摘要:

AbstractRecent research in the area of peripheral dopamine (DA) receptors has led to the identification of two distinct subtypes of DA receptors, activation of which results in marked changes in the cardiovascular and renal function consisting of hypotension, bradycardia, diuresis, and natriluresis. Peripheral DA receptors mediating these effects are subdivided into DA‐1 and DA‐2 subtypes. The development of selective DA‐1 and DA‐2 receptor agonists and antagonists has made it possible to furhter characterize DA receptors located at various sites within the cardiovascular system. It is now established that activation of DA‐1 receptors located on blood vessel produces vasodilation, whereas stimulation of DA‐2 receptors on postganglionic sympathetic nerves results in the inhibition of norepinephrine release. The renal effects of DA receptor agonists either involve activation of specific DA receptors at various sites in the kidney and/or result from renal hemodynamic changes produced by these compounds. The concept of developing selective DA receptor agonists as therapeutic agents in the treatment of cardiovascular disorders has been proposed by several investigators. Fenoldopam (SK&F 82526) represents one of these new orally active DA receptor agonists developed for potential use in the treatment of hypertension and ischemic renal disease. In animal experiments fenoldopam was shown to produce hypotension and increase renal blood flow. It produced natriuresis and diuresis, and these effects were due to the activation of DA‐1 receptors. Recent clinical studies show that fenoldopam decreases blood pressure and renal vascular resistance and causes diuresis and natriuresis in hypertensive patients. The antihypertensive action of fenoldopam is mediated by a decrease in total peripheral resistance. There are increases in heart rate and plasma renin activity in hypertensive patients. Fenoldopam also improves left ventricular performance in patients suffering from congestive heart failure. These initial studies with fenoldopam show that peripheral DA‐1 receptor stimulation may represent an effective approach in the treatment of cardiovascular diseases. Future research in this area should be aimed toward developing DA‐1 receptor agonists that have longer duration of action and do not evoke renin release, while maintaining the beneficial effe

ISSN:0272-4391    

DOI:10.1002/ddr.430100302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractProof of the protective properties against cerebral hypoxic hypoxidosis of a new potentially nootropic drug, tenilsetam (TEN), were studied as compared with 5 mg co‐dergocrine mesylate (CDM) in a double‐blnd, placebo‐controlled trial. Hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% N2, equivalent to 6,000 m altitude, which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. They received randomized after an adapation session placebo, 150 mg, 300 mg, and 900 mg TEN and 5 mg CDM. Blood gases, quantitative EEG, and psychometric measures were obtained under normoxic (21% O2) and hypoxic (9.8% O2) conditions before as well as 2,4,6, and 8 hr after oral drug administration. Blood gas analysis demonstrated under hypoxia a drop in PO2from 91 to 37 mm Hg and in PCO2from 38 to 33 mm Hg, while pH increased from 7.41 to 7.47. Under these hypoxic conditions, computer‐assisted spectral analysis of the EEG showed an increase of delta/theta, decrease of alpha, and increase of superimposed fast beta activity indicative of deterioration in vigilance. The latter was documented at the behavioral level by deterioration of intellectual and mnestic functions, psychomotor activity, performance in a reaction time task, mood, and wakefulness. Both TEN and CDM attenuated this brain dysfunction, although in a different manner. Whereas TEN induced an increase in alpha and decrease of fast beta activity as compared with placebo, 5 mg CDM attenuated delta/theta and increased alpha‐adjacent beta activity. Multivariate analysis based on changes in all EEG‐variables exhibited the highest dosage TEN and the reference substance significantly different from placebo. Psychometric data added—despite high variance—further evidence for antihypoxidotic/nootropic properties of both drugs, as psychometric performance under hypoxia deteriorated by 45% after placebo, while after 5 mg CDM, 150 mg, 300 mg, and 900 mg TEN only by 25, 27, 39, and 22%, respectively. Based on changes in all 12 psychometric variables obtained at all times, 900 mg, but also 150 mg TEN as well as 5 mg CDM, were significantly different from placebo. Under normoxic conditions, multivariate analyses did not show any significant differences to placebo, and only singular neurophysiological and behavioral change

ISSN:0272-4391    

DOI:10.1002/ddr.430100303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe effect of various pharmacological interventions on the collecting phase of cystometrogram (CMG) has been investigated by means of a new cystometric procedure in urethane‐anesthetized rats. The method involves the transvesical infusion, through a needle inserted in the bladder dome, of warm (37°C) saline at a rat (2.8 ml/h) simulating a maximal hourly diuresis value for this species. In these conditions bladder voiding is produced through the activation of a supraspinal vesico‐vesical reflex. Either chemical (6‐hydroxydopamine, reserpine) or surgical (section of hypogastric nerves) sympathectomy produced a picture of detrusor hyperreflexia and urine dripping, mimicking cystometric finding of human disease. This new procedure may be useful for screening and development of new drugs for treatment of urinary incont

ISSN:0272-4391    

DOI:10.1002/ddr.430100304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractThe effect of cholecystokinin octapeptide (CCK‐8) on the performance of platform‐jumping avoidance behavior was investigated in the rat. CCK‐8 was injected subcutaneously once in different doses immediately after training trials. The number of avoidance responses remained high 5 and 10 days after the CCK‐8 administration and the greatest effect was observed with doses of 10 and 100 ng/kg, while in control saline group the number of responses decreased after 5 days. Larger doses of CCK/8 were less effective, probably due to a sedative

ISSN:0272-4391    

DOI:10.1002/ddr.430100305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

摘要:

AbstractYohimbine potentiation of lethality in mice has been used as a model for the prediction of antidepressant agent [Quinton, 1963]. However, prior to death or at sublethal doses, yohimbine induces clonic convulsions. In Swiss‐Webster mice (20–28 g) individually placed in clear plastic cylinders, the CD50(median convulsive dose) for yohimbine‐induced seizures was 22.7 (18.9−27.3) mg/kg sc (subcutaneously). For anticonvulsant screening, compounds were administered intraperitoneally at appropriate pretreatment times prior to the CD95dose of yohimbine (45 mg/kg sc). The following anxiolytic and GABA‐mimetic agents administered intraperitoneally dose‐dependently antagonized yohimbine‐induced clonic convulsions: diazepam (ED50) = 0.26 mg/kg); chlordiazepoxide (2.0 mg/kg); CGS 9896 (0.82 mg/kg); CL 218,872 (3.7 mg/kg); zopiclone (19.0 mg/kg); tracazolate (61.3 mg/kg); clonazepam (0.02 mg/kg); phenobarbital (9.0 mg/kg); valproic acid (81.1 mg/kg); trimethadione (163.0 mg /kg); muscimol (0.82 mg/kg); AOAA (16.0 mg/kg); clonidine (0.22 mg/kg); and baclofen (4.0 mg/kg). On the other hand, the antiepileptic agents diphenylhydantoin, ethosuximide, and carbamazepine as well as the benzodiazepine antagonists CGS 8216 and RO 15 1788 were inactive. The neuroleptics haloperidol, chlorpromazine, and thioridazine were inactive, while clozapine displayed anticonvulsant activity (ED50= 30.4 mg/kg). Other inactive compounds include phenotolamine, propranolol, atropine, alpha‐methyltyrosine, PCPA, reserpine, buspirone, DMI, and imipramine. Since yohimbine has been reported to be anxiogenic in animals and man, this assay may be relevant for the prediction of anxiolytic agents. Furthermore, compounds active in this test have shown anxiolytic activity in behavioral con

ISSN:0272-4391    

DOI:10.1002/ddr.430100306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430100307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430100301

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1987

数据来源: WILEY