The effects of nadolol on experimental arrhythmias were investigated and compared with those of propranolol and alprenolol. The arrhythmias were induced by either ouabain, holothane plus adrenaline or acute coronary occlusion in anesthetized dogs. All three β-blocking drugs in a does range of 10 to 200μg/kg inhibited halothane plus adrenaline-induced arrhythmias. These drugs also attenuated coronary occlusion-induced ventricular arrhythmias as well as other electrical abnormalities such as electrical alternation and conduction delay. Among the three drugs, nadolol was the most potent in suppressing both types of arrhythmias. Contrary to the potent effects on these arrhythmias, nadolol was ineffective against ouabain-induced arrhythmias even in a dose of 3 mg kg, while propranolol and alprenolol were significantly effective in a dose of 100μg/kg. It is probable that the anti-arrhythmic effect of nadolol is exclusively due to its β-blocking activity.

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Effect of a new anti-inflammatory drug which has a little ulcer inducing property on gastrointestinal tract, TA-60 (2-[4-(3-methyl-2-butenyl) phenyl] propionic acid), on the prostaglandin (PG) metabolism was investigated. TA-60 inhibited the PGE₂ biosynthesis of the bovine seminal vesicle microsome dose-dependently. The inhibition constant (K_i) of TA-60 was approximately 8 μM. The potency of TA-60 was approximately the same and two times that of ibuprofen (IP) and phenylbutazone (PBZ), respectively. TA-60 did not show the time dependent inhibition of the PGE₂ biosynthesis unlikely to indomethacin (IM). The decrease in the PGE₂ contents in the stomach of the rats by TA-60 reached a plateau and the content was not decreased to less than a certain level. The PGE₂ content of the intestine was not changed by TA-60. TA-60 did not inhibit the activity of the PG degradating enzyme, 15-hydroxy PG dehydrogenase (15-OH-PG-DH) of the gastric mucosa like the other non-steroidal anti-inflammatory drugs (NSAIDs) : IP, PBZ and IM. These results suggest that the slight ulcerating effect of TA-60 on the gastrointestinal tract might be resulted from the small decreasing effect of TA-60 on the gastrointestinal level of PGE₂.

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The usefulness of the renal clearance of endogenous N¹-methylnicotinamide (NMN) as a probe for estimating the renal blood flow (RBF) was examined in rats. And the effect of experimental acute renal failure (ERF) on RBF was also examined in rats treated with glycerol, folate, salicylate, uranium and gentamicin by using this method. No significant difference was shown between the values of RBF determined by the NMN method and conventional p-aminohippurate (PAH) method in both the in tact (control) and glycerol-ERF rats, suggesting the usefulness of the NMN method in determining RBF. No significant difference was also shown in RBF between the control and all ERF-rats studied, through significant decreases in the renal clearance of NMN and renal extraction ratio (ER) were observed in the ERF-rats except the gentamicin-treated rats. It was suggested that the endogenous NMN would be a useful probe to estimate RBF without constant infusion of exogenous substances.

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The plasma insulin and serum glucose levels were compared after the subcutaneous and intravenous administration of porcine and human insulin in rats. While no difference was observed in plasma insulin or serum glucose levels with either insulin after intravenous administration, the plasma insulin levels and hypoglycemic effects of human insulin were greater than those of porcine insulin after subcutaneous administration. At various time intervals, radioactivity in subcutaneous tissue was assayed for insulin and/or its metabolites by gel filtration. Using these data, the absorption and degradation rate constants of these substances were estimated according to a one-compartment model. The degradation rate constants of human insulin was approximately half of that for porcine insulin.

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We compared the in vitro degradation of porcine and human insulin in the subcutaneous tissue of rat. The insulin degrading activity was largely confined to the 160000×g supernatant fraction of subcutaneous tissue. The degradation of human insulin was approximately half that of porcine insulin in the supernatant fraction. The degradation of porcine insulin in subcutaneous tissue was inhibited by bacitracin, leupeptin, phosphoramidon, and Z-Gly-Pro-Leu-Gly, though the human insulin degradation was not. The degradation of both insulins was accelerated by glutathione. While the proteolytic enzyme activities of cathepsin-B and collagenase-like peptidase were detectable in subcutaneous tissue, chymotrypsin, elastase, kallikrein, α-thrombin, and trypsin activities were almost negligible. These in vitro studies suggest that human insulin is comparatively stable against proteolytic enzymes, probably collagenase-like peptidase or cathepsin-B, in the subcutaneous tissue, which support the in vivo evidence.

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The effect of dicyclomine, a cholinergic blocking agent, on the in situ intestinal absorption, plasma clearance, biliary excretion of dexamethasone was examined in rats. The plasma concentrations and area under the plasma concentration-time curve (AUC) of dexamethasone after both a single and repeated oral coadministration with dexamethasone phosphate (4mg/kg) and dicyclomine (4mg/kg) were significantly reduced compared with those after dexamethasone alone, without the alteration of elimination rate. The in situ absorption study also indicated that the absorption of dexamethasone was reduced to about a half after repeated coadministration of the two drug. The renal plasma flow (RPF) in coadministration group was significantly enhanced compared with that of dexamethasone alone. The biliary excretion of dexamethasone was reduced, in proportion to the plasma concentrations, by dicyclomine. Therefore, dicyclomine should be administered taking much care in the corticosteroid treatment, because of producing the decrease in absorption.

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Arotinolol (S-596, ARL) is a β-adrenoceptor blocking drug with weak α-adrenoceptor blocking activity, and may be classified into the fourth generation. Antihypertensive effects of ARL were studied for 12 weeks in spontaneously hypertensive (SHR) rats. Propranolol (PPL) was used as the reference drug. ARL (20 and 100mg/kg per day, p.o.) and PPL (100mg/kg per day, p.o.) treatments significantly decreased heart rate, within a week after the drug treatments had started and thereafter. Tail blood pressure (BP), determined by prewarming the rat at 50°C for 3min, was slightly higher in the two ARL treated groups than in the control. Tail BP was slightly lower in the PPL treated group than in the control. Mean BP determined directly at the 12th week was lower in the two ARL and PPL groups than in the control by more than 20mmHg. Both ARL (100mg/kg per day) and PPL (100mg/kg per day) treatments significantly reduced incidences of the vascular lesions, and also prevented the decrease of kidney weights usually asociated with mild vascular lesions. Furthermore, these treatments showed a tendency to decrease plasma renin (PRC) and aldosterone (PAC) concentrations determined 20h after the last administration. As mean BP must be more reliable than tail BP, it was concluded that ARL (20 and 100 mg/kg per day) showed almost the same chronic antihypertensive activity in SHR rats as PPL (100mg/kg per day). Preventive effects of ARL on development of vascular lesions also supported the above view.

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Single neuronal activity was recorded extracellularly in the ventrobasal (VB) nucleus of the thalamus in non-adjuvant arthritic rats under urethane (1200mg/kg, i.p.) anesthesia. The effects of morphine and indomethacin on the evoked responses elicited by noxious stimuli such as transcutaneous electrical stimulation (TES) or tibial nerve electrical stimulation (TNES), or non-noxious stimulation such as repetitive brushing were examined. Intravenous administered morphine (0.1, 0.3 and 1mg/kg) depressed the evoked responses elicited by either TES or TNES without affecting any background activities. In contrast, intravenous administered indomethacin (1, 3 and 10mg/kg) depressed the evoked responses induced by TES, but failed to depress the evoked responses induced by TNES. At doses of 3 and 10mg/kg, indomethacin slightly depressed the background activities of the nociceptive neurones. Depressant effects of morphine were restored by intravenous naloxone (0.5 mg/kg) administration, but not observed in case of indomethacin. The evoked responses induced by non-noxious stimulation failed to depress either indomethacin or morphine administration. These results suggest that the site of action of indomethacin in non-adjuvant arthritic rats is mainly in the periphery. In contrast, morphine produced an antinociceptic action due to the central mechanism.

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A new method for the assay of Na⁺, K⁺-adenosine triphosphatase (Na⁺, K⁺-ATPase) inhibition has been devised involving the determination of enzymatically produced adenosine diphosphate (ADP) and unchanged adenosine triphosphate (ATP) by high-performance liquid chromatography (HPLC). The substrate, ATP, was incubated with the enzyme preparation in the presence of an inhibitor. The incubation mixture was filtered through a membrane filter, and ADP and ATP in the filtrate were separated by (HPLC). The inhibitory effect of a cardiac steroid on the enzymic reaction was estimated by measuring the peak area ratio of ADP to ADP plus ATP on the chromatogram. The proposed assay method has proved to be satisfactory with respects to simplicity, sensitivity, and reproducibility.

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A rapid and simple method for preparation of ²⁰³Hg-labeled methylmercuric chloride (CH₃²⁰³HgCl) from ²⁰³HgCl₂ and methylcobalamin is described. More than 99% of ²⁰³Hg was methylated with methylcobalaminin 0.01N HCl during 1h. CH₃²⁰³HgCl formed during the reaction was repidly and completely separated from cobalamins and unreacted ²⁰³HgCl₂ by CM-Sephadex C-25 minicolumn. The low cost procedure for preparation of CH₃²⁰³HgCl can be completed within 2h and yields an inorganic ²⁰³Hg-free CH₃²⁰³HgCl which is useful in methylmercury toxicology.

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Cimetidine, a histamine H₂ receptor antagonist, is known to have some effects on central nervous system, and is reported to emerge in the cerebrospinal fluid (CSF). We evaluated the elimination of cimetidine from CSF by the method of ventriculo-cisternal perfusion in rats. The extraction ratio of cimetidine at the low perfusate concentration (14nM) was 0.190±0.023 (n=3), while that significantly (p<0.02) decreased to 0.0916±0.081 (n=3) at the high concentration (4mM). No significant difference was observed in the production rate of CSF between these two concentrations. These findings suggest that cimetidine is excreted from CSF to blood by a saturable transport system.

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