Effects of bucumolol, a β-adrenergic blocking agent, on blood pressure and the renin angiotensin system were studied in spontaneously hypertensive rats (SHR). The results were compared with those of propranolol at an equipotent does in β-adrenergic blocking activity. Bucumolol lowered blood pressure and decreased plasma renin concentraton (PRC) in both acute and long-term experiments. There was a significant correlation between percent changes in blood pressure and PRC following a single administration of bucumolol. Decrease in PRC persisted for the 6-week observation period despite the sustained reduction in blood pressure. On the other hand, propranolol did not lower blood pressure in acute experiment while it decreased renin release. These results suggest that inhibition of renin release is involved in the antihypertensive action of bucumolol.

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Simple compartment models are presented to describe various aspects of enterohepatic circulation pharmacokinetics of an analgesic (l-ST-2121) in rats reported previously. Appearance of trigonometric functions in the analytically integrated blood level equation adequately describes the periodic nature of the process.

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With the aim of finding a prospective therapeutic compound with a promising potential for the treatment of urolithiasis, we evaluated the effectiveness of a new potent inhibitor of urease, N-(pivaloyl) glycinohydroxamic acid. The present study revealed that N-(pivaloyl) glycinohydroxamic acid effectively inhibited the alkalinization of urine and the stone formation in vitro and in vivo, due to its strong inhibitory potency against the ureolytic activity of intact Proteus mirabilis. The possibility of the clinical application of this compound in the prevention of struvite stone formation caused by infection of urea-splitting bacteria awaits evaluation of the safety of this compound.

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We have devised a simple method to determine the ratios of cardiac to vascular β-receptor blockage (C : V ratios) in normotensive rats anesthetized with pentobarbital, and applied it to six β-adrenergic blocking drugs (β-blockers). Mean blood pressure (BP) and heart rate (HR) were recorded. Isoproterenol (3 ng-100 μg/kg, i.v.) was cumulatively injected before and after the intravenous administration of β-blockers at two dose-levels. Thus shifts of the dose-response curves in BP and HR were observed. "In vivo pA₂" values were calculated in molar doses per kg by Schild plots. The C : V ratio was calculated as antilogarithm of the difference of the mean in vivo pA₂ value in HR from that in BP. Those of atenolol, bometolol, bunitrolol, pindolol, propranolol, and sotalol were 9.77, 8.13, 2.95, 1.38, 1.20, and 0.71, respectively.

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An attempt was made to analyse the factors which might determine the time course of the end-plate current. The end-plate current was measured by clamping the membrane potential of the crayfish muscle fiber. The calculated glutamate-induced current was in good agreement with the observations obtained, suggesting that the presented kinetic model explained well the practical phenomenon. The kinetic model could be applied also to explain the depolarization change induced by prolonged application of glutamate. The semilogarithmic plots of the falling phase of calculated glutamate-induced currents gave an approximately straight line. The slope of the line yielded an apparent desensitization rate constant, and the relationship between the true and apparent desensitization rate constants was determined, but it was suggested that the desensitization rate could not be determined from the slope of the decay of glutamate-induced current alone.

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Excretion and metabolites in urine and feces of mice after oral administration of 1-hexylcarbamoyl-5-fluorouracil-6-¹⁴C (¹⁴C-HCFU) or 5-fluorouracil-6-¹⁴C (¹⁴C-FU) were examined. After oral administration, about 90% of ¹⁴C-HCFU was excreted in urine within 48 h but not in feces. Major radioactive compounds in urine were 1-(3-carboxypropylcarbamoyl)-5-fluorouracil (CPRFU), FU, 5, 6-dihydro-5-fluorouracil (DHFU) and α-fluoro-β-alanine (FBAL). Excretion ratio of these metabolites within 48 h was 13.5, 32.5, 20.2 and 23.9%, respectively, CPRFU and FU were rapidly excreted in urine after ¹⁴C-HCFU administration followed by DHFU and FBAL. Excretion of the latter two degradation products of FU was slower. On the other hand, major metabolites in urine after ¹⁴C-FU administration were DHFU and FBAL, but intact FU was slightly excreted. Excretion ratio of FU, DHFU and FBAL within 48 h was 4.8, 58.1 and 28.2%, respectively.

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Rat cholinesterase (ChE) activities were measured by DTNB-method after an oral administration of fenitrothion, and the following facts were observed. The inhibited plasma ChE (pseudo ChE) obtained within several hours after the administration was spontaneously reactivated at 10°C or over, whereas no reactivation was observed at 1°C. Neither red blood cell nor brain ChE (true ChE) was spontaneously reactivated. In vitro, the spontaneous reactivation was also observed in rat plasma ChE inhibited by oxon-type of fenitrothion. In case the activity of plasma ChE obtained 30 min after administration was determined by ΔpH-method, the activity was higher than the actual value, because of the spontaneous reactivation taking place during an incubation for 1 h at 37°C. It is suggested from these results that an utilization of ΔpH-method is unsuitable for the measurement of the activity of inhibited ChE which is spontaneously reactivated.

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Bometolol is a cardiospecific β-adrenergic blocking drug. The effect on blood pressure was determined in hypertensive rats in acute and subchronic experiments. In acute experiment bometolol, 10-30 mg/kg, p.o., was given to spontaneously hypertensive rats ; deoxycorticosterone and salt hypertensive rats ; and two kidney, one clip hypertensive rats. Blood pressure was determined continuously for 8 h and after 24 h in unanesthetized condition. The blood pressure lowered by bometolol was dose-dependent in three types of hypertension. In subchronic experiment, bometolol at a dose of 10-30 mg/kg or 100-300 mg/kg, p.o., were given for 5 weeks to deoxycorticosterone and salt hypertensive rats ; and two kidney, one clip hypertensive rats. Bometolol did not show antihypertensive effect in either type of hypertension, although bometolol decreased heart rate dose-dependently. Bometolol treatment at the above doses decreased plasma renin activity, heart and kidney weights, and incidence of vascular lesion in either hypertensive rat. Toxic symptom was seen 3 days after bometolol treatment of 300 mg/kg in deoxycorticosterone and salt hypertensive rats.

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Cathepsin B isolated from carrageenin-induced granuloma tissue was separated into two peaks (one large and one small) on CM-cellulose column chromatography. The cathepsin B activities from the peritoneal macrophages and polymorphonuclear leukocytes were eluted at the positions identical to those of the larger (P-1) and the smaller (P-II) peaks, respectively. Similarly, the cathepsin B activities in the P-I and P-II fractions from granuloma tissue corresponded to those from macrophages and leukocytes, respectively, in isoelectric focusing in polyacrylamide gel. Both the cathepsin B activities were completely inhibited by iodoacetamide and leupeptin, but phenylmethanesulfonyl fluoride and o-phenanthroline were ineffective. The molecular weight of the cathepsin B of the cellular origin and granuloma tissue was approximately 24, 000 by gel filtration. The pI value of cathepsin B in the P-I and P-II fractions from granuloma tissue was 5.09 and 5.18, respectively. These results strongly suggest that two types of cathepsin B in granuloma tissue may be different in cellular origin and may be isozymes.

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Harmine, a hallucinogen with potent monoamine oxidase inhibitory properties, induced abnormal behavior, including tremor, scratching, head twitch and cage biting, in the mouse. A dose-dependent tremor was produced by all routes of administration of harmine. Although oxotremorine tremor was markedly suppressed by atropine, harmine tremor was unaffected by cholinergic drugs, remarkably inhibited by dopaminergic drugs, antidepressants and diazepam, mildly diminished by p-chlorophenylalanine, markedly augmented by 5-hydroxytrptophan and mildly increased by α-methyl-p-tyrosine. These findings suggest that a catecholaminergic (particularly dopaminergic) and serotonergic system imbalance plays an important role in the manifestation of harmine tremor. In view of these characteristics, harmine tremor may be useful as an effective experimental model for the evaluation of antiparkinsonism drugs, along with oxotremorine tremor because of the different mechanism of occurrence. In addition, harmine tremor appears to be useful in characterizing the properties of antidepressant drugs.

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Various kinds of flavoenzymes such as NADPH-cytochrome c reductase, NADH-cytochrome b₅ reductase, xanthine oxidase, lipoamide dehydrogenase and NADH dehydrogenase supplemented with their electron donors exhibited the sulfoxide reductase activity in the presence of a partially purified soluble factor from guinea pig liver. The present study suggests that new electron transfer systems in which the soluble factor functions as an electron carrier coupled with flavoenzymes described above are responsible for the sulfoxide reduction.

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Specific antisera against oxprenolol, a beta adrenoceptor blocking agent, were produced in rabbits immunized with oxprenolol hemiglutarate-bovine serum albumin conjugate. The antiserum, beta galactosidase labelled oxprenolol and 4-methylumbelliferyl-β-D-galactoside as substrate were used to develop an enzyme immunoassay for oxprenolol. The assay can reliably detect as little as one ng of oxprenolol directly from plasma. The plasma concentrations of oxprenolol in spontaneously hypertensive rats were determined by an enzyme immunoassay after a single and multiple oral doses for 14 consecutive days. Oxprenolol was rapidly absorbed from the gastrointestinal tract and was quickly eliminated from plasma. Plasma concentrations-time data conformed to equations describing one-or two-compartment open kinetic model. No significant differences in pharmacokinetic parameters were observed between after a single dose and multiple doses.

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Effects of pregnant mare serum gonadotropin (PMS) and estradiol on the formation of 13, 14-dihydroprostaglandin F_2α (13, 14H₂-PGF_2α) from prostaglandin F_2α (PGF_2α) and 13, 14-dihydro-15-ketoprostaglandin F_2α (15KD-PGF_2α) in the ovarian homogenate of rats were examined. PMS and estradiol were given to the rats (s.c.) on the first day of diestrus, and the ovaries were removed 24 hours after treatment with each hormone. PMS stimulated the formation of 13, 14H₂-PGF_2α from PGF_2α and 15KD-PGF_2α, and estradiol markedly inhibited the formation of 13, 14H₂-PGF_2α from PGF_2α and 15KD-PGF_2α. However, the formation of 15KD-PGF_2α from PGF_2α did not change with PMS and estradiol. These results indicate that 13, 14H₂-PGF_2α formed in rat ovary may play some important role in ovarian function and may be regulated by gonadotropins and ovarian steroids.

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