By the analysis of skin surface lipids, the activity of the sebaceous glands in normal or abnormal conditions and the functions of skin surface lipids can be studied. There are various methods to collect skin surface lipids, e.g., the cup method, etc. Among all of these methods, the most widely used is the cup method, which gives excellent accuracy and reproducibility. However, the use of this method is painful for the subject, and it is difficult to use on small animals. To overcome these disadvantages, a new device for the sampling of skin surface lipids was made and compared with the cup method. The device consisted of a cell and a collector. The cell was fixed in the sampling position, vaccumed by an aspirator, and as solvent flowed through the cell, the skin surface lipids were collected. By this suction method, the same degree of accuracy and reproducibility as the cup method was obtained. The use of this device allows a reduction of sampling time, removal of samples from any part of the body and experiments on most small animals. Also the discomfort of the subject is reduced.

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Experimental hyperlipidemia was induced in ddY, C57BL, BALB and ICR strain mice and in Wistar rats. By feeding the animals a high cholesterol diet (HCD) for 2 weeks or by administering a high fat emulsion for a week, plasma level of total cholesterol (TC) increased in these animals. The increment of TC in mice was less than that of TC in rats. In rats, plasma level of triglyceride (TG) increased, but it decreased in mice of all these strains. Plasma level of high density lipoprotein cholesterol (HDL-C) decreased in rats and mice except BALB mice. By feeding these animals a HCD, the relative liver weight increased in rats and mice. In rats, clofibrate (CF), 100 mg/kg/day, decreased TC and TG and increased HDL-C, and nicotinic acid (NA), 100 mg/kg/day, decreased TC and increased HDL-C. However, in mice, CF decreased TC only in ICR mice fed a HCD. The hypolipidemic effects of gemfibrozil, LK-903 and pirozadil were also studied in rats and ICR mice.

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An accelerating effect by TRQ-consecutive administration perorally on bile secretion in rats was investigated in comparison with phenobarbital (PB)-administered rats. The bile secretion velocity was increased significantly by administration of TRQ (25, 50, 100 mg/kg/day) or PB (50 mg/kg/day) compared to the control group. A 24% increase in the ratio of the liver weight to body weight was observed in the PB-administered group, but in the TRQ-administered group, a slight increase (5%) was seen compared with the control group. The concentration of excreted bile acid in the bile of rats to which TRQ and PB were administered were lower than that of the control group. However, when excreted bile acid content was represented in terms of wet liver weight, no difference was seen in the TRQ-administered group, but a 17% decrease was observed in the PB-administered group compared with the control group; and also, almost the same results were obtained with regards to the cholesterol and phospholipid in the bile. Though there was no difference of Na⁺, K⁺, or Cl^- concentration in bile between the TRQ or PB-administered group and the control group, more Na⁺, K⁺ or Cl^-/g wet liver was excreted in TRQ-treated group than the PB-administered group. TRQ was excreted through the bile duct promptly after an i.v. injection without an increase in the bile secretion, suggesting that the excretion of TRQ and its metabolites were not accompanied by the increase in bile secretion. These results indicate that the accelerating effect of TRQ on bile secretion was presumably derived from bile acid non-dependent bile secretion such as PB; however, a different pharmacological mechanism between TRQ and PB was presumed from the discrepancy of the decomposition in the secreted bile and of drug-metabolizing enzyme induction. Thus, it was suggested that there was a possibility that the accelerating action of bile secretion by TRQ was attributed to the activating effect of TRQ on the hepatocytes.

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The preventive effect of sulfamonomethoxine (Smm) and ormetoprim (Omp) medicated in combination against leucocytozoon infection in chickens was tested in field trials. In trial 1, medication was given continuously throughout the experimental period. In trial 2, medication was given for seven days and no medication was given for the next seven days; then this schedule for the medication was repeated throughout the experimental period. In trial 1, almost complete prevention was obtained when Smm and Omp were added to the feed at the level of l2 ppm and l4 ppm, respectively, or at the level of 15 ppm and 5 ppm, respectively. Only a partial effect was obtained, however, when these drugs were used at the level of 9 ppm and 3 ppm, respectively. In trial 2, a nearly complete effect was obtained when Smm and Omp were added to the feed at the level of 18 ppm and 6 ppm respectively, but we found no effect when these drugs were used at the level of 15 ppm and 5 ppm, respectively. There were no significant differences among the groups as to the weight gain.

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In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of thromboxane A₂ (9, 11-epithio-11, 12-methano TXA₂: s-TXA₂) produced a dose-dependent contraction. The histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an involvement of H₁ receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an S₂ antagonist, but also by cinanserin and methysergide. Relaxation induced by serotonin in preparations treated with high concentrations of ketanserin were inhibited by cinanserin and methysergide. Norepinephrine contracted coronary arteries treated with propranolol. Contractile responses to norepinephrine were reversed to relaxations by prazosin, which were abolished by treatment with yohimbine. Contractile responses to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA₂. Contractile responses to serotonin were also potentiated by low concentrations of histamine or s-TXA₂. Removal of the endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of endogenous vasoconstrictors, including histamine, serotonin, TXA₂ and norepinephrine, may play an important role in producing coronary vasospasm.

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Liver cirrhosis was induced by consecutive CCl₄-treatment of rats (0.5 ml/kg, s.c., 2 times/week) to investigate the effect of TRQ on the acceleration of fibrosis in the liver. An increase of hydroxyproline content in the liver of rats began 12 weeks after the CCl₄ treatment and a 1.9-fold increase was observed at week 14 compared with non-CCl₄ treated rats. Histamine in the liver increased about 2 times at week 14. Increased numbers of mast cells were seen in the area of proliferated collagen fiber in the liver under microscopic observation, and also a good correlation was recognized between the number of mast cells and the progression of fibrosis. An administration of TRQ to the rats for 2 weeks from week 13 resulted in significant suppression of both the increase in hydroxyproline and histamine in the liver dose-dependently compared with the CCl₄ control group. Both progression of collagen and increase in mast cell numbers were also suppressed by TRQ dose-dependently under histopathological observation; at the same time the decrease in mast cells was recognized to correspond to the decrease in hydroxyproline and histamine in the liver. Thus, it was suggested that increased mast cells participated in the biosynthesis of collagen. Though the elevated serum transaminases, alkaline phosphatase and leucine amino peptidase were also suppressed by TRQ administration, the protein biosynthesis activity of the liver and lowered serum total cholesterol were not improved as much as the other parameters. From these results, it was shown that TRQ was especially and remarkably effective in suppressing the acceleration of fibrosis, and one of the pharmacological mechanisms of this action may be ascribed to the inhibitory effect of TRQ on the activation of mast cells by some stimulants.

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Budralazine was evaluated for its effects on glucose and lipid metabolism in diabetic SHR. 1) SHR treated with 10% sucrose solution as drinking water for 3 months exhibited an impaired glucose tolerance with higher serum insulin levels and a reduction of ΣΔIRI/ΣΔBS. This model was, therefore, considered to resemble hypertensive patients with non-insulin-dependent diabetes (NIDD). Streptozotocin (30 mg/kg, i.v.)-treated SHR had a glucose intolerance with lower serum insulin levels and a reduction of ΣΔIRI/ΣΔBS, suggesting a similarity to hypertensive states with insulin-dependent diabetes (IDD) in humans. 2) Repeated administration of budralazine (15 ?? 60 mg/kg/day, p.o.) had no effect on glucose tolerance, insulin secretion, serum electrolytes and lipid levels in Wistar rats, SHR, IDD-SHR and NIDD-SHR. Budralazine caused a significant decrease in systolic blood pressure in IDD-SHR and NIDD-SHR as well as in SHR. 3) Repeated administration of furosemide (50 ?? 100 mg/kg/day, p.o.) resulted in a marked reduction in glucose tolerance, ΣΔIRI/, ΣΔBS and serum potassium in Wistar rats. These effects of furosemide were more pronounced in SHR and IDD-SHR (IDD-SHR>SHR) and were reduced by either KCl supplement or administration of triamterene. Thus, furosemide-induced glucose intolerance seems, at least partially, to be attributed to potassium loss which led to decreased insulin secretion. From these results, it is possible that budralazine may be useful for the treatment of hypertensive patients with diabetes.

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The effect of labetalol (alpha- and beta- adrenoceptor blocking agent) on the respiratory organs of guinea pig was investigated in vivo and in vitro. The asthmatic symptoms which were induced by inhalation of histamine were relieved by pretreatment with labetalol (1 ?? 5 mg/kg, i.p.) in most cases. Propranolol, on the contrary, aggravated distinctly the histamine-induced asthma, although phentolamine and diphenhydramine relieved the asthma. Experiments carried out in vitro showed that labetalol relaxed the tonus of isolated tracheal preparation, shifting the histamine dose-response curve to the right and downward. Thedown shifting by labetalol was dose-dependent and much more sensitive than that by papaverine, and it disappeared after pretreatment of propranolol. Thus, it was considered that labetalol exerted a relaxing action on the tracheal preparation by a beta₂-adrenoceptorpartial agonist action (intrinsic sympathomimetic activity, ISA). Since labetalol in high concentration also shifted the histamine dose-response curve parallel to the right as seen with phentolamine or diphenhydramine, it was considered that labetalol exerted not only an alpha-blocking action but also an antihistaminic action.

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The cause of sex differences in the pressor response to l-adrenaline in adult rats (Tomori, 1986) was further examined using normal and castrated adult rats. Blood pressure was determined by the tail-cuff method. A prolonged elevation of blood pressure in male rats shown after an injection of l-adrenaline (50 μg/kg, s.c.) was almost completely suppressed by phentolamine (50 μg/kg, s.c.), and the slight l-adrenaline-induced increase in blood pressure in female rats was reversed to a decrease by phentolamine. Pretreatment with propranolol (200 μg/kg, s.c.) enhanced the pressor action of l-adrenaline in males and enhanced it to a greater extent in females. Castration resulted in a significant decrease in basal pressure in males and no change in females. Pressor responses to l-adrenaline in castrated male and female rats showed a minor alteration. In clonidine (20 μg/kg, s.c.)-treated normal rats, l-adrenaline induced an increase in blood pressure in males, but caused a decrease in females. In clonidine-treated castrated male rats, however, l-adrenaline administration induced a decrease in blood pressure. l-Adrenaline injection to yohimbine (1 mg/kg, s.c.)-treated rats induced a prolonged elevation of blood pressure in males and a transient elevation in females as shown in rats treated with l-adrenaline alone. In yohimbine-treated castrated rats, a decrease in the blood pressure was observed in males and a slight increase was observed in females after l-adrenaline administration. The present results suggest that the central pressor regulatory system is involved in the sex difference in pressor response to exogenous l-adrenaline and that androgens play a role to somehow maintain a higher pressor responsiveness to 1-adrenaline in male rats.

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Effect of long-term oral administration of the converting enzyme inhibitor (2R, 4R)-2-(o-hydroxyphenyl)-3-(mercaptopropionyl)-4-thiazolidinecarboxylic acid (SA446) in combination with hydrochlorothiazide or propranolol on the development of hypertension was examined in spontaneously hypertensive rats (SHR). The development of hypertension in SHR was markedly suppressed by the treatment with SA446 (45 mg/kg, p.o.) for 17 weeks from 8 weeks of age, the pre-stage of hypertension. Long-term administration of hydrochlorothiazide (20 mg/kg, p.o.) also showed an obvious antihypertensive effect, but the effect was less potent than that of SA446. On the other hand, propranolol (20 mg/kg, p.o.) showed a slight or little antihypertensive effect. The combined administration of hydrochlorothiazide and SA446 produced a more potent antihypertensive effect than the administration of SA446 alone. On the other hand, the combined use of propranolol had no influence on the antihypertensive effect of SA446 by long-term administration in SHR. Plasma renin activities measured after 17 weeks treatment of the drugs indicated that the reninangiotensin system was activated by hydrochlorothiazide. These results suggest that the antihypertensive effect of long-term administration of SA446 in SHR is enhanced by the combined administration of diuretics such as hydrochlorothiazide, which activates the renin-angiotensin system.

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Male Sprague-Dawley rats (230 ?? 280 g), either fasted for 15-24 hr or non-fasted prior to experiments, were used. Misoprostol (3 ?? 100 μg/kg, p.o.) dose-dependently inhibited the development of 150 mM HCl·aspirin (100 mg/kg)-, 150 mM HCl·60% ethanol-, and aspirin (150 mg/kg)-induced gastric lesions. Misoprostol (30, 100 μg/kg, p.o.), given twice daily for 4 days, significantly inhibited prednisolone (50 mg/kg given once daily for 4 days)-induced gastric lesions. Misoprostol (30 or 2×300 μg/kg, p.o.) also significantly inhibited water-immersion stress (21°C, 10 hr)-induced gastric lesions or mepirizole (200 mg/kg)-induced duodenal lesions, respectively. In contrast, misoprostol (30 ?? 300 μg/kg, p.o.) hadno effects on indomethacin (25 mg/kg)- and mepirizole (200 mg/kg)-induced gastric lesions. Misoprostol (30 μg/kg, p.o.) had no effect on gastric secretion in pylorus-ligated preparations (4 hr), but it (100 or 300 μg/kg, p.o.) significantly increased the volume and pepsin output. Gastric motility, either normal or enhanced with indomethacin (25 mg/kg), was inhibited by misoprostol (30 or 300 μg/kg, p.o.). Misoprostol (30 μg/kg, i.d.) significantly stimulated duodenal HCO₃^- secretion. Mechanisms by which misoprostol inhibits various gastric lesions remain unknown. However, the stimulatory activity on duodenal HCO₃^- secretion appears to be involved in the preventive effect of misoprostol on the development of duodenal lesions. The effects of cimetidine and 16, 16-dimethyl PGE₂ were also studied and compared with those of misoprostol.

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