Effects of a new adrenergic β-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other β-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the β or α-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day), propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the β-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596 (10 ?? 50 mg/kg) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic α-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the Ist administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.

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We investigated the role of renal sympathetic tone and central noradrenergic neurons in the mechanism for natriuretic and antihypertensive effects of potassium supplement in DOCA-salt hypertensive rats. Systolic blood pressure of DOCA-salt rats continued to rise during 4 weeks of DOCA-salt (1% NaCl) treatment. In contrast, 0.2% KCl or 1% KCl supplement attenuated the development of the hypertension dose-relatedly. One percent KCl supplement attenuated sodium retention and prevented the increased sodium space in DOCA-salt rats. Whereas norepinephrine turnover rate in the kidney of DOCA-salt rats after the 4-week treatment was markedly accelerated, it was normalized by 0.2% KCl or 1% KCl supplement. On the other hand, norepinephrine turnover rates in the hypothalamus and medulla oblongata of DOCA-salt rats were delayed, while they were restored by the KCl supplement. These results suggest that potassium supplement in DOCA-salt rats attenuated the development of the hypertension and that it may be attributed to the restoration of sodium retention and thereby volume expansion. It appears that the restoration of either the increased renal sympathetic tone or the decreased noradrenergic nerve activity in the brain-stem may be involved in the natriuretic and anti-hypertensive effects of potassium supplements in DOCA-salt hypertensive rats.

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Anti-ulcerogenic effects of trimoprostil, a prostaglandin E₂ (PGE₂) derivative, were studied in comparison with those of PGE₂, cimetidine and sulpiride. Trimoprostil and PGE₂ given p.o. prevented the formation of gastric lesions produced by absolute ethanol, 0.2N NaOH, 0.6N HCI and hypertonic NaCl solutions in rats and aspirin-induced fecal occult bleeding in dogs. Although both prostaglandins did not alter the gastric mucus content, they equivalently prevented the stress-induced decrease in the mucus content in rats. The duration of these effects of trimoprostil was longer than those of PGE₂. Cimetidine and sulpiride did not exert such cytoprotective effects. Trimoprostil inhibited stress-induced gastric ulcer formation in rats more markedly than PGE₂, cimetidine and sulpiride. Trimoprostil and PGE₂ at the cytoprotective dose (30 μg/kg, p.o.) did not change the gastric blood flow in conscious rats. In Shay rats, trimoprostil at doses larger than the cytoprotective doses inhibited the gastric acid secretion when given p.o., but was not effective when given i.d. PGE₂ exerted the similar action, but the potency was clearly weaker than that of trimoprostil. In Heidenhain-pouch dogs, trimoprostil also inhibited the gastric acid secretion stimulated by pentagastrin more markedly than did cimetidine. In conclusion, trimoprostil at doses smaller than the antisecretory doses exerted gastric cytoprotective action with a longer duration than that of PGE₂, probably through the preservation of the mucus barrier. Such cytoprotection was not found with cimetidine and sulpiride.

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Two experiments were done to examine the effect of quinine (Q) on methamphetamine (MA)-induced anorexia in rats. They were fasted throughout (water allowed ad libitum) except for a period of 6 hr (10:00-16:00) every day when powder food was offered. In the first experiment, the drug-admixed food (DAF) method was used for testing the effect of MA in combination with Q and MA alone on food consumption and the growth curve. However, the possibility exists that MA plus Q-admixed food increases the aversive reaction. Considering this possibility, we used the injection method in the second experiment. Rats received Qorally by a stomach tube and MA by subcutaneous injection. The injection was made 30 min before the presentation of food. In the DAF method, food consumption and weight of the MA and MA plus Q groups were inhibited. The inhibitions of the MA plus Q group were more potent than that of the MA group. In the injection method, the inhibitions of food consumption and growth curve in the MA plus Q group were significantly different from that of the MA group and were dose-dependent on MA. Tolerance to MA, as index of MA- induced anorexia, developed rapidly in the injection method, while tolerance to MA in the DAF method did not develop during the experiment. These results indicate that Q can markedly potentiate MA- induced anorexia.

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The present study was undertaken to quantify the circulating kinins in patients with various cardiovascular diseases using a newly developed radioimmunoassay technique and to evaluate this method in terms of its clinical application. For the determination of bradykinin (BK), this assay uses a rabbit anti-serum which has been injected with kallidin. This assay shows good specific activity, recovery and reproducibility. In order to avoid the formation of kinin as well as to block its inactivation, human blood samples were collected with a polypropylene syringe containing an inhibitor mixture (EDTA, trasylol, 1-10-phenanthroline, soybean trypsin inhibitor, polybrene). 1) The plasma BK concentration in normal human subjects, in patients with essential hypertension, effort angina and other cardiac diseases were 12.2, 9.2, 8.0 and 14.0 pg/ml, respectively. 2) Thirty min after captopril (12.5 mg, p.o.) administration, blood pressure and pulmonary wedge pressures decreased, and cardiac output increased accompanied with increases in plasma renin activity, plasma BK concentration and plasma norepinephrine concentration. 3) During the cold pressor test, both plasma BK concentration and blood pressure increased in the normal human subjects, whereas plasma BK levels decreased and blood pressure increased in the patients with hypertension. This radioimmunoassay for plasma BK determination makes it possible to measure plasma BK concentration in patients with various cardiac diseases.

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