To study the effects of Ca antagonists on hypertension induced cardiac and vascular hypertrophy, diltiazem, at the doses of 30 and 60mg/kg, p. o., twice a day was administered to SHR from 4 to 16 weeks of age. In addition to suppression of developing blood pressure, left ventricular wet weight was significantly decreased in diltiazem treated SHR. Calcium contents of the abdominal aorta was significantly decreased in this group. On the other hand, in SHR, diltiazem at the dose of 60mg/kg, p. o., decreased mean blood pressure about 45mmHg and decreased heart rate about 70beats/min. Plasma renin activity was significantly elevated, but plasma aldosterone concentration was not changed under this condition. In conclusion, diltiazem can suppress hypertension induced cardiac hypertrophy. In addition to the decrease in the afterload, moderate baroreflex induced augmentation of sympathetic drive and lack of volume overload through the reninangiotensin-aldosterone system was shown to contribute to this effect.

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The effect of HPS (halofuginonepolystyrene sulfonate), a derivative of halofuginone with lower toxicity, on natural leucocytozoon and coccidial infection in broiler chickens was evaluated in a floor pen trial. The experiment was conducted from one day to 10 weeks of age. On leucocytozoon infection, HPS added to the diet was completely effective at 60ppm, fairly effective at 40ppm and ineffective at 20ppm. On the other hand, HPS concentrations of 20ppm, 40ppm and 60ppm were completely effective on coccidial infection. HPS at 40ppm which corresponds to the recommended level of halofuginone (3ppm) and at 60ppm had no adverse effect on the weight gain in experimental birds.

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The addition of ouabain to the Na⁺, K⁺-ATPase [EC. 3. 6. 1. 3] of pig kidney modified with N-[p-(2-benzimidazolyl) phenyl] maleimide gradually increased the fluorescence and the amount of phosphoenzyme from Pi with the same time course in the presence of 0.43mM Mg²⁺, 16mM Na⁺, 27μM ADP and 27μM Pi. The extent of the increment of the fluorescence intensity was dependent on the concentration of ouabain. A Hill plot of the data showed that n (Hill coefficient) and K_1/2 (apparent affinity) were equal to 0.27 and 0.84μM, respectively. Addition of ouabain to give 93μM increased the intensity to the highest level, similar to that of K⁺-sensitive phosphoenzyme (E₂P), and increased the extent of phosphorylation to half the amount of E₂P formed with Mg²⁺, Na⁺ and ATP. ADP inhibited the phosphorylation from Pi without affecting the binding of ouabain. The extent of the fluorescence intensity induced by ouabain in the presence of 0.43mM Mg²⁺, 16mM Na⁺ and 27μM ADP was the same irrespective of the presence of 27μM Pi. Addition of inorganic phosphate to give 2.6mM accelerated the rate of fluorescence increase and 27μM ADP retarded it without affecting the extent of the increment. The addition of ouabain to the Na⁺-bound enzyme increased the fluorescence with time to a level similar to that of E₂P. These results and those of others indicate that ouabain can bind to nonphosphorylated Na⁺, K⁺-ATPase, and the relative fluorescence intensity of ouabain bound Na⁺, K⁺-ATPase was similar to that of E₂P irrespective of the phosphorylation.

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A simple technique to examine the effects of drugs on the gastric secretion response to the secretagogues without anesthesia was shown in this paper. The administration of bethanechol (1mg/kg, s. c.), histamine (15mg/kg, s. c.) or pentagastrin (0.25mg/kg, i. p.) significantly increased the gastric volume and the total acid output in the pylorus-ligated rat. These responses to the secretagogues were inhibited by N-butylscopolamine, urogastrone or cimetidine dose-dependently. N-butylscopolamine (0.5mg/kg, i. p.) inhibited the response to bethanechol but not that to pentagastrin or histamine. Cimetidine (5mg, kg, i. p.) inhibited not only the response to histamine but also the acid response to bethanechol or pentagastrin. Urogastrone (5mg/kg, i. p.) inhibited the response to these three secretagogues. The ratio of the total acid output to the gastric volume was also examined in each of the cases. Somatostatin (0.1mg/kg, i. p.) inhibited the response to pentagastrin, but not that to bethanechol or histamine. On the other hand, an analogue of somatostatin (SS-1; 0.1mg/kg, i. p.) inhibited the response to bethanechol but not that to pentagastrin or histamine.

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Iminodibenzyl derivatives have been prepared in our laboratories for development as psychotropic drugs. Among them, carpipramine and clocapramine have already been introduced for clinical use as neuroleptic drugs. In the present study, the pharmacological properties of Y-516, a new iminodibenzyl derivative, were compared with those of carpipramine, clocapramine, haloperidol and sulpiride. Y-516 inhibited apomorphine (0.5mg/kg, s. c.)-induced hyperactivity in mice, apomorphine (10mg/kg, s. c.)-induced hypothermia in mice, apomorphine (0.1mg/kg, s. c.)-induced vomiting in dogs, methamphetamine (2mg/kg, s. c.)-induced hyperactivity in mice and methamphetamine (50mg/kg, i. p.)-induced mortality in grouped mice. Y-516 also suppressed both lateral hypothalamic self-stimulation behavior in rats and circling behavior induced by methamphetamine (5mg/kg, i. p.) in rats with unilateral 6-hydroxydopamine lesions of the striatum. In these tests, Y-516 was 2_??_3 times more potent than clocapramine, but less potent than haloperidol. The inhibitory effect of Y-516 on apomorphine (1.25mg/kg, i. v.)-induced gnawing behavior in rats was slightly more potent than that of clocapramine. Y-516 in combination treatment with methamphetamine (5mg/kg, i. p.) did not induce mortality in rats; however, carpipramine and sulpiride did. The cataleptogenic action of Y-516 was almost equipotent to that of clocapramine. From these results, Y-516 possesses a post-synaptic dopamine receptor blocking action similar to that of the iminodibenzyl antipsychotic drugs, suggesting its potential usefulness as an antipsychotic drug.

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All Wistar rats showed hypertension when they were given heatstress and administered metyrapone (200μg/kg/day), a cholesterol-11-β-hydroxylase inhibitor. The addition of saline loading potentiated the hypertensive state. The hypertension in MH-rats was blocked by a low dose (1mg/kg) of propranolol, a dose which was insufficient to cure the Spontanous Hypertensive rats, and by a very low dose (20ng/kg) of 1-dopa with carbidopa treatment, but not by haloperidol, sulpiride, or prazosin. Striatal dopamine (DA) of MH-rats was increased significantly. These results suggested that the hypertension of MH-rats was related to the inhibition of central DA release. Since MH-rats showed the availability of propranolol clearly, this may be a useful model for hypertension.

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The systemic and topical antiinflammatory activities of budesonide (B) were studied in rats and mice and compared with those of commercially available steroids. Betamethasone 17-valerate (BV) was used as the main reference compound, and fluosinolone acetonide (FA), hydrocortisone 17-butyrate (HB) and hydrocortisone 21-acetate (HA) were also used. B given systemically had stronger antiinflammatory effect than BV on carrageenin edema, cotton pellet granuloma, adjuvant arthritis, croton oil edema, PCA reaction, Arthus reaction, contact hypersensitivity and histamine or serotonin skin reaction. The potency of antiinflammatory activity of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was in the order of FA, B, BV, HB and HA. B given locally also produced stronger antiinflammatory effects than BV on carrageenin edema, cotton pellet granuloma, croton oil edema and contact hypersensitivity. The order of potency of the 5 compounds in carrageenin edema, croton oil edema and contact hypersensitivity tests was the same as by systemic application. In general, the ratio of the dose required to cause atrophy of the thymus and adrenals to the dose required to produce the antiinflammatory effect was the greatest with B by both systemic and local application. The results suggest that B has a stronger antiinflammatory activity with fewer systemic side effects than conventional steroid compounds.

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The antiinflammatory effect of topically applied budesonide ointment on carrageenin induced paw edema in rats, croton oil induced ear edema in rats, passive cutaneous anaphylaxis (PCA) in rats and picrylchloride induced contact hypersensitivity in mice was studied and compared with those of commercially available ointments containing betamethasone 17-valerate, hydrocortisone 21-acetate, hydrocortisone 17-butyrate or fluocinonide. The five ointments had almost the same degree of activity against the carrageenin induced paw edema. Budesonide ointment was strongest in inhibiting the croton oil induced ear edema. Budesonide and fluocinonide ointments were stronger than the other 3 ointments in inhibiting PCA and picrylchloride induced hypersensitivity. No clear atrophic effect on the thymus or adrenal was observed with any of the ointments at the doses tested. When the effect of budesonide ointment was compared with that of budesonide cream, there were no differences in activity between the two formulations. The results suggest that budesonide is a useful drug with a superior topical antiinflammatory activity.

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