Search

A mutant mouse (wriggle mouse sagami, WMS) with neurological disorders was found in a colony of the BALB/c strain. The clinical signs included tremor, dystonia and involuntary movements. The concentrations of the neurotransmitter substances, noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and acetylcholine (ACh), were measured simultaneously with their metabolites in dissected brain regions by high-performance liquid chromatography with electrochemical detection. The turnover of 5-HT was significantly higher in the cerebral cortex, hippocampus, hypothalamus, midbrain and pons-medulla of WMS than of the genetic control, BALB/c. The intrastriatal DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were increased. However, there was no evidence to suggest an increase in turnover rate of this neurotransmitter. An increase in concentration of and decrease in turnover rate of NA were observed in the cerebellum of this mutant. These findings suggest that multiple disturbance of the neurotransmitter system was largely responsible for the manifestation of the clinical signs of WMS.

The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.

Hemodynamic effects of captopril were examined in chronic one-kidney, one clip renal hypertensive rabbits and normotensive controls either in normal sodium or in sodium depletion. The mean arterial pressure (MAP) of hypertensive and normotensive rabbits in sodium depletion did not differ from that in normal sodium, while plasma renin activity (PRA) was elevated by sodium depletion. The cardiac output of sodium depleted groups decreased slightly. The increase in total peripheral resistance was greater in hypertensive than in normotensive groups. The MAP in all groups was decreased by acute administration of captopril irrespective of sodium intake. The decrease in MAP in the sodium-depleted hypertensive group was correlated with the control values of PRA, but no correlation was observed in other groups. Captopril significantly reduced the cardiac output of the sodium-depleted hypertensive group, but not of the other groups. These results show that: (1) the lowering effect of captopril on arterial pressure is not mediated only by blocking of the renin-angiotensin system, and (2) the decrease in cardiac output with captopril in sodium depleted hypertensive rabbits is an important factor in the reduction in the arterial pressure.

The effect of ketanserin (KET), a specific 5-hydroxytryptamine2 (5-HT2) receptor blockade, on pressor response to vasoactive substances was examined in rats with one-kidney, one clip renal artery stenosis of 2 days' duration (2-day clipped rat) and in rabbits with renal artery stenosis of 3 days' duration (3-day clipped rabbits). The 2-day clipped rats showed hyperresponsiveness to norepinephrine (NE), arginine vasopressin (AVP) and 5-HT. All hyperresponsiveness were attenuated by a subdepressor dose of KET. The infusion of KET, 10 micrograms/kg/min for 30 minutes, decreased mean arterial pressure of the 3-day clipped rabbits; the dose did not alter blood pressure of the normal controls. Exaggerated pressor response to NE was observed in the 3-day clipped rabbits and was abolished by a subdepressor dose of KET, 2.5 micrograms/kg/min. These results suggest that 5-HT may be involved in the enhanced pressor response to vasoconstrictor substances in the 2-day clipped rats and 3-day clipped rabbits, and that it may also play an important role in maintaining blood pressure in the 3-day clipped rabbits.

Guanabenz (WY-8678) was given to pregnant rabbits to examine its effects on the dams and their fetuses. The drug was administered orally to rabbits at does of 10, 8, 5 and 1 mg/kg/day from the 6th to 18th days of gestation. The vehicle used was 5%-Arabic Gum at dose level of 10 ml/kg, and a control experiment where only the vehicle was administered was also conducted. The results obtained were as follows. 1. Concerning the effects on the dams, the symptoms of decrease in spontaneous movement and sedation were observed at 10 mg/kg. However, mean body weight, food consumption, and organ weight were not influenced by Guanabenz. 2. In the observation of the fetuses, no difference was observed among groups in the number of corpora lutea, the number of implantations, implantation rate, the number of resorption, the number of dead fetuses, the number of live fetuses, sex ratio, mean body weight of the fetuses, mean body length of the fetuses, and mean placenta weight of the fetuses. 3. No difference was observed among groups regarding external malformations, visceral malformations, skeletal malformations, skeletal variations and degree of ossification in the fetuses. From these results, it is concluded that Guanabenz has no teratogenic potential in pregnant rabbits and on effect no fetuses at doses of 8 mg/kg or lower.

Mizoribine, an immunosuppressive agent developed and marketed in Japan, was tested in experimental keratoplasty and in Behçet's disease. The drug, 2 to 4 mg/kg of body weight, administered systemically or as 10% eyedrops five times daily, suppressed immune reaction after keratoplasty in rabbits. It seemed effective in 18 cases including 12 regrafted eyes. In 29 cases of Behçet's disease, the average recurrence rate dropped from once per month to once every three months in one year. Mizoribine is safe, easy to use, and may be of some value by itself or in combination with other drugs in the treatment of uveitis and in the prevention of corneal graft reaction.

Exogenously administered vasopressin (VP) augments ACTH secretion stimulated by CRH. This study was performed to elucidate the role of endogenous VP in potentiating CRH-induced ACTH secretion in man. Synthetic human CRH (100 micrograms) was injected iv into seven normal men after they had been water loaded (20 mL/kg; 60 and 30 min before CRH injection; WL-CRH test) and water deprived (water restriction for 18 h before CRH injection; WD-CRH test). Blood samples were obtained before and 5, 15, 30, 60, 90, and 120 min after CRH injection at 0900 h for determination of plasma ACTH, cortisol, arginine vasopressin (AVP), CRH, and catecholamine levels and osmolality. Urine was obtained immediately before and 120 min after CRH injection for determination of osmolality. The mean plasma AVP levels were significantly higher during the WD-CRH test [1.8 +/- 0.4 (+/- SE) to 1.9 +/- 0.4 pmol/L] than during the WL-CRH test (0.6 +/- 0.1 to 0.9 +/- 0.1 pmol/L). The mean plasma ACTH and cortisol levels rose significantly from basal (4.5 +/- 0.6 pmol/L and 320 +/- 20 nmol/L, respectively) to peak values of 14.0 +/- 2.1 pmol/L at 30 min and 700 +/- 50 nmol/L at 60 min, respectively, during the WD-CRH test. During the WL-CRH test, mean basal plasma ACTH and cortisol levels were 3.5 +/- 0.7 pmol/L and 420 +/- 50 nmol/L, respectively, and reached peak values of 7.7 +/- 1.1 pmol/L at 60 min and 550 +/- 40 nmol/L at 30 min, respectively. Both the mean peak levels and integrated ACTH and cortisol responses were significantly higher during the WD-CRH than during the WL-CRH test. There was no significant difference between the plasma CRH and catecholamine concentrations in both tests. These results suggest that endogenous AVP potentiates CRH-stimulated ACTH secretion and, thus, plays a physiologically significant role in regulating CRH-stimulated ACTH and cortisol secretion in man.

Manometric study was performed to investigate the effects of cisapride, a new non-antidopaminergic gastrointestinal prokinetic compound, on interdigestive lower esophageal sphincter pressure (LESP) and gastroduodenal motility using infused catheter technique. The subjects consisted of 9 healthy volunteers and 29 patients with progressive systemic sclerosis (19), reflux esophagitis (8) and others (2). 4 mg of cisapride was given by bolus injection, continuous infusion or oral administration. The following results were obtained: Intravenous and oral cisapride increased LESP compared with basal pressure. Especially, bolus injection of cisapride caused a significant elevation of LESP during 30 minutes after administration. After administration of cisapride, gastroduodenal motility was accelerated gradually, then inducing IMC-like contractions. By bolus injection, IMC-like contractions were induced in healthy subjects more frequently than in patients group. On the other hand, motility index of stomach and duodenum showed persistent increase in patients group compared with healthy subjects. Cisapride-induced IMC-like contractions initiated from LES and upper part of stomach and mediated to duodenum, though aborad migration was not confirmed in the present study.

SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 micrograms of SMS (4 subjects/dose) or a placebo (6 subjects) to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61 +/- 0.09, 4.91 +/- 0.30 and 8.52 +/- 1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50 and 100 micrograms of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110 +/- 3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50 and 100 micrograms of SMS, the plasma TSH levels were 43.8 +/- 19.4, 33.9 +/- 9.4 and 24.9 +/- 3.2%, respectively, of the basal values. The results suggest that SMS suppresses secretion of TSH from the normal thyrotrophs in man and thus also that attention should be paid to possible hypothyroidism during the long-term treatment of patients such as those with acromegaly with this potent analogue of SRIF.

A comparative study of the ability to block the amine pump was carried out on tricyclic antidepressants including dothiepin and northiaden in vivo. Dothiepin was found to prevent the 6-OHDA-induced depletion of cardiac noradrenaline but not the PCA-induced depletion of intracerebral serotonin. Northiaden, an active metabolite of dothiepin, also possessed the same ability with a greater potency than the parent drug. Neither compound affected the biosynthesis of catecholamines and indoleamine. However, neither dothiepin nor northiaden affected 5-HT uptake, as was also observed with imipramine and amitriptyline. These results suggest that the clinical efficacy of dothiepin may be due to inhibition of the amine pump, especially of the catecholamine uptake mechanism, which is qualitatively the same as for imipramine and amitriptyline.

The effects of guanabenz, guanfacine and clonidine on alpha-adrenoceptors were investigated in isolated rat vas deferens and rabbit aortic strip. All 3 drugs at low concentrations (10(-9)-10(-8) M) caused inhibition of twitch responses of the rat vas deferens induced by nerve stimulation. These effects were competitively antagonized by yohimbine. Guanfacine and clonidine at relatively high concentrations (10(-6)-10(-4) M) produced contractions of the rat vas deferens which were antagonized by prazosin. These contractile responses were not much affected by denervation. Prazosin-sensitive contractions by guanfacine and clonidine were also observed in the rabbit aortic strip, which were not affected by reserpine pretreatment. In both tissues, the intrinsic activity of guanfacine was almost identical to that of norepinephrine, whereas that of clonidine was less than one half. Guanabenz and clonidine showed a competitive antagonistic effect against norepinephrine and phenylephrine in both the rat vas deferens and rabbit aorta, the antagonisms being similar in potency. The results indicate that all 3 drugs are potent agonists on the presynaptic alpha 2-adrenoceptor. In contrast, on the postsynaptic alpha 1-adrenoceptor, guanfacine and guanabenz showed only agonistic and antagonistic actions, respectively, whereas clonidine exhibited partial agonistic characteristics.