steps (total duration 55 min), AChE was inhibited by soman to 95-100%. HI 6 could reactivate about 20% of the inhibited enzyme. All effectors increased the AChE reactivatability by HI 6 when added before aging was started. The maximal increase in reactivatability was higher in the presence of 1.6 mM suxamethonium (+35.8%) and 150 microM decamethonium (+40%) than of 22 mM TMA (+22.5%) and 8.3 mM hexamethonium (+19.2%). If the effectors were added after 5 min of aging they increased the activity of soman-inhibited AChE, but to a considerably smaller extent than HI 6. A good correlation of the respective Kii values and the effective concentrations of these drugs was observed, indicating that an allosteric binding site of AChE might be involved in the protective effect of these drugs.     

In-vitro and in-vivo protection of acetylcholinesterase by eseroline against inactivation by diisopropyl fluorophosphate and carbamates

The protective action of eseroline--(3aS,8aR)-1,2,3,3a,8,8a-hexahydro-1,3 a, 8-trimethyl-pyrrolo[2,3-b]indol-5-ol--salicylate against (DFP) diisopropyl fluorophosphate and carbamate poisoning of cholinesterases (ChEs) has been examined in-vitro with human erythrocytes and purified preparations of electric eel acetylcholinesterase (AChE) and of horse serum butyrylcholinesterase (BuChE), and in-vivo using mice. Eseroline afforded 50% protection (ED 50) of erythrocyte AChE against inactivation by 1 microM DFP, physostigmine or neostigmine, at concentrations of 4.3, 22 and 23.5 microM, respectively, while for eel AChE protection against 10 and 30 microM DFP, 0.3 and 1 microM physostigmine and 1 microM neostigmine the eseroline ED 50 values were 0.3, 0.4, 0.7, 1.9 and 5.6 microM, respectively. On the other hand, up to 0.3 mM eseroline did not appreciably affect the inhibitory action of the same drugs on horse serum BuChE. Eseroline concentrations in the range 0.1-1 mM were able to reactivate 20-42% of erythrocyte AChE previously inhibited by 100 microM physostigmine, but failed to reactivate the DFP (10 microM)-pretreated enzyme to any extent. Finally, eseroline salicylate injected into mice (10 mg kg-1 s.c.) protected an average of 82 and 26% of the animals against lethal doses of DFP (7 mg kg-1 s.c.) and physostigmine sulphate (1 mg kg-1 i.p.) respectively, which were administered 15 min later. These results indicate that the protective activity of eseroline correlates well with its own anti-ChE profile, and that the effectiveness of the protection depends largely on the rate of AChE inhibition by the agents used to inactivate the enzyme.     

Contribution of prostaglandins to the activity of guinea-pig phrenic and chicken esophageal parasympathetic nerves

In order to clarify the role of prostaglandins (PGs) in the activity of cholinergic neurones other than the ileal myenteric plexus, the effects of indomethacin (IND) and PGE2 on the contractile responses and the release of acetylcholine (ACh) induced by electrical stimulation were investigated in isolated guinea-pig phrenic nerve-diaphragm and chicken parasympathetically innervated oesophagus preparations. In the guinea-pig phrenic nerve-diaphragm preparations, IND at 56 microM did not affect the twitch responses induced by direct or indirect electrical stimulation. PGE2 at 1 microgram/ml augmented the twitch responses induced by direct or indirect stimulation of submaximal, but not of supramaximal intensity. The amounts of ACh released from the phrenic nerve by electrical stimulation were unaffected by IND (56 microM). PGE2 (0.01-1 microgram/ml) inhibited the ACh release by the nerve stimulation of high frequency (50 Hz) in a concentration-dependent manner. The inhibitory effect of PGE2 was less clear on the ACh release by lower frequency (1 Hz). Neither IND nor PGE2 affected the ACh release induced by 40 mM-K+. In the chicken parasympathetically innervated oesophagus preparation, IND (2.8-5.6 5.6 microM) augmented the twitch responses induced by the nerve stimulation at a frequency of 0.017 Hz, but not those produced by train pulse (5 sec at a frequency of 1 or 10 Hz). This augmentation was reversed by the application of PGE2 at 10 ng/ml. PGE2 at 10 ng/ml produced a transient inhibition of the twitch responses induced by 0.017 Hz or train pulses.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro protection of acetylcholinesterase and butyrylcholinesterase by tetrahydroaminoacridine. Comparison with physostigmine.

The protective action of 1,2,3,4-tetrahydro-9-aminoacridine (THA) against the long-lasting inactivation of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) brought about by diisopropylfluorophosphate (DFP) and physostigmine, as well as by neostigmine in the case of AChE only, was evaluated by a dilution technique using Electrophorus electricus AChE and horse serum BuChE as target enzymes. In parallel experiments, the ability of physostigmine itself to protect these enzymes from DFP was evaluated and compared with that of THA. THA pretreatment was seen to prevent in a dose-dependent manner the inhibition of both AChE and BuChE. However, it was appreciably more potent towards AChE than towards BuChE. THA mean EC50 values for protecting AChE against 10, 40 and 100 microM DFP were 0.04, 0.16 and 0.45 microM, respectively; against 1 microM physostigmine the value was 1.8 microM and against 1.2 microM neostigmine it was 3.0 microM. The THA mean EC50 value for protecting BuChE against 3 microM physostigmine was 0.55 microM and the values for protecting against 3, 10 and 40 microM DFP were 1.5, 3 and greater than 10 microM, respectively. The protective action of THA was time independent: recovery of the maximal enzymic activity was immediate upon dilution. Unlike THA, the protective action of physostigmine developed progressively after dilution and was maximal within 3-4 (AChE) or 6-8 hr (BuChE). Under our experimental conditions, 0.3 microM physostigmine protected approximately 70% of AChE from 40 microM DFP and 5 microM physostigmine protected 9 and 47% of BuChE from 40 and 3 microM DFP, respectively. The results of this work suggest that THA exerts its protective action by shielding the active site of AChE and BuChE from the attack of the inactivating agents on account of its higher enzymic affinity, whereas the protective action of physostigmine against DFP takes advantage also of the carbamylation of the enzyme. These results are in line with the hypothesis that protection of AChE is the primary mechanism responsible for the antidotal action of THA against organophosphorus poisoning.     

Synergistic and antagonistic pharmacodynamic interaction between ranitidine and cisapride: a study on the isolated rabbit intestine.

The present study examines the pharmacodynamic interaction between the H(2)-receptor antagonist ranitidine and the prokinetic agent cisapride on the isolated rabbit intestine. Ranitidine produced a concentration-dependent contractile effect on the duodenal, ileal and ascending colon preparations, with EC(50)values of 1.35 x 10(-4)M for the duodenum, 1.2 x 10(-4)M for the ileum and 1.15 x 10(-4)M for the ascending colon. The effect of cisapride on the ranitidine contractile effect was dependent on the cisapride concentration used. Thus, cisapride, at concentrations from 10(-10)up to 5 x 10(-7)for the duodenum and the ascending colon and up to 10(-6)M for the ileum, potentiated the contractile responses of the preparations to ranitidine. However, at higher concentrations cisapride produced a non-competitive inhibition of the intestinal contractile responses to ranitidine with IC(50)values of 4.2 x 10(-5)M for the duodenum, 1.65 x 10(-5)M for the ileum and 3.2 x 10(-6)M for the ascending colon. These data show that cisapride may modify the contractile responses of the isolated rabbit intestine to ranitidine, having a potentiating effect up to a certain concentration and an antagonistic one at higher concentrations. In conclusion, co-administration of the above drugs may lead to enhanced or reduced intestinal motility.     

Actions of domperidone on the opioid system in isolated guinea-pig ileum: differences between dopamine antagonists on opioid system

1. To validate the relationship between the dopaminergic, opioidergic and cholinergic nervous systems, we evaluated the effect of domperidone, a dopamine (D2) antagonist, on the opioid system in myenteric plexus-longitudinal muscle preparation isolated from the guinea-pig ileum. 2. One micromolar of domperidone did not affect the 0.1 Hz-evoked (duration 0.5 ms, maximum intensity) twitch response, but concentration dependently inhibited the twitch response between concentrations of 2 and 20 microM, and the inhibition was maximum after 20-30 min at the highest concentration used (20 microM). 3. Acetylcholine-evoked contraction on basal tension was also not inhibited by 1 microM domperidone, but the contraction was concentration dependently inhibited at concentrations of 10-100 microM in a non-competitive manner. 4. One micromolar of domperidone, however, increased post-tetanic twitch inhibition, an indicator of the release of endogenous opioids. This increase was completely antagonized by 1 microM naloxone. Twitch inhibition induced by dynorphin 1-13 (0.1-10 nM) was not affected by 1 microM domperidone, but increased the maximum twitch inhibition caused by morphine (0.1-1 microM). 6. These results might reflect the existence of an interaction between the dopaminergic and opioidergic system without the inhibition of the cholinergic system. Dopamine antagonists increased opioid action, an action that may depend more on the increased release of endogenous opioids than on supersensitivity of the opioid receptor.     

Interaction of ethanol and L-glutamate in the guinea pig ileum myenteric plexus.

The guinea pig ileum longitudinal muscle myenteric plexus has recently been shown to contain receptors for excitatory amino acids like L-glutamate which are pharmacologically similar to the N-methyl-D-aspartate (NMDA) receptor subtype in the central nervous system (CNS). The present study utilized the longitudinal muscle myenteric plexus preparation to determine whether the reported ability of acute ethanol treatment to inhibit NMDA receptor activation in mammalian CNS preparations also occurs in the periphery. In the absence of Mg2+, L-glutamate (3-100 microM) induced transient contractions in longitudinal muscle myenteric plexus that could be blocked by atropine. Contractile responses to L-glutamate were completely blocked by D,L-2-amino-5-phosphonovalerate (APV; 100 microM) and Mg2+ (600 microM). Preincubation with ethanol (30-100 mM) for 2 min inhibited contractions to L-glutamate by up to 50% and caused additive inhibition with 100 microM Mg2+. Ethanol (65 mM) inhibition of L-glutamate (60 microM) contractions increased from 30% after a 2 min preincubation to a maximum of 60% following 10 min. Ethanol (65 mM) inhibited contractions induced by acetylcholine (0.1 microM), 5-hydroxytryptamine (0.1 microM) or histamine (0.3 microM), by no more than 10% suggesting that impairment of smooth muscle or cholinergic neuronal activity were not likely responsible for the 40% inhibition of L-glutamate contractions seen with ethanol. A previously identified contractile response to ethanol (10-300 mM), occurring immediately after addition to the longitudinal muscle myenteric plexus preparation, was still present in Mg2+ deficient buffer.(ABSTRACT TRUNCATED AT 250 WORDS)     

A further study on the kinetics of the subcellular current events at the mouse end-plate in the presence of cimetidine and ranitidine

The cholinomimetic activity of Cimetidine and Ranitidine has been demonstrated by several authors. In the aim to better understand the phenomenon, we analyse the miniature end-plate current decay time. The prolongation of the decay phase of the synaptic current induced by the "selective" H2-antagonist Ranitidine, and to a lesser extent and at higher concentrations by Cimetidine, resembles that of the cholinesterase inhibitors. These agents usually prolong the quantal conductance change having little or no effect on the channel lifetime. The results of our previous experiments, which data were obtained by analyzing the "voltage" events, either spontaneous or evoked, of a classic frog preparation, showed a marked alteration of the temporal parameters. These effects, obtained at higher drug concentrations than those used in the present work, are now better defined by deriving extracellularly the "current" events. The results are also compared with those obtained by assaying the cholinesterase inhibitor Eserine, under the same experimental conditions.     

Interaction of ranitidine with liver microsomes

1. Ranitidine interacts with liver microsomes from rats pretreated with different inducers of cytochrome P-450 to produce substrate difference optical spectra with a peak at 426-429 nm and a trough at 390-400 nm. 2. Cytochrome P-450 reduced with dithionite in the presence of ranitidine produced substrate difference spectra with a peak at 447 nm. 3. Ks values for the interaction of ranitidine with cytochrome P-450 (not reduced), calculated from double reciprocal plots, were in the range 1.4-2.8 mM. 4. The O-dealkylation of 7-ethoxycoumarin and of p-nitroanisole was inhibited by the presence of ranitidine and the inhibition was of a mixed type. Kii and Kis values were: for inhibition of 7-ethoxycoumarin dealkylation, 0.8 to 9 mM, and 0.16 to 0.67 mM, respectively; for inhibition of p-nitroanisole dealkylation, 5.8 to 13.7 mM, and 1 to 4.5 mM, respectively. 5. The I50 values for 7-ethoxycoumarin dealkylation was 1.8 mM and for p-nitroanisole dealkylation about 7.2 mM (microsomes from phenobarbital-pretreated rats). 6. The e.p.r. spectra of cytochrome P-450 from phenobarbital-pretreated rats, in the presence of ranitidine, reveal two types of interaction depending on the ranitidine concentration. At lower concentrations of ranitidine, a ligand exchange reaction with an oxygen atom is indicated, and at higher concentrations are with nitrogenous or thioether ligand of ranitidine.     

Pharmacological properties of kryptopyrrole and its oxidation products on isolated sciatic nerve of rat and on guinea-pig ileum.

1 Kryptopyrrole (2, 4-dimethyl, 3-ethylpyrrole) inhibited conduction in rat sciatic nerve by a local anaesthetic action. 2 Tone and both spontaneous and electrically-induced contractions of guinea-pig ileum were also inhibited by kryptopyrrole. The concentration of kryptopyrrole required for 50% inhibition of a maximum twitch tension (ID50) was 0.085 mM. 3 Oxidation products of kryptopyrrole with chromatographic properties similar to those of urinary constituents reported in schizophrenia and hepatic porphyrias had little or no effect at similar concentrations. 4 Dose-response curves to exogenous acetylcholine in guinea-pig ileum were shifted to the right by kryptopyrrole, with loss of parallelism and reduction in the maximum contraction. 5 Acetylcholine overflow from ileal segments at rest and during electrical stimulation was reduced by kryptopyrrole. 6 These results on ileal segments are consistent with kryptopyrrole having both a post-junctional site of action, presumably directly on the muscle, and a pre-junctional site reducing the output of acetylcholine from the myenteric plexus. 7 The significance of these findings is discussed in relation to a possible clinical pathological role for these compounds.     

Protection against diisopropylfluorophosphate intoxication by meptazinol

The protective action of meptazinol against diisopropylfluorophosphate (DFP) was evaluated in mice which were not receiving any other therapy and in preparations of electric eel AChE and horse serum BuChE. Meptazinol injected subcutaneously in mice produced a dose-dependent reduction in the mortality resulting from a LD99.1 (8 mg/kg sc) of DFP administered later. The effectiveness of protection was inversely correlated to the time between meptazinol and DFP administrations. Under these conditions, the ED50s (95% confidence limits) of meptazinol given 15, 30, and 60 min before poisoning were 7.2 (6.4-8.1), 15.8 (13.7-18.2), and 28 (23.5-33.3) mg/kg, respectively, while full protection (100% of survivors) was obtained with 15, 30, and 60 mg/kg drug doses, respectively. Meptazinol was completely ineffective against DFP-induced lethality when administered 3 min after the poison. The protective ratio of 30 mg/kg meptazinol injected 15 min before DFP was 5.0. Pretreatment of mice with 15, 30, and 60 mg/kg meptazinol 15 min before DFP (8 mg/kg) increased brain AChE activity in DFP-treated mice from 5 +/- 0.5% to 16.2 +/- 2.5%, 42.5 +/- 4%, and 81.2 +/- 4% of control values, respectively, while it failed to increase plasma BuChE activity. Finally, concentrations of meptazinol ranging between 0.1 and 10 microM were found to afford complete protection of eel AChE against irreversible inhibition by 40 microM DFP. By contrast, horse serum BuChE was not protected against the same inhibitor by concentrations of meptazinol up to 1 mM. It is concluded that protection against DFP intoxication by meptazinol is most probably due to its protective action toward AChE.     

Inhibitory effects of H2-receptor antagonists on platelet function in vitro.

To evaluate in vitro inhibitory effects of four types of histamine H2-receptor antagonist (H2-receptor antagonists), famotidine, roxatidine, cimetidine and ranitidine, on platelet function, we examined aggregating potency and P-selectin levels with agonist-induced aggregation. Ranitidine and cimetidine inhibited, in concentration of 0.35 mM, the secondary aggregation induced by 5 microM adenosine diphosphate (ADP), the aggregation induced by 1 microg/mL collagen and 3 microM arachidonic acid. All of H2-receptor antagonists inhibited, in concentration of 1.4 mM, the aggregation induced by ADP, collagen and arachidonic acid. Ranitidine and cimetidine reduced markedly, in same concentration, P-selectin levels after induction of aggregation by 5 microm ADP, 1 microg/mL collagen and 3 microM arachidonic acid. When classified by the strength of inhibitory action, ranitidine and cimetidine were strong, followed by famotidine and roxatidine. It is considered that inhibitory effects of H2-receptor antagonists on platelet function are weaker than those of acetylsalicylic acid (ASA), since ASA inhibited platelet aggregation in concentration of 100 microM. No relationship was observed between inhibitory effects of H2-receptor antagonists on platelet aggregation induced by above agonists and the presence or absence of imidazole ring in the chemical structure.     

Action of mifentidine and ranitidine on the isolated rat uterus

The new H2-antagonist mifentidine (compound marked DA 4577) was tested for its inhibitory effect on the relaxation induced by histamine on the rat uterus and was compared with the well known H2-blocker ranitidine. Mifentidine was shown to be more effective than ranitidine (about 10 times). However whereas ranitidine behaved as a "classical" competitive antagonist, mifentidine at concentrations of 10(-7) M, caused a remarkable depression of the maximum response to histamine. This "unsurmountable" antagonism may connected with a tight binding of the compound to the receptor with a consequent low degree of dissociation. Ranitidine, but not mifentidine, at concentrations of 10(-5) M was able to potentiate the stimulatory effect of acetylcholine thus confirming also in the uterus its cholinergic-like effects so far observed mainly in the gastrointestinal tract.     

Acetylcholine hydrolysis during neuromuscular transmission in the synaptic cleft of skeletal muscle of mouse and chick

Inhibition of acetylcholinesterase (AChE) by more than 80% by neostigmine or physostigmine resulted in a failure of tetanic contraction (100 Hz) in the isolated mouse nerve-diaphragm preparation. In the chick biventer cervicis muscle, however, the tetanic contraction was well maintained and even outlasted the period of nerve stimulation after inactivation of AChE. The concentration of (+)tubocurarine for 70% block of the indirect twitch response of the mouse diaphragm at 0.1 Hz was increased from 0.67 to 0.99 to 1.21-2.03 microM in the presence of neostigmine (0.15-1.5 microM) which inhibited AChE by 70% or more, while that to depress the tetanic contraction (50 Hz) was increased from 0.38 to 0.42 to 0.53-0.69 microM. In the chick muscle, physostigmine at 2.4 microM increased the concentration of (+)tubocurarine for 70% block of the twitch response from 1.68 to 4.14 microM, whereas that for block of the response to exogenous acetylcholine (ACh) was increased from 1.47 to 74.6 microM. On single stimulation, the relative peak concentrations of acetylcholine (ACh) at the postsynaptic receptor site of the mouse diaphragm and chick biventer cervicis were estimated to be increased by about 110 and 120% respectively, after complete inhibition of AChE. In the chick muscle, physostigmine increased the relative concentration of ACh by about 40-fold at the receptor site for exogenously applied ACh. It is concluded that the intrinsic ACh released from the nerve terminal is hydrolyzed by about 50% during the time of diffusion across the synaptic cleft whereas most of exogenous ACh is hydrolyzed before reaching the target.     

Ranitidine but not famotidine releases acetylcholine from the guinea pig myenteric plexus

The effects of the histamine H2-receptor antagonists ranitidine and famotidine on acetylcholine release have been studied in the guinea pig myenteric plexus longitudinal muscle preparation incubated with [3H]-choline. Ranitidine (3 x 10(-5)-3 x 10(-4) M) dose-dependently increased the resting release of acetylcholine and that evoked by electrical stimulation. The effect was present only in strips perfused with 10(-5) M physostigmine. The effect of ranitidine was inhibited by tetrodotoxin and hexamethonium. Famotidine (10(-5)-3 x 10(-4) M) was totally ineffective in modifying both the resting release and that evoked by field stimulation. Ranitidine did not antagonize the inhibitory effect of oxotremorine, which specifically activates negative feedback mechanisms via presynaptic muscarinic receptors.     

Calcium dependence of baclofen- and GABA-induced depression of responses to transmural stimulation in the guinea-pig isolated ileum

Both baclofen and gamma-aminobutyric acid (GABA) induced a dose-dependent depression of cholinergic twitch contractions in the transmurally stimulated guinea-pig isolated ileum. Over a range of 0.6-2.4 mM Ca2+, the degree of depression was inversely related to the Ca2+ concentration, with an increased sensitivity and sinistral shift of the dose-response curve at lower Ca2+ concentrations. Partial occupation of Ca2+ channels by Ruthenium Red (0.1 microM) also potentiated the depressive responses to baclofen and GABA. It is concluded that these agonists, acting through GABAB receptors, limit the availability of Ca2+ required for neurotransmitter release in myenteric motor nerves.     

Changes in the levels and forms of rat plasma cholinesterases during chronic diisopropylphosphorofluoridate intoxication

The effect of chronic administration of diisopropylphosphorofluoridate (DFP) on the levels and forms of plasma cholinesterase (ChE), were studied in male Wistar albino rats sacrificed at different time intervals after various schedules of treatment. In particular the inhibition and recovery rate of the enzymatic activity was evaluated for butyrylcholinesterase (BuChE), determined using butyrylthiocholine (BuThCh) as substrate and for acetylcholinesterase (AChE), measured using acetylthiocholine (AcThCh) in the presence of iso-OMPA 0.1 mM. At 1 1/2 and 24 hr after the DFP treatments, BuChE was considerably more depressed than was the case for AChE. Moreover, the recovery of BuChE proceeded more slowly, its activity being restored only seven days after the last treatment, while the recovery of AChE was completed 72 hr after the end of the treatments. Plasma molecular forms were separated by polyacrylamide gel electrophoresis and were revealed by enzymatic reaction with BuThCh or AcThCh as substrates. By using selective inhibitors, five main molecular forms of BuChE and two of AChE were found to exist in control plasma samples. A differential inhibition and recovery rate was observed among these forms after DFP intoxication. At 1 1/2 hr after the treatments, the BuChE activity was too low to be detected on the gels, but 24 hr thereafter, the quantitative determination of the different forms, performed by scanning densitometry, showed a significant increase of the two faster migrating ones. At the following time intervals, the electrophoretic pattern returned progressively towards normality. The faster migrating forms are therefore probably the first synthesized in the process of recovery of BuChE activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ketamine inhibits the anticholinesterase activity of ranitidine and physostigmine

1. The present study was performed to investigate the effect of ketamine on the contractile responses induced by the H₂-receptor antagonist ranitidine and the anticholinesterase agent physostigmine on the isolated guinea pig ileum.2. The contractile responses induced by ranitidine and physostigmine on the guinea pig ileum were significantly prevented, in a concentration-dependent manner, by ketamine, while the ones induced by acetylcholine were not modified. The contractile responses induced by acetylcholine were inhibited by exogenous acetylcholinesterase. Ranitidine and physostigmine inhibited the above reduction, and this effect was significantly prevented by ketamine in a concentration-dependent manner.3. These findings show that ketamine inhibits the contractile effect of ranitidine and physostigmine on the guinea pig ileum. This inhibition caused by ketamine seems to be associated with the protection of acetylcholinesterase against the inhibition by ranitidine and physostigmine.     

石杉碱乙的抗胆碱酯酶作用

目的：测试石杉碱乙的抗胆碱酯酶作用并与他克林进行比较,方法：比色法用于测定胆碱酶活性。结果：石杉碱乙和他克林对ＢｕＣｈＥ和ＡＣｈＥ抑制的ＩＣ５０值的比率分别为６５．８和０．５４,石杉碱乙对乙酰胆碱酯酶有更强的选择性抑制作用。石杉碱乙灌胃对脑内ＡＣｈＥ的抑制作用明业强于他克林,而他克林对ＢｕＣｈＥ的抑制作用强于石杉碱乙,并有严重副反应,单次灌胃石杉碱乙在４小时内对脑内ＡＣｈＥ产生较对稳定的抑制作用,