Protective effect of eptazocine, a novel analgesic, against cerebral hypoxia-anoxia in mice

Cerebral protective effect of eptazocine, a mu-antagonist-kappa-agonist, was investigated using mice subjected to hypoxia-anoxia. Eptazocine (1 to 10 mg/kg) prolonged the survival time of mice subjected to KCN (3 mg/kg, i.v.) injection in a dose-dependent manner, and this effect was completely inhibited by naloxone (5 mg/kg). EKC, U50,488H, opioid kappa-agonists, also had such an effect, but were weaker than eptazocine. In mice exposed to hypobaric hypoxia (190 mmHg), eptazocine (3, 10 mg/kg) and EKC (10 mg/kg) prolonged the survival time, but morphine (5 mg/kg) and pentazocine (10 mg/kg) shortened the time. The eptazocine effect was attenuated by either naloxone (5 mg/kg) or atropine (0.5 mg/kg), different from what was seen in the case of physostigmine and diazepam, and the combination of eptazocine (1 mg/kg) and physostigmine (0.075 mg/kg) had a potentiating effect. MR-2266, a selective kappa-receptor antagonist, inhibited the eptazocine effect more potently than naloxone. These results suggest that eptazocine elicited its cerebral protective effect via its binding with opioid kappa-receptors and probably an activation of the central cholinergic system.     

Anti-hypotensive effects of M6434, an orally active alpha 1-adrenoceptor agonist, in rats.

The anti-hypotensive effects of M6434 were evaluated and compared with those of other orally active sympathomimetics in rats. Oral administration of M6434 (0.5-2.0 mg/kg) and midodrine (1.0-5.0 mg/kg) also produced a dose-related increase in mean arterial pressure in normotensive rats. The pressor effect of M6434 was about 4 times more potent than that of midodrine. Both M6434 and midodrine caused a dose-dependent decrease in heart rate. The pressor effect of M6434 (1.0 mg/kg) did not diminish after its repeated administration for 7 days. The pretreatment with M6434 (0.5-1.0 mg/kg) and midodrine (2.0-5.0 mg/kg) improved the orthostatic index in the experimental model of postural hypotension in rats. The effect of M6434 on postural hypotension was about 5 times more potent than that of midodrine. Intravenously injected M6434 (3-300 micrograms/kg) produced a dose-dependent increase in the blood pressure of pithed rats. These results suggest that M6434 possesses a potent antihypotensive activity which is superior to that of midodrine, and M6434 may be useful in the treatment of essential and postural hypotension.     

Effect of DP-1904, a thromboxane synthetase inhibitor, on antigen- and spasmogen-induced bronchoconstriction in rodents

The effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetra-hydronaphthalene-2-car boxylic acid hydrochloride], a selective thromboxane synthetase inhibitor, was examined on antigen- and spasmogen-induced bronchoconstriction in rodents. Oral administration of DP-1904 (1, 3, 10 mg/kg) as well as OKY-046 (sodium (E)-3[4-(1-imidazolylmethyl)-phenyl]-2-propanoate, 100 mg/kg), significantly inhibited immunoglobulin G-mediated bronchoconstriction in actively sensitized guinea pigs. Immunoglobulin E-mediated bronchoconstriction in actively sensitized rats was also inhibited by both DP-1904 (1, 10 mg/kg) and OKY-046 (100 mg/kg). DP-1904 (3-30 mg/kg) and OKY-046 (30 mg/kg) suppressed leukotriene D4-induced bronchoconstriction in guinea pigs. In these models, the endogenous levels of thromboxanes significantly increased following the stimulus (antigen and leukotriene D4). DP-1904 (10 mg/kg) inhibited the increase in thromboxane level in both plasma and bronchial alveolar lavage fluid. These actions of DP-1904 persisted for more than 12 h, indicating a long-lasting effect of DP-1904 on bronchoconstriction. The results showed that the biological activity of DP-1904 in our rodents models is more potent than that of OKY-046 (Ozagrel), which is available as an anti-asthma agent in Japan.     

Effects of ropinirole on various parkinsonian models in mice, rats, and cynomolgus monkeys

Ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride) a nonergoline dopamine receptor agonist with high affinity for native dopamine D(2)-like receptors in human caudate tissue, was tested with respect to the stimulation of postsynaptic brain dopamine receptors in standard preclinical models of Parkinson's disease. Additionally, in these animal models the antiparkinsonian activity of ropinirole was compared to that of bromocriptine. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the turning behavior in 6-OHDA-lesioned rats were 20.17 mg/kg (14.27-26.88 mg/kg) and 11.99 mg/kg (9.37-14.17 mg/kg), respectively. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the catalepsy induced by reserpine were 18.55 mg/kg (15.29-22.99 mg/kg) and 12.56 mg/kg (10.25-14.64 mg/kg), respectively. Ropinirole and bromocriptine had no effect on the tremors induced by oxotremorine in mice, whereas atropine markedly suppressed the tremors. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the tremors in VMT-lesioned monkeys were 0.18 mg/kg (0.12-0.29 mg/kg) and 2.63 mg/kg (1.06-6.45 mg/kg), respectively. In rodent parkinsonian models, bromocriptine was more potent than ropinirole; however, in the nonhuman primate parkinsonian model, ropinirole was a more potent inhibitor of parkinsonian activity than bromocriptine. This study suggests that ropinirole is a dopamine D(2)-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.     

Effects of a new anti-inflammatory imidazole derivative, fenflumizole, on platelet aggregation in the rabbit

The antiplatelet effect of fenflumizole, compared with aspirin or ticlopidine, was examined in in vitro, ex vivo and in vivo situations of the rabbit. Unlike ticlopidine, fenflumizole and aspirin effectively inhibited in vitro the platelet aggregation elicited by arachidonate and collagen. The activity of fenflumizole was 350 times more potent than that of aspirin. Fenflumizole (0.3-3 mg/kg) given p.o. was 4.2 and 8.1 times more potent than aspirin in inhibiting arachidonate- and collagen-induced platelet aggregations, respectively. Ticlopidine (300 mg/kg, p.o.) resulted in only weak effects on the aggregations. Fenflumizole (3 mg/kg) as well as aspirin (10 mg/kg) given p.o., unlike ticlopidine (300 mg/kg), effectively prevented the arachidonate-induced sudden death.     

Discriminative stimulus properties of cocaine. Effects of apomorphine, haloperidol, procaine and other drugs

In pigeons trained to discriminate between the presence and absence of 3 mg/kg of cocaine, combinations of intramuscularly injected (i.m.) procaine (0.7-7.0 mg/kg) plus cocaine (0.3-3.0 mg/kg) did not alter the drug (cocaine)-dose generalization curve as compared to cocaine alone although tests with large doses of procaine given alone (30.0 and 56.0 mg/kg) engendered dose-related responding appropriate to cocaine. Apomorphine (0.56 mg/kg, i.m.) also elicited more than 50% cocaine-appropriate responding, as did doses of 10 mg/kg of intragastrically administered cocaine, given by gavage at the opening of the proventriculus; of the two treatment-test intervals (15 and 30 min) examined the generalization effect was greater at 30 min as compared to 15 min after administration. D-Lysergic acid diethylamide (0.1 mg/kg) morphine (3.0 mg/kg), pentobarbital (10.0 mg/kg), and delta 9-tetrahydrocannabinol (0.3 mg/kg) caused less than 16% pecking responses on the cocaine-appropriate key. The discriminative stimulus effects of cocaine (3.0 mg/kg) were attenuated in a dose-related manner by the neuroleptic haloperidol (dose range tested: 0.1-1.0 mg/kg). Neither the antagonism, nor the substitution tests with haloperidol were accompanied by a significant change in the percentage of responding on the initially selected position (key) by the pigeons.     

Anxiolytic-like profile of propofol, a general anesthetic, in the plus-maze test in mice

The present study was performed to investigate the effect of propofol on anxiety using the elevated plus-maze test. Groups of mice received propofol (20, 40, 60 mg/kg) or diazepam (2 mg/kg), caffeine (30 mg/kg), L-arginine (100 mg/kg), m-chlorophenylpiperazine (m-CPP, 2.5 mg/kg) and then were placed in an elevated plus-maze that was composed of two opposite closed arms and two opposite open arms. Propofol (20, 40, 60 mg/kg) and diazepam (2 mg/kg) significantly increased the percentage of time spent in the open arms compared to control. Caffeine (30 mg/kg) and m-CPP (2.5 mg/kg) decreased the percentage of time spent in the open arms and these effects were antagonized when propofol (40 mg/kg) was administered before the test. L-arginine (100 mg/kg) has also produced anxiogenic effect and this effect was not prevented by propofol. All drugs used in this study did not significantly change locomotor activity. These results suggest that propofol has anxiolytic effect in plus-maze test.     

TRK-820, a selective kappa-opioid agonist, produces potent antinociception in cynomolgus monkeys

TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride) has been shown to be a potent opioid kappa-receptor agonist with pharmacological properties different from those produced by kappa1-opioid receptor agonists in rodents. To ascertain whether or not these properties of TRK-820 would be extended to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly (i.m.) produced a potent antinociceptive effect that was 295- and 495-fold more potent than morphine with the 50 degrees C and 55 degrees C hot-water tests, respectively, and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine in the 50 degrees C hot-water test. The duration of antinociceptive effects of TRK-820 treatment (0.01 and 0.03 mg/kg, i.m.) lasted more than 6 h, which was much longer than those of U-50,488H. The antinociception produced by the higher dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine (3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine and naloxone effectively inhibited the antinociception induced by the higher doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively. These results indicate that the antinociception induced by TRK-820 is less sensitive to nor-binaltorphimine and suggest that it is mediated by the stimulation of a subtype of kappa-opioid receptor different from the kappa-opioid receptor in cynomolgus monkeys.     

Antihypertensive effect of arotinolol (S-596), a new adrenergic beta blocking agent, on experimental hypertension

Effects of a new adrenergic beta-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other beta-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the beta- or alpha-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day) propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the beta-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596, (10-50 mg/kg/day) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic alpha-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the 1st administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.     

The behavioral effects of heptyl physostigmine, a new cholinesterase inhibitor, in tests of long-term and working memory in rodents.

We assessed the effects of heptyl physostigmine, a new cholinesterase inhibitor, in a mouse tail-flick (TF) test, a mouse and rat passive avoidance test, a rat conditioned suppression-of-drinking (CSD) test, a rat Random Interval (RI) response rate test and a rat delayed matching-to-position (DMTP) test. In the TF test, a dose of 8.0 mg/kg of heptyl induced a significant antinociceptive effect that was in excess of 75% of the maximum possible effect 300 minutes after administration. In the mouse passive avoidance test, a dose of 3.0 mg/kg of heptyl fully reversed, and a dose of 1.0 mg/kg partially reversed, a scopolamine-induced (0.2 mg/kg) deficit. In the rat passive avoidance test, a dose of 8.0 mg/kg fully reversed a scopolamine-induced (0.2 mg/kg) deficit, while a dose of 4.0 mg/kg of heptyl was without effect. In the same experiment, a dose of 0.6 mg/kg of physostigmine partially reversed the scopolamine-induced deficit. In the CSD test, a dose of 8.0 mg/kg of heptyl fully reversed, and doses of 1.0 and 4.0 mg/kg of heptyl partially reversed, the deficit induced by scopolamine (0.4 mg/kg). In the RI response rate test, doses of 8.0 mg/kg and 0.6 mg/kg of physostigmine fully suppressed lever pressing for food rewards. Doses of 4.0 mg/kg of heptyl and below had no effect on lever-pressing rates. In the working memory test (DMTP), 4.0 mg/kg heptyl partially reversed the scopolamine-induced deficit (0.2 mg/kg) in the number of correct choices made, but did not affect the scopolamine-induced deficit in the number of trials completed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of morphine,d-amphetamine,and pentobarbital on shock and light discrimination performance in rats

The effects of 2 and 4 mg/kg morphine sulfate, 0.5 and 1 mg/kg d-amphetamine sulfate, and 6 and 12 mg/kg pentobaribital sodium were tested in rats in two different discrete-trial two-choice discrimination tasks. The discriminative stimuli for one task were high and low intensity shocks. In the other, correct choices were signaled by the position of a brief light flash. Morphine (4 mg/kg) significantly disrupted performance of both tasks, with more reliable disturbance occurring in the shock discrimination animals. Pentobarbital (12 mg/kg), while exerting noticeable effects on gross motor behavior, had little effect on discrimination performance; d-amphetamine (1 mg/kg) was disruptive of discrimination performance in only some animals. The results indicate that much of the effect of relatively low doses of morphine on the shock discrimination performance of rats may be due not to its putative specific antinociceptive properties, but to alterations in conceptual-judgmental processes or decreases in motivation (e.g., hunger) unrelated to pain.     

Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis

RATIONALE: Several studies have provided evidence that antagonists and partial agonists of glycine(B) receptors exhibit an anxiolytic-like activity in different animal models. OBJECTIVE: Using the conflict-drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of D-cycloserine (DCS), a partial agonist of the glycine(B) site of the N-methyl-D-aspartate (NMDA) receptor complex. Diazepam was used as a reference drug. RESULTS: DCS (200 and 300 mg/kg) and diazepam (5 mg/kg) produced an anxiolytic-like effect in rats by increasing the number of shocks accepted. We also demonstrated that NMDA (15 mg/kg) reduced the anxiolytic-like activity of DCS (200 mg/kg), whereas glycine (800 mg/kg) and flumazenil (10 mg/kg) did not affect the anticonflict effect of DCS (200 mg/kg). The anticonflict effect of diazepam (5 mg/kg) was totally blocked by flumazenil (10 mg/kg). CONCLUSION: The obtained results have shown that DCS exhibits an anxiolytic-like activity which depends on NMDA receptors rather than on glycine(B) or benzodiazepine sites.     

A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.     

Pharmacological studies on timiperone, a new neuroleptic drug Part II: General pharmacological properties

General pharmacological properties of 4'-fluoro-4-[4-(2-thioxo-1-benzimidazolinyl) piperidino] butyrophenone (timiperone), a new neuroleptic drug, were compared with those of haloperidol. 1. Central nervous system: In behavioral observation, timiperone showed a typical neuroleptic profile at doses of 0.1 mg/kg p.o. and more (mice). The drug produced a moderate hypothermia at 10 mg/kg p.o. (rabbits), a mild increase in pain threshold at 3 mg/kg p.o. (mice and rats) and a slowing of cortical EEG at 1 mg/kg i.v. (cats). ED50 values of drug for the potentiation of ether and alcohol anesthesia were 0.34 and 0.22 mg/kg p.o., respectively (mice). Timiperone ahd neither an anticonvulsant activity at 30 mg/kg p.o. (mice) nor an effect on the spinal reflex at 1 mg/kg i.v. (cats). These effects of timiperone on the central nervous system were almost similar to those of haloperidol. 2. Respiratory and cardiovascular system: At dose of 0.03 mg/kg i.v. and more, timiperone produced transient increases in respiratory rate and regional arterial blood flow which were accompanied by a fall in blood pressure (dogs). Haloperidol had qualitatively similar effect, but was weaker than timiperone. Both drugs at high concentration (3X10-6 g/ml) exerted negative inotropic and chronotropic effect in isolated atrial preparations (guinea-pigs), and non-competitively antagonized the positive chronotropic action of isoprenaline. Atropine (2.5X10-7 g/ml) failed to modify the chronotropic action of timiperone (3X10-6 g/ml). 3. Autonomic nervous system: Timiperone at 0.1 mg/kg p.o. and haloperidol at 0.3 mg/kg p.o. induced a moderate miosis (rabbits) and antagonized blood responses to noradrenaline and acetylcholine (dogs). Both drugs at 1 mg/kg i.v. had no ganglion-blocking activity (cats). 4. Smooth muscle: In isolated guinea-pig ileum and vas deferens, timiperone and haloperidol (10-5 g/ml) antagonized the contractile responses of the muscles to various spasmogens, Both drugs at approximately 10-6 g/ml decreased spontaneous motility of the isolated rat uterus and inhibited the gastric secretion at 1 mg/kg i.p. (rats). At high doses, both drugs inhibited the gastrointestinal propulsion (mice), motility (dogs) and gastric emptying rate (rats), and had no damaging effect on the gastric mucosa (rats). 5. Skeletal muscle: At 0.1 mg/kg i.v., timiperone and haloperidol slightly enhanced twitch response of the anterior tibial muscle to electrical stimulation (rabbits). 6. Urine volume and urinary electrolytes: Timiperone and haloperidol showed a diuretic effect at 3 mg/kg p.o. whereas they inhibited urine output and electrolytes excretion at 30 mg/kg p.o. (rats).     

Betaxolol, a cardioselective beta-adrenoceptor antagonist, attenuates ischemic myocardial acidosis in dogs

The effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial acidosis were studied in dog hearts, in which the left anterior descending coronary artery was partially occluded for 90 min, and were compared with those of atenolol and propranolol. Myocardial ischemia produced a decrease in myocardial pH (measured by a micro glass pH electrode) and an elevation of the ST segment of epicardial ECG (assessed by a surface electrode). Betaxolol (0.01, 0.03 or 0.1 mg/kg), atenolol (0.03 or 0.1 mg/kg) or propranolol (0.03 or 0.1 mg/kg), when injected i.v. 30 min after ischemia, restored myocardial pH and the ST segment of ECG that had been altered by partial occlusion. However, the effect of betaxolol on myocardial acidosis was more potent than that of atenolol or propranolol. The decrease in (+)dp/dt by betaxolol (0.03 mg/kg) was less potent than that by atenolol (0.1 mg/kg) and equivalent to that by propranolol (0.1 mg/kg), although the restorations of myocardial acidosis by the drugs were almost equivalent. These results have confirmed that beta-adrenoceptor antagonists attenuate the ischemia-induced myocardial acidosis and have shown that among three beta-adrenoceptor antagonists, betaxolol is the most effective in improving myocardial acidosis with a relatively weak effect on myocardial contractile function.     

Quinpirole, 8-OH-DPAT and ketanserin modulate catalepsy induced by high doses of atypical antipsychotics

The effect of the selective dopamine D2 receptor agonist quinpirole, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2A receptor antagonist ketanserin on catalepsy induced by atypical antipsychotics clozapine, risperidone, olanzapine and sertindole at higher doses was studied in rats. Haloperidol (0.5, 1 and 2 mg/kg), clozapine (50 and 75 mg/kg) and olanzapine (15 and 30 mg/kg) produced catalepsy dose-dependently while sertindole at doses up to 40 mg/kg failed to produce catalepsy in rats. However, sertindole (15, 30 and 45 mg/kg) produced a cataleptic effect in mice in a dose-dependent manner. At a high dose (5 mg/kg), risperidone produced catalepsy in rats. Quinpirole (0.05 and 0.1 mg/kg) reversed the cataleptic effect of haloperidol (2 mg/kg), risperidone (5 mg/kg), olanzapine (30 mg/kg) and sertindole (45 mg/kg). Quinpirole (0.05 and 0.1 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15 and 0.3 mg/kg) dose-dependently reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg) without affecting the cataleptic effect of olanzapine. However, the higher dose (0.45 mg/kg) of 8-OH-DPAT reversed it significantly. 8-OH-DPAT (0.3 mg/kg) reversed clozapine (75 mg/kg)-induced catalepsy. 8-OH-DPAT (0.15, 0.3 and 0.45 mg/kg) failed to reverse sertindole-induced catalepsy. Ketanserin (0.75 and 1.5 mg/kg) completely reversed catalepsy induced by haloperidol (2 mg/kg) and risperidone (5 mg/kg). Ketanserin (0.75 and 1.5 mg/kg) dose-dependently reversed olanzapine (30 mg/kg) and sertindole (45 mg/kg)-induced catalepsy without any effect on clozapine (75 mg/kg)-induced catalepsy. A higher dose (3 mg/kg) of ketanserin reversed clozapine-induced catalepsy. The present study suggests that atypical antipsychotics show fewer extrapyramidal symptoms (EPS) due to greater modulation of the serotonergic system. Therefore, an antipsychotic with dopamine D2/5-HT2A antagonistic action and 5-HT1A agonistic action may prove to be superior to the existing antipsychotics.     

Antihypertensive activity of alacepril, an orally active angiotensin converting enzyme inhibitor, in renal hypertensive rats and dogs

Alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219) showed a dose related and long lasting antihypertensive effect in renal hypertensive rats (two-kidney, one-clip), a typical renin dependent hypertensive model. The maximum hypotensive potency of alacepril (1-30 mg/kg) after single oral administration was slightly weaker than that of captopril (1-30 mg/kg). Judging from the AOC (area over the antihypertensive curve) value, the overall antihypertensive activity of alacepril was 3 times more potent than that of captopril on a weight basis. The long lasting antihypertensive effect of alacepril in renal hypertensive rats was also confirmed by once daily successive oral administration (1-2 mg/kg/d). In renal hypertensive dogs, alacepril (3 mg/kg) showed a stable and sustained hypotensive effect, and its duration of action was longer than that of captopril. Although alacepril did not possess a significant in vitro angiotensin converting enzyme (ACE) inhibitory activity, orally given alacepril (5.6-56.1 mg/kg) produced a potent and prolonged in vivo ACE inhibition which was estimated by suppression on angiotensin-I (310 ng/kg i.v.) induced pressor response in conscious normotensive rats. The prolonged in vivo ACE inhibitory activity of alacepril (5.6 mg/kg) was also observed in conscious normotensive dogs. These results suggest that the disposition and metabolism of orally given alacepril are responsible for the prolonged ACE inhibition and, concomitantly, for exerting the long lasting antihypertensive effect. Consequently, alacepril is a novel orally active ACE inhibitor having a potent and prolonged antihypertensive activity, and these properties suggest that alacepril is favorable for the treatment of hypertension.     

Effects of cadralazine on the respiration, circulation, kidney, autonomic nervous system, digestive system, blood and so on

The general pharmacological effects of cadralazine and its major metabolite ISF 2405 were studied by comparing them with those of hydralazine. Cadralazine at 3.0 mg/kg, i.v., increased respiratory movement and heart rate and decreased blood pressure in cats. Cadralazine at 3.0 mg/kg, i.v., inhibited the hypertensive response induced by adrenaline, but showed little effect on the hypotensive response induced by acetylcholine in cats. Cadralazine and ISF 2405 at 10(-4) g/ml had negative chronotropic effects on isolated guinea-pig atria. The drug at 2.5 mg/kg, p.o., inhibited the passage of BaSO4 in the gastrointestinal tract in mice. The drug at 5.0 mg/kg, i.d. or more inhibited gastric secretion in rats. Cadralazine, except at higher doses, had little effect on spontaneous gastric motility and uterine spontaneous movement in rats. Cadralazine at 2.5 mg/kg, p.o., or more reduced or tended to reduce urine volume and urinary excretion of electrolytes. The drug showed little effect on coagulation and osmotic fragility in blood cell in rats nor on hemolysis and platelet aggregation in rabbits. ISF 2405, however, showed slight or moderate influence on hemolysis at concentrations as high as 0.01-1.0%. Cadralazine at 5.0 mg/kg, p.o. or more antagonized carrageenin-induced hind paw edema in rats. In conclusion, these effects of cadralazine were found to be qualitatively identical with those of hydralazine.     

The hemodynamic effects of lacidipine in anesthetized dogs: comparison with nitrendipine, amlodipine, verapamil, and diltiazem.

The hemodynamic effects of lacidipine in anesthetized, open-chest dogs were compared with those of nitrendipine, amlodipine, verapamil and diltiazem. Lacidipine administered intravenously induced dose-related, long-lasting reductions in systemic and coronary vascular resistance with corresponding increases in aortic flow and coronary blood flow. The hypotensive effect (ED25 for mean blood pressure reduction = 0.006 mg/kg) was still significant 120 min after administration with all doses tested. Nitrendipine was equipotent with lacidipine in reducing the mean blood pressure (ED25 = 0.005 mg/kg), but its effect was shorter acting (significant effect at 120 min only with the highest dose tested). Amlodipine caused a marked and long-lasting hypotension though at higher doses than lacidipine (ED25 = 0.50 mg/kg). Short-lasting hypotensive responses were also detected with verapamil (ED25 = 0.1 mg/kg) and diltiazem (ED25 = 0.12 mg/kg). A reflex increase in heart rate was observed with lacidipine, nitrendipine, and amlodipine, whereas verapamil and diltiazem showed a dose-related bradycardia. No effect on AV conduction was observed with lacidipine and nitrendipine, whereas amlodipine, verapamil, and diltiazem produced second- to third-degree AV block at the highest doses tested. Lacidipine and nitrendipine caused a reflex increase in contractile index at all doses, whereas amlodipine was more similar to verapamil since a marked decrease in contractile index was detected at the highest dose. Diltiazem was practically devoid of negative inotropic effect.