Effects of lisuride, a central dopaminergic agonist of the ergot type, on the biosynthesis, release and metabolism of dopamine at the dopaminergic nerve terminals of the rat brain were studied under several experimental conditions. 1) In the rat whose impulse flow of dopamine neurons and the activity of aromatic amino acid decarboxylase were inhibited by the pretreatment with γ-butyrolactone and with 3-hydroxybenzylhydrazine (NSD 1015), respectively, DOPA formation in the neostriatum and limbic forebrain were decreased significantly by the s.c. administration of lisuride at the dosage known to be ineffective on the postsynaptic dopamine receptor. 2) When it was measured by the accumulation of 3-methoxytyramine in the neostriatum and limbic forebrain of pargyline (MAO inhibitor)-pretreated rats, lisuride at the low dosage caused the inhibition of not only the spontaneous release of dopamine from the nerve terminal to the synaptic cleft, but also the release induced with methamphetamine. 3) In the rat whose dopamine biosynthesis was inhibited with α-methyl-p-tyrosine, lisuride caused the suppression of dopamine metabolism, resulting in significant increases of dopamine histofluorescence in the nucleus caudatus, olfactory tubercle and median eminence. As to the effect on dopamine histofluorescence, apomorphine at 1 mg/kg was equipotent to lisuride at 50 μg/kg. It was concluded from these results that lisuride administered at low dosage interacts preferentially with the presynaptic dopamine receptor, hereby causing the suppressive effects on the tyrosine hydroxylase reaction and the dopamine release mechanism in the dopamine nerve terminals of the brain.

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The effects of KB-1043, a new non-steroidal anti-inflammatory agent, on prostaglandin (PG) and SRS-A synthesis were investigated and compared with those of reference drugs. KB-1043 (3× 10^-5 ?? 3× 10^-4M) inhibited the PG synthesis induced by PG synthetase prepared from bovine seminal vesicles. The IC50 value was 1.33× 10^-4M. The activity of KB-1043 was less than that of indomethacin, but was about 8 times stronger than that of aspirin. However, KB-1043 (10^-6 and 10^-5M) did not increase the SRS-A released from sensitized guinea pig lung. With a concentration of 10^-4M, KB-1043 decreased the SRS-A release. On the other hand, indomethacin (10^-6 and 10^-5M), mefenamic acid (10^-6 and 10^-5M), phenylbutazone (10^-5 and 10^-4M) and aspirin (10^-4 and 10^-3M) distinctly increased the SRS-A release from sensitized guinea pig lung.

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Pharmacological actions of lisuride hydrogen maleate (lisuride) were studied by using isolated organs. 1) Lisuride at 2.2 μM exerted a negative chronotropic effect on guinea-pig atria, the effect being antagonized completely by 2.9 μM sulpiride. 2) α-Adrenolytic action of lisuride was observed in the rat vas deferens and β-adrenolytic action in the rabbit trachea, respectively. The former (ID50=64 nM) was potent and equivalent to that of phentolamine, whereas the latter (ID50=26μM) was only 1/30 as compared to that of propranolol. 3) Anti-5-hydroxytryptamine action (ID50=11 nM) was detected in the rat stomach and anti-histamine (ID50=15 nM) in the guinea-pig ileum, respectively. In these respective activities, lisuride was equipotent to methysergide and diphenhydramine. 4) Lisuride showed a spasmodic action, which may be categolized as an ergot alkaloid action, on the guinea-pig ileum and on rabbit renal artery. A weak positive inotropic action of lisuride was also observed in guinea-pig atria. In the rat uterus, however, no uterotonic action of lisuride was detected. It is concluded that, in addition to its known effects on the central nervous system, lisuride possesses potent peripheral anti-5-hydroxytryptamine and anti-histamine activities.

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Effects of antitussive drugs on the phrenic nerve activities during the cough reflex were investigated by means of a power spectrum analysis as a quantitative evaluation of each of the frequency band components of the phrenic nerve activities in anesthetized dogs. The efferent activities of the phrenic nerve were recorded from the central cut end of the phrenic nerve. Each fraction of the phrenic nerve activity was fractionated into bands spanning a range of 100 Hz each by a variable filter and analyzed using a program for the power spectrum analysis. The increase in power of each of the frequency band components was observed during the cough reflex induced by mechanical stimulation of the tracheal mucosa. Particularly, the power of the 2 ?? 100 Hz band components increased significantly as compared with the other frequency band components. An i.v. administration of codeine (3 mg/kg) significantly inhibited the increase in power of all frequency band components during the cough reflex. After administration of dextromethorphan (10 mg/kg, i.v.) or fominoben (8 mg/kg, i.v.), the increase in power of the 2 ?? 100 Hz band components of the phrenic nerve activity during the cough reflex was decreased significantly for 5 ?? 10 min; however, the other frequency band components were not affected. These results provide some evidence for a difference between these three antitussive drugs with respect to the mechanisms of action in the process of the central integration for the cough reflex.

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The possible alteration of central dopaminergic (DA) function, which accompanies the development and persistence of hypertension, was studied in SHRSP by measuring the lisuride-induced locomotor activity and the swimming ability. 1) When administered at a dosage of 50 μg/kg, lisuride, a DA agonist, induced significant increases of the locomotor activity in one- and 2-month-old Wistar Kyoto rats (WKY), but not in the 6 month-old rat. Differing from the response of WKY, SHRSP showed only a moderate increase in the locomotor activity at the age of one month (means of systolic blood pressure: 128 mmHg) and apparently no increase at the age of 2 months (176 mmHg). In 6 month-old SHRSP (238 mmHg), hypomotility but not hypermotility was induced by the lisuride administration. 2) Though no significant difference was detected at the age of 4 months, the swimming ability of SHRSP at the age of 8 months was deteriorated significantly as compared to that of WKY, and the impaired swimming performance of SHRSP was improved by the administration of lisuride. These results indicate that some alterations in the synaptic sites of the central DA neuron occurred already at an early stage of the hypertensive development, followed under persistent hypertension by the progressive deterioration of the motor-coordination ability as detected in the swimming ability.

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Eight month-old SHRSP were treated s.c. with lisuride (50 μg/kg per day) for 5 weeks to examine the effect of the central dopaminergic agonist on the deterioration of swimming ability that occurred and progressed under persistent hypertension. General observations on signs and symptoms and histopathological examinations were also carried out with the same rats to evaluate the drug effect on the deterioration of hypertensive symptoms. The poor swimming performance of hypertensive SHRSP was improved significantly by the direct action of lisuride with a maximal effect at the 2nd week of the treatment, although the progress of the deterioration itself was not prevented by the chronic treatment. One week after the drug treatment, 2 out of 8 rats in the control group but none in the lisuride-treated group exhibited the abnormal behavior with aggressiveness, a typical sign of the occurrence of cerebrovascular lesions. Furthermore, macroscopic and histopathological examinations carried out 2 weeks after the drug treatment revealed that severities of the histopathological lesions such as myocardiac necrosis and arteriolosclerosis in the kidney, adrenal and testis were significantly lower in the lisuride-treated group than in the control.

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Effects of azosemide on urinary volume, urinary and plasma electrolyte levels and plasma urea nitrogen (PUN) and creatinine (PCr) levels were studied in rats with HgCl₂-induced acute renal failure pretreated with SA-446, an angiotensin I converting enzyme inhibitor, or propranolol, a β-blocker which is known to inhibit reninangiotensin (R-A) system; and the effects were compared with those of furosemide. At 3 hr after a single s.c. injection of 2 mg/kg of HgCl₂, plasma renin activity (PRA) showed a 1.8 fold increase which was significantly different as compared with that before treatment with HgCl₂. Although the PRA thereafter reduced and reverted to the normal level by 24 hr, PUN and PCr levels still continued to increase later. At 24 hr after the injection of 2 mg/kg of HgCl₂, azosemide and furosemide even at the large dose of 320 mg/kg p.o. had little or no effect on diuresis. At 2, 9 and 23 hr after the injection of 2 mg/kg of HgCl₂, the animals were orally treated with SA-446 at 50 mg/kg once or propranolol at 80 mg/kg once. When azosemide at 320 mg/kg was orally administered at 1 hr after the last treatment with SA-446 or propranolol, it resulted in 4.4 and 3.8, 2.2 and 4.5 fold increases in urinary volume and urinary Na⁺, K⁺ and Cl^- excretions, respectively, in the case of pretreatment with SA-446; while 2.5 and 3.4, 1.8 and 3.1 fold increases in urinary volume and urinary Na⁺, K⁺ and Cl^- excretions, respectively, were observed in the case of propranolol. Although this drug alone had little effect on PUN and PCr levels, it caused a potent reducing action of both parameters by pretreatment with SA-446 and a tendency of a reducing action by that with propranolol. The potentiation of the diuretic action of azosemide by pretreatment with the blocker of the R-A system was somewhat greater than that of furosemide. It is suggested from these results that the R-A system may partly participate in the development of HgCl²-induced acute renal failure of rats and the combination of azosemide with SA-446 or propranolol in the phase of elevated PRA may be beneficial for potentiating the diuretic action of this drug.

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The physical dependence liability of guanabenz, a hypotensive agent with central noradrenergic α₂-agonistic activity, was investigated. 1) Guanabenz showed a potent analgesic effect nearly equipotent to morphine by the modified Haffner's method, and repeated p.o. treatment resulted in the development of tolerance to the effect. 2) In the combined treatment of guanabenz with morphine or hexobarbital, it potentiated morphine analgesia and prolonged hexobarbital hypnosis in a dose dependent manner. 3) The natural withdrawal signs appearing in morphine or barbital dependent mice was suppressed by guanabenz; however, the effect was accompanied by a marked loss of body weight and weakness of the animals, and especially the dose required for the suppression of barbital withdrawal signs was extremely high and was even lethal in some cases. A substitution test in barbital dependent mice showed that guanabenz could not substitute for barbital. In the primary dependence test after 30 days oral treatment with guanabenz, no appreciable withdrawal signs were observed after discontinuation of the administration. Thus, from the results obtained in the present experiments, it is revealed that guanabenz possesses no physical dependence liability of the morphine or barbital type.

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