Nature of alpha receptors implicated in the hypertensive effect of high doses of isoprenaline in dogs and rats

Isoproterenol injected intravenously in dogs (3 mg/kg-1) and rats (5 mg/kg-1) induced an increase in blood pressure. After alpha 1 blockade (by AR-C 239, 0.1 mg . kg-1 i.v.) or alpha 2 blockade (by yohimbine, 1 mg/kg-1 i.v.) isoproterenol, as adrenaline, again induced an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2 adrenoceptor blocking agent after an alpha 1 adrenoceptor blocking agent, and vice versa. These results are compatible with stimulation by high doses of isoproterenol of both alpha 1 and alpha 2 adrenoceptors to produce increase in blood pressure.     

Biological effects of a proglumide derivative as cholecystokinin antagonist in conscious dogs

In conscious dogs we studied the effects of a new cholecystokinin (CCK) antagonist (coded CR 1505) on CCK8-stimulated exocrine pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of CCK8 (25-400 ng kg-1h-1) were infused i.v. Experiments were repeated against a background infusion of CR 1505 at different doses (0.1, 1 and 10 mg kg-1h-1). The lowest dose of CR 1505 had no biological effects. However, at the upper two doses the compound significantly inhibited the CCK8-stimulated PP release. Furthermore, a significant inhibition of exocrine pancreatic protein secretion was observed with 10 mg kg-1h-1 of CR 1505 (P less than 0.05). The results suggest that CR 1505 could be a useful tool in defining the physiological role of CCK in vivo.     

Effects of clonazepam on picrotoxin-induced convulsions.

The convulsant effects of four doses of picrotoxin (PX)-2, 3, 4, and 6 mg/kg s.c.-were evaluated in the first part of the study. The 4-mg/kg dose, which elicited minimal seizures in all animals, generalized tonic-clonic (major) seizures in 75% of rats and fatal outcome in 69% of rats, was chosen for the second part, i.e. for testing the anticonvulsant action of clonazepam (Rivotril Roche, 0.1 or 1 mg/kg i.p.). Clonazepam exhibited a dose-dependent action against PX-induced seizures, being more efficient against major than against minimal seizures.     

Analgesic activity of Piper longum Linn. root

Piper longum root, commonly called Kandantippili, is traditionally used to treat rheumatism, insomnia, palsy and epilepsy. But a scientific study on its central actions is not available. This study screens P. longum root for opioid type analgesia using rat tail-flick method and for NSAID type analgesia using acetic-acid writhing method. Pentazocine (ip) and ibuprofen (oral) are used as respective drug controls. An aqueous suspension of P. longum root powder is given orally to mice and rat in doses of 200, 400 and 800 mg/kg. The delay in reaction time for thermal stimulus in rats and the number of writhings to chemical stimulus in mice are determined in each group. The results are analysed statistically. The 400 and 800 mg/kg doses of P. longum show significant NSAID type of analgesia (P < 0.001). Both Ibuprofen (40 mg/kg) and P. longum (800 mg/kg) show 50% protection against writhing. The delay in reaction time to thermal stimulus was less than 6% for different doses of P. longum as against 100% for pentazocine. This indicates that P. longum root has weak opioid but potent NSAID type of analgesic activity.     

Cicaprost inhibits metastases of animal tumors.

Since an involvement of platelet aggregation in the metastatic process has been found, platelet activation inhibitors were investigated for their potential to reduce tumor metastases. Recent in-vitro and in-vivo investigations showed an antimetastatic effect of prostacyclin (PGI2) and stable prostacyclin analogues. This study concentrates on the effect of the stable prostacyclin analogue Cicaprost (Schering AG) on tumor metastases in two metastasizing tumors of rodents. C57BL/6 mice bearing s.c.-implanted M5076 reticulum sarcoma were treated with Cicaprost in doses of 0.1-1.0 mg/kg throughout the experiment. Cicaprost in all doses tested reduced the number of liver metastases in a statistically significant manner. The 1.0 mg/kg dose, which decreases the median number of liver metastases to more than 93% compared to the control, was most effective. Cicaprost in the 0.5 mg/kg dose reduced the number of liver metastases in mice bearing i.v.-implanted M5076 reticulum sarcoma. In Cop-Fisher rats bearing s.c.-implanted spontaneously metastasizing R3327 MAT Lu prostate carcinoma, Cicaprost in a dose of 1.0 mg/kg p.o. daily strongly reduced the number of lung metastases. These results indicate that Cicaprost is a potent inhibitor of tumor metastases in different tumor models in rodents.     

Interaction between GABAergic anticonvulsants and the NMDA receptor antagonist MK 801 against MES- and picrotoxin-induced convulsions in rats

The interaction between GABAergic (barbiturates, diazepam, ethanol) and other (phenytoin) anticonvulsants and the N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 in protecting rats against maximal electroshock (MES)- and picrotoxin-induced (10 mg/kg) convulsions was studied. MK 801 (0.1 to 5 mg/kg) showed anticonvulsant responses against MES-induced convulsions in a dose dependent manner, higher doses showing severe muscle relaxation, motor incoordination, and anticonvulsant action. It also produced stereotypic head movement, circling behavior, and affected locomotion. When subanticonvulsant dose (1 mg/kg) of MK 801 was simultaneously administered with subprotective doses of GABAergic anticonvulsants, it significantly potentiated the effects of barbiturates, as compared to other agents. At 1 mg/kg, MK 801 did not offer protection against tonic convulsions though protected (100%) the animals from mortality due to picrotoxin-induced convulsions. It potentiated the effect of a subprotective dose (5 mg/kg) of pentobarbital, but not of diazepam, against tonic convulsions. However, no mortality was observed in either group. The antiglutamate action of barbiturates, particularly that of pentobarbital, may contribute to the observed potentiating response between pentobarbital and MK 801.     

Regulation of Histamine Turnover via Muscarinic and Nicotinic Receptors in the Brain

To clarify the regulation of central histaminergic (HAergic) activity by cholinergic receptors, the effects of drugs that stimulate the cholinergic system on brain histamine (HA) turnover were examined, in vivo, in mice and rats. The HA turnover was estimated from the accumulation of tele-methylhistamine (t-MH) during the 90-min period after administration of pargyline (65 mg/kg, i.p.). In the whole brain of mice, oxotremorine, at doses higher than 0.05 mg/kg, s.c., significantly inhibited the HA turnover, this effect being completely antagonized by atropine but not by methylatropine. A large dose of nicotine (10 mg/kg, s.c.) also significantly inhibited the HA turnover. This inhibitory effect was antagonized by mecamylamine but not by atropine or hexamethonium. A cholinesterase inhibitor, physostigmine, at doses higher than 0.1 mg/kg, s.c., significantly inhibited the HA turnover. This effect was antagonized by atropine but not at all by mecamylamine. None of these cholinergic antagonists used affected the steady-state t-MH level or HA turnover by themselves. In the rat brain, physostigmine (0.1 and 0.3 mg/kg, s.c.) also decreased the HA turnover. This inhibitory effect of physostigmine was especially marked in the striatum and cerebral cortex where muscarinic receptors are present in high density. Oxotremorine (0.2 mg/kg, s.c.) and nicotine (1 mg/kg, s.c.) also decreased the HA turnover in the rat brain. However, these effects showed no marked regional differences. These results suggest that the stimulation of central muscarinic receptors potently inhibits the HAergic activity in the brain and that strong stimulation of central nicotinic receptors can also induce a similar effect.     

Anticonvulsant effects of phencynonate hydrochloride and other anticholinergic drugs in soman poisoning: neurochemical mechanisms

Previous studies have paid little attention to the anticonvulsant effect of anticholinergic drugs that act on both muscarinic (M) and nicotinic (N) receptors during soman-induced seizures. Therefore, with the establishment of a soman-induced seizures model in rats, this study evaluated the efficacy in preventing soman-induced convulsions of two antagonists of both the M and N receptors, phencynonate hydrochloride (PCH) and penehyclidine hydrochloride (8018), which were synthesized by our institute, and of other anticholinergic drugs, and investigated the mechanisms of their antiseizures responses. Male rats, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with the oxime HI-6 (125 mg kg-1, i.p.) 30 min before they were administered soman (180 microg kg-1, s.c.). All animals developed seizures subsequent to this treatment. Different drugs were given at different times (5, 20 and 40 min after seizures onset) and their anticonvulsant effects were monitored and compared using the two variables, i.e. the dose that could totally control the ongoing seizures, as well as the speed of seizures control. The anticonvulsant effects of atropine, scopolamine and 8018 decreased with the progression of the seizures, and they eventually lost their anticonvulsant activity when the seizures had progressed for 40 min. In contrast, PCH showed good anticonvulsant effectiveness at 5 and 20 min, and especially at 40 min after seizures onset. Of the anticholinergic drugs tested, atropine, scopolamine, and 8018 showed no obvious protection against pentylenetetrazol (PTZ)-induced convulsions or N-methyl-D-aspartate (NMDA)-induced lethality in mice. However, PCH antagonized the PTZ-induced convulsions in a dose-dependant manner with an ED50 of 10.8 mg kg-1, i.p. (range of 7.1-15.2 mg kg-1) and partly blocked the lethal effects of NMDA in mice. PCH also dose-dependently inhibited NMDA-induced injury in rat primary hippocampal neuronal cultures, suggesting a possible neuroprotective action in vivo. In conclusion, our study suggests that the mechanisms of PCH action against soman-induced seizures might differ from those of the M receptor antagonists atropine and scopolamine, and that of the antagonist of both the M and N receptors, 8018. The pharmacological profile of PCH might include anticholinergic and anti-NMDA properties. Compared with the currently recommended anticonvulsant drug diazepam, with known NMDA receptor antagonists such as MK-801 and with conventional anticholinergics such as scopolamine and atropine, the potent anticonvulsant effects of PCH during the entire initial 40 min period of soman poisoning, and its fewer adverse effects, all suggest that PCH might serve as a new type of anticonvulsant for the treatment of seizures induced by soman.     

The ethanol-induced open-field activity in rodents treated with isethionic acid, a central metabolite of taurine.

The effect of isethionic acid, a central metabolite of taurine, on ethanol-induced locomotor activity was investigated in rodents. Ten minutes following an (i.p.) simultaneous administration of ethanol (0.0, 1.5, 2.0, 2.5, 3.0, 3.5 g/kg) and isethionic acid (0.0, 22.5, 45.0, 90.0, 180.0 mg/kg), mice were placed in the open-field chambers and locomotor activity was measured during a ten-minute testing period. A significant interaction was found between isethionic acid and ethanol. Isethionic acid pre-treated mice (45.0, 90.0 and 180.0 mg/kg) showed a higher locomotor activity than the saline group at 2.5 and 3 g/kg of ethanol. In a second study, isethionic acid (45 mg/kg) and ethanol (1 g/kg) were simultaneously injected to rats. Ten minutes after the two treatments, rats were placed in the open-field chamber for a 30-minute period. The depressant effects that ethanol produced on rat locomotion were amplified by the same dose of isethionic acid as it affected ethanol-induced locomotion in mice (45 mg/kg). However, isethionic acid did not change the spontaneous locomotion at any of the doses tested in mice or rats. Since no differences in blood ethanol levels were detected in both mice and rats, the interaction between isethionic acid's action and ethanol-related locomotion does not seem to be due to different rates of absorption of ethanol or any other pharmacokinetic process related to ethanol levels. The current study displayed that isethionic acid, administered intraperitoneally, behaves in a similar way to its immediate precursor, taurine, by amplifying ethanol-induction of the locomotor activity.     

Effects of N-methylnaloxone and N-methylnaltrexone on nociception and precipitated abstinence in mice

Subcutaneous administrations of naloxone and naltrexone have already been shown to enhance nociceptive reactions in mice. The present study was undertaken to examine the effects of N-methyl-naloxone and N-methylnaltrexone on nociception using the hot plate test (dose range: 0.3 to 30 mg kg-1s.c.). The latter compounds were selected to differentiate the central and peripheral components of hyperalgesia. Unlike naloxone, N-methyl-naloxone did not produce hyperalgesia. Similarly low doses of N-methylnaltrexone did not enhance the jumping response. However, a high dose of N-methylnaltrexone (30 mg kg-1 s.c.) significantly reduced the jumping latencies 2 h after its administration. This phenomenon indicated that it might be converted to an active metabolite. Further, N-methylnaloxone and N-methylnaltrexone were very weak in precipitating the signs of abstinence in mice rendered acutely dependent on morphine. Two factors, poorer penetration into the CNS and steric hindrance, might render the N-methylated antagonists weak. Hence, both these factors should be considered when interpreting the effects after quaternary derivatives of opioid antagonists.     

Combined cocaine hydrolase gene transfer and anti-cocaine vaccine synergistically block cocaine-induced locomotion

Mice and rats were tested for reduced sensitivity to cocaine-induced hyper-locomotion after pretreatment with anti-cocaine antibody or cocaine hydrolase (CocH) derived from human butyrylcholinesterase (BChE). In Balb/c mice, direct i.p. injection of CocH protein (1 mg/kg) had no effect on spontaneous locomotion, but it suppressed responses to i.p. cocaine up to 80 mg/kg. When CocH was injected i.p. along with a murine cocaine antiserum that also did not affect spontaneous locomotion, there was no response to any cocaine dose. This suppression of locomotor activity required active enzyme, as it was lost after pretreatment with iso-OMPA, a selective BChE inhibitor. Comparable results were obtained in rats that developed high levels of CocH by gene transfer with helper-dependent adenoviral vector, and/or high levels of anti-cocaine antibody by vaccination with norcocaine hapten conjugated to keyhole limpet hemocyanin (KLH). After these treatments, rats were subjected to a locomotor sensitization paradigm involving a "training phase" with an initial i.p. saline injection on day 1 followed by 8 days of repeated cocaine injections (10 mg/kg, i.p.). A 15-day rest period then ensued, followed by a final "challenge" cocaine injection. As in mice, the individual treatment interventions reduced cocaine-stimulated hyperactivity to a modest extent, while combined treatment produced a greater reduction during all phases of testing compared to control rats (with only saline pretreatment). Overall, the present results strongly support the view that anti-cocaine vaccine and cocaine hydrolase vector treatments together provide enhanced protection against the stimulatory actions of cocaine in rodents. A similar combination therapy in human cocaine users might provide a robust therapy to help maintain abstinence.     

Induction of micronuclei in bone marrow of mice exposed to 1, 2 or 3 daily doses of urethane

Urethane was studied for its potential to induce micronuclei in bone marrow of CD-1 mice following various dosing and sampling schedules. It was found that: (1) mice dosed for 3 days by gavage with urethane at daily doses of 300, 600 and 1200 mg.kg-1 showed no increases in micronuclei compared to normal control values; (2) mice injected with 3 daily intraperitoneal (i.p.) doses of urethane at 400 and 1200 mg.kg-1 demonstrated substantial and dose-related increases in micronuclei; (3) mice given urethane at i.p. doses of 400 mg.kg-1 for 1, 2 and 3 days showed protocol related micronucleus yields with triple greater than single greater than double dosing, while mice given urethane at i.p. doses of 1200 mg.kg-1 showed a different trend with double greater than single dosing, the triple-dosing regimen proving cytotoxic to the bone marrow; (4) mice exposed i.p. to 400 mg.kg-1 of urethane had more micronuclei when sampled at 24 h than at 48 h after 1 or 2 daily treatments, while mice dosed i.p. with 1200 mg.kg-1 of urethane showed more micronuclei at 48 h than at 24 h after a single treatment, the double-dosing protocol being toxic to the marrow; (5) female mice were more susceptible to bone-marrow micronucleus induction than males with both quantitative and qualitative sex differences noted, depending on dose, regimen and sample.     

Effects of the administration of progesterone and adrenal medullectomy on the plasma fibrinogen levels in rats with surgical injury (laparotomy)

The probable r?le played by the adrenal medulla in the decrease of plasma fibrinogen due to the administration of progesterone (0.5 mg kg-1 day-1 during 72 h) in rats submitted to surgical injury (laparotomy) was studied. The results obtained lead to assume that the decrease of plasma fibrinogen observed in laparotomized rats injected with progesterone is indirectly produced through inhibition of the adrenal medulla. The action of progesterone on the plasma fibrinogen would be a pharmacological effect of the drug, since in doses of 0.10 mg kg-1 day-1 the decrease of the fibrinogen is not observed in laparotomized rats. The administration of progesterone in non injured rats does not modify the plasma fibrinogen as compared to the group of non injected rats.     

Psychopharmacological profile of hydro-alcoholic extract of Euphorbia neriifolia leaves in mice and rats

The leaf extract of E. neriifolia significantly reduced apomorphine-induced stereotypy in mice at all doses (100, 200, 400 mg/kg body weight) in mice and rats and was devoid of catalepsic effect thereby, suggesting specific dopaminergic receptor modulating activity. The extract (400 mg/kg) potentiated pentobarbitone-induced hypnosis. It showed protection against maximal electro-shock-induced convulsion at 400 mg/kg. E. neriifolia leaf extract had anxiolytic action at 400 mg/kg by increasing the percentage of time spent in open arm in elevated plus-maze. The extract did not reverse scopolamine-induced amnesia on elevated plus-maze. It increased transfer latency at 200 and 400 mg/kg and also in combination with scopolamine. These results indicated anti-anxiety, anti-psychotic and anti-convulsant activity of E. neriifolia leaf extract in mice and rats. Phytochemical study showed the presence of steroidal saponin, reducing sugar, tannins, flavonoids in the crude leaf extract     

Measurement of HPRT mutations in splenic lymphocytes and haemoglobin adducts in erythrocytes of Lewis rats exposed to ethylene oxide

Young adult male Lewis rats were exposed to ethylene oxide (EO) via single intraperitoneal (i.p.) injections (10-80 mg kg-1) or drinking water (4 weeks at concentrations of 2, 5, and 10 mM) or inhalation (50, 100 or 200 ppm for 4 weeks, 5 days week-1, 6 h day-1) to measure induction of HPRT mutations in lymphocytes from spleen by means of a cloning assay. N-ethyl-N-nitrosourea (ENU) and N-(2-hydroxyethyl)-N-nitrosourea (HOENU) were used as positive controls. Levels of N-(2-hydroxyethyl)valine (HOEtVal) adducts in haemoglobin (expressed in nmol g-1 globin) were measured to determine blood doses of EO (mmol kg-1 h, mM h). Blood doses were used as a common denominator for comparison of mutagenic effects of EO administered via the three routes. The mean HPRT mutant frequency (MF) of the historical control was 4.3 x 10(-6). Maximal mean MFs for ENU (100 mg kg-1) and HOENU (75 mg kg-1) were 243 x 10(-6) and 93 x 10(-6), respectively. In two independent experiments, EO injections led to a statistically significant dose-dependent induction of mutations, with a maximal increase in MF by 2.3-fold over the background. Administration of EO via drinking water gave statistically significant increases of MFs in two independent experiments. Effects were, at most, 2.5-fold above the concurrent control. Finally, inhalation exposure also caused a statistically significant maximal increase in MF by 1.4-fold over the background. Plotting of mutagenicity data (i.e., selected data pertaining to expression times where maximal mutagenic effects were found) for the three exposure routes against blood dose as common denominator indicated that, at equal blood doses, acute i.p. exposure led to higher observed MFs than drinking water treatment, which was more mutagenic than exposure via inhalation. In the injection experiments, there was evidence for a saturation of detoxification processes at the highest doses. This was not seen after subchronic administration of EO. The resulting HPRT mutagenicity data suggest that EO is a relatively weak mutagen in T-lymphocytes of rats following exposure(s) by i.p. injection, in drinking water or by inhalation.     

Relationship between experimental results in mammals and man: II. Cytogenetic analysis of bone-marrow cells after treatment of cytembena and cyclophosphamide-cytembena combination

Cytogenetic analysis and the micronucleus test of bone-marrow cells was used to study the possible extrapolation of results from experimental animals to man.Cytembena was given i.p. in doses of 5, 10, 20, 40 and 80 mg/kg body wt. to Wistar rats in doses of 20, 40 and 80 mg/kg body wt. to ICR mice an dto Chinese hamsters. Five patients with various types of malignancy, so far medically untreated, received 20 mg Cytembena/kg body wt i.v.A combination of Cytembena and cylophosphamide was applied i.p. in single equal doses 1 : 1 of 5, 10, 20, and 40 mg/kg body wt to ICR mice, Chinese hamsters and Wistar rats. Patients were given i.v. 20 mg Cytembena and 20 mg cyclophosphamide/kg body wt.Bone-marrow cells were examined 24 h after the administration.The frequency of abnormal metaphases and chromosomal breaks after Cytembena treatment was low; nonetheless, the indicated dose-effect relationship was found in all the rodents used. The frequency of chromosomal breaks was 2–3 times higher in rodents in comparison with man, after treatment with a dose of 20 mg Cytembena/kg body wt.Highest frequencies of induced aberrations were found in mice. The rodents appeared to be 3–4 times more sensitive to the induction of chromosomal breaks and abnormal metaphases than man, after a dose of 20 mg Cytembena and 20 mg cyclophosphamide/kg body wt.     

Comparison of anticonvulsant effect of ethanol against NMDA-, kainic acid- and picrotoxin-induced convulsions in rats

The anticonvulsant effect of ethanol against N-methyl-D-aspartic acid-(NMDA), kainic acid-, and picrotoxin-induced convulsions was studied in rats. Ethanol (2 g/kg, ip) offered protection against these agents, and it was most effective against picrotoxin and least effective against kainic acid. MK801, NMDA receptor antagonist, also provided protection against these agents. However, it was most effective against NMDA and least effective against kainic acid. Ineffective doses of MK801 (0.1 mg/kg, ip) and ethanol (0.5 g/kg, ip), when administered concurrently, had a facilitatory anticonvulsant effect, thereby providing protection against mortality following severe convulsions induced by NMDA or picrotoxin, but not against kainic acid. The protective effect of ethanol against NMDA- and kainic acid-induced neurotoxicity, in contrast to picrotoxin-induced toxicity, was not reversed by imidazodiazepine, Ro 15-4513, an ethanol antagonist. Furthermore, Ro 15-4513 did not produce any proconvulsant effect with NMDA or kainic acid. These findings suggested that the anticonvulsant actions of ethanol may be attributed to its ability to antagonize NMDA-mediated excitatory responses and facilitate the GABAergic transmission.     

Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent

BACKGROUND: Tardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D2 and serotonin 5-HT1A receptors in in vitro competition binding assays. In the present work, we tested its p-toluenesulfonyl derivative (TPBIA) for behavioral effects in rats, related to interactions with central dopamine receptors and its antioxidant activity. METHODS: Adult male Fischer-344 rats grouped as: i) Untreated rats: TPBIA was administered i.p. in various doses ii) Apomorphine-treated rats: were treated with apomorphine (1 mg kg-1, i.p.) 10 min after the administration of TPBIA. Afterwards the rats were placed individually in the activity cage and their motor behaviour was recorded for the next 30 min The antioxidant potential of TPBIA was investigated in the model of in vitro non enzymatic lipid peroxidation. RESULTS: i) In non-pretreated rats, TPBIA reduces the activity by 39 and 82% respectively, ii) In apomorphine pretreated rats, TPBIA reverses the hyperactivity and stereotype behaviour induced by apomorphine. Also TPBIA completely inhibits the peroxidation of rat liver microsome preparations at concentrations of 0.5, 0.25 and 0.1 mM. CONCLUSION: TPBIA exerts dopamine antagonistic activity in the central nervous system. In addition, its antioxidant effect is a desirable property, since TD has been partially attributed, to oxidative stress. Further research is needed to test whether TPBIA may be used as an antipsychotic agent.     

Protective effect of polysaccharides-enriched fraction from Angelica sinensis on hepatic injury

A polysaccharides-enriched fraction from the root of Angelica sinensis, which is known for its antiulcer action on the gastrointestinal tract, was isolated and studied for its hepato-protective effect in rodents. Intra-gastric administration of Angelica sinensis polysaccharides-enriched fraction (AP) at the doses of 50 or 75 mg/kg dose-dependently prevented liver toxicity induced by acetaminophen in mice but did not affect the serum acetaminophen concentration. It normalized the rises of serum alanine transferase (ALT) and hepatic nitric oxide synthase (NOS) activities and the decrease of glutathione level in the liver. It also reduced the hepatic malondialdehyde (MDA) concentration. The protective effect was less evident in the carbon tetrachloride (CCl4)-treated animals including mice and rats. In the rat the elevated serum ALT level was unaffected though the MDA level was similarly reduced by the higher dose of AP. In these animals, CCl4 increased the hepatic glutathione level instead while the NOS activity remained unchanged. These findings suggest that the pathogenic mechanisms of both acetaminophen and CCl4 are different. AP is more effective in the protection against liver damage induced by acetaminophen, which is associated with the glutathione depletion and nitric oxide synthase activation in the liver.     

Angiotensin-converting enzyme inhibitory and antihypertensive activities of pivalopril (RHC 3659-(S))

Pivalopril (RHC 3659-(S); (S)-N-cyclopentyl-N-(2-methyl-3-pivaloylthiopropionyl) glycine) is a new compound with a hindered sulfur group that has been compared to captopril for oral angiotensin-converting enzyme (ACE) inhibition in rats and dogs and antihypertensive activity in rats. In separate groups of conscious normotensive rats, pivalopril (0.03-1.0 mg/kg, orally [p.o.]) produced a dose-related antagonism of angiotensin I (AngI)-induced pressor effects. The ED50 for pivalopril and captopril was 0.1 mg/kg. In conscious normotensive dogs, pivalopril (incremental doses of 0.01-1.0 mg/kg, p.o.) produced a dose-related antagonism of AngI pressor effects. The ED50 was 0.17 mg/kg for pivalopril and 0.06 mg/kg for captopril. At equieffective doses the two compounds had similar durations of action. In sodium-deficient, conscious spontaneously hypertensive rats (SHR), pivalopril (1-100 mg/kg, p.o.) produced a dose-related reduction in mean arterial pressure. The potency and duration were similar to those of captopril. In the sodium-replete SHR, 5 days of oral dosing with pivalopril, 100 mg/(kg . day), decreased mean arterial pressure more effectively than captopril, 100 mg/(kg . day). No tolerance developed to the antihypertensive effect of either drug. It is concluded that pivalopril is a potent, orally effective ACE inhibitor and antihypertensive agent.