ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00287.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Beta‐adrenergic receptors (β/‐AR) belong to the large multigenic family of receptors coupled to GTP‐binding proteins. Three subtypes have been identified: β1‐, β2‐ and β3‐AR. Much of the work delineating the precise pharmacological comparison of the three β‐ARs has come from investigations with stably transfected Chinese hamster ovary cells (CHO cells). This review discusses the structure and function of β3‐AR in various species and presents new findings on a number of β3‐AR ligands including carazolol, tertatolol and CL 316,243 which were found to be selective and potent β3‐AR agonists and ZD 2079 and salmeterol which appear to display full but non‐subtype selective agonistic activity. Species‐related variations of the β3‐AR pharmacology have been shown for propranolol and bupranolol. With the ongoing characterization of the β3‐AR at the molecular and cellular level, and with the advent of computer‐assisted molecular modelling to aid in the determination of the three‐dimensional structure of the receptor, it is thought that novel β3‐AR compounds will become a

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00288.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Twenty five years ago, experimental procedures such as adrenalectomy and corticosteroid administration (to intact rats) allowed the recognition of direct and indirect controls of central 5‐HT synthesis rate by corticosteroids. These effects indicated that the activity of the hypothalamo‐pituitary‐adrenal (HPA) axis, whether under basal conditions or during stress, is endowed with a modulatory action upon serotonergic neurons. Nowadays,in situhybridisation,in vitroautoradiography, and radioligand binding on the one hand, and electrophysiological, behavioural, and neuroendocrinological responses on the other hand, are tools that allow the analysis of direct corticosteroid effects upon 5‐HT receptors. Among the dozen of 5‐HT receptors identified so far, four receptors (namely the 5‐HT1A, 5‐HT1B, 5‐HT2A, and 5‐HT2Creceptors) — and the 5‐HT uptake system — have been the focus of studies aimed at detecting corticosteroid modulatory effects. The results that are reviewed herein indicate that hippocampal 5‐HT1Areceptors are under the tonic inhibitory control of corticosterone. This control is directly exerted at the level of the 5‐HT1Areceptor gene, essentially through mineralocorticoid receptors; as well, electrophysiological findings bring support for an additional modulation of hippocampal 5‐HT1Areceptor‐mediated functions by indirect (ie5‐HT1Areceptor gene‐independent) genomic actions of corticosteroids. In keeping with the respective effects of stressful stimuli and psychotropic drugs upon the HPA axis and central serotonergic systems, it is likely that these corticosteroid‐5‐HT1Areceptor interactions in the hippocampus have consequences in the pathophysiology of mood disorders. However, because the data regarding a corticosteroid control of other 5‐HT receptors are either scarce and contradictory (eg5‐HT1B, 5‐HT2A, 5‐HT2Creceptors and 5‐HT uptake systems) or lacking, it is at the present time unknown whether corticosteroids exert other effects on 5‐HT receptor‐med

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00289.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Behind the classic beta1, and beta2‐adrenoceptors, recent molecular and pharmacological studies have described a new receptor, called the beta3‐adrenoceptor, in various mammalian tissues (brown and white adipose tissue, digestive smooth muscle). Few authors have investigated the putative existence of the beta3‐adrenoceptor in the cardiovascular system. This paper reviews the available data.In vitrostudies show that beta3‐adrenoceptor agonists (BRL 37344, CGP 12177) induce a relaxation of fragments of rat carotid artery which is not antagonized by propranolol. In dogs, these drugs elicit a decrease in blood pressure due to peripheral vasodilation and an increase in heart rate which is of baroreflex origin. The vasodilating effects are mainly observed in cutaneous and adipose tissue vessels and cannot be explained by any known transductional mechanism. Activation of this vascular β3‐adrenoceptor requires higher doses of catecholamines than for β1‐ or β2‐adrenoceptors. In humans, the cardiovascular effects of beta3‐adrenoceptor agonists are explained by the activation of beta1‐ or beta2(and not beta3‐)‐adrenoceptors. These studies suggest the presence of vascular (but not cardiac) beta3‐adrenoceptors in dogs. In other species, including man, the presence of such cardiac β3‐adrenoceptors remains to be resolved. Their physiolo

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00290.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—The proarrhythmic effects of 3‐hydroxy‐hydroquinidine (3‐OH‐HQ) and quinidine were compared in a canine model of QT‐dependent ventricular arrhythmias. Eight hypokalemic ([K+] ≤ 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2‐day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 μg/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3‐OH‐HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+ 39 ± 18 and + 28 ± 22 msec, respectively) and after the high dose (+ 51 ± 29 and + 50 ± 22 msec). Quinidine was more arrhythmogenic than 3‐OH‐HQ: 7/8 dogs (p ≤ 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3‐OH‐HQ infusion (low dose: 1 dog). Addition of propranolol‐induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3‐OH‐HQ). Thus 3‐OH‐HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00291.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha2‐adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha2‐adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino‐metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the β‐adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4 mgṁkg−1, iv) increased within 5–15 minutes, plasma noradrenaline (600%), insulin levels (300%), free‐fatty acids (79%) and salivary secretion (143%). Atropine (0.2 mgṁkg−1, iv) suppressed yohimbine‐induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free‐fatty acids (102%) plasma levels. Administration of nadolol (1 mgṁkg−1, iv) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free‐fatty acids (4%) plasma levels. These results show that yohimbine‐induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone. Thus, blockade of alpha2‐adrenoceptors induced a simultaneous activation of adrenergic and cholinergic systems. This pattern can explain the spectrum of side effects observed with yohimbine in man and suggests new potential clinical uses fo

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00292.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—The present work has determined the activities of aromatic L‐amino acid decarboxylase (AAAD) and evaluated the presence of an active transport system for dopamine in renal tissues of developing dogs (newborn puppies less than 24 hours after birth, animals at the age of 10 days and 2 months) and adult animals. AAAD activity (Vmax, in pmol/mg protein/h) as determined in kidney homogenates was found to be in the adult dog kidney (Vmax= 3216 ± 268) higher (p<0.05) than that occurring in the three other groups of animals; no significant difference on AAAD activity was observed between the 10 day‐old (Vmax= 1139 ± 185) and the 2 month‐old dogs (Vmax= 783 ± 23). AAAD activity in newborn puppies (Vmax= 259 ± 40) was markedly lower than in the three other groups. A considerable amount of the total dopamine formed from added L‐DOPA in kidney slices, depending on the age, was found to escape into the incubation medium. The application of the Michaelis‐Menten equation to the net transport of newly‐formed dopamine has allowed the identification of a saturable (carrier‐mediated transfer) and a non‐saturable component (diffusion). The Vmax(nmol/g/15 min), Km(μM) values for the saturable component and diffusion constant (μmol−1) were as follows: adult (Vmax= 112 ± 16; Km= 319 ± 35; diffusion constant = 0.0009 ± 0.0001), 2 month‐old (Vmax= 19 ± 5; Km= 48 ± 14; diffusion constant = 0.0007 ± 0.0002), 10 day‐old (Vmax= 25 ± 3; Km= 69 ± 20; diffusion constant = 0.0033 ± 0.0007) and newborn (Vmax= 6 ± 1; Km= 16 ± 6; diffusion constant = 0.0095 ± 0.0010). In conclusion, renal AAAD develops with age, though some AAAD activity can already be detected at birth. The dopamine outward transporter appears to be considerably immature at birth, but undergoes rapid maturation within the next 10 days; however, development of AAAD and of the renal dopamine outward transporter still proceedes

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00293.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case‐control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the st

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00294.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Modafinil, a new psychostimulant, was evaluated in eight healthy volunteers subjected to 60 hours of sleep deprivation. During continued wakefulness, vigilance was evaluated by self‐assessment questionnaires, analogue visual scales, multiple sleep latency tests (MSLT), sleep logs, and continuous ambulatory electroencephalographic recordings (EEG). Modafinil (200 mg) or a placebo was given every 8 hours for three days; the sessions were separated by a 15 day wash out period. Results indicated a satisfactory level of vigilance, both subjective and objective, after the administration of modafinil, characterised by the quasi total absence of microsleep episodes which gradually occurred under placebo conditions. The confirmed wakening potency of modafinil makes this substance suitable for therapeutic use in patients with sleep disorders such as Gelineau's syndrome and hypersom

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00295.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Summary—Fifty‐three consecutive patients with active duodenal ulcer (DU) were randomly included in a double‐blind, double‐dummy study to test the healing and relapsing rate of two treatment regimens: famotidine 40 mg nocte for 4–8 weeks, followed by 20 mg for 12 months after healing of the ulcer and colloidal bismuth (CBS) (240 mg bid) for 4–8 weeks, followed by placebo maintenance treatment. The results of the short term period confirmed the efficacy of CBS in healing DU (24/25 in CBS group and 19/23 in famotidine group). However, the relapse rate in the CBS‐treated group was higher (77.8% at 12 months) than in the famotidine group (35.7%) (p= 0.041). Only 7 patients (41.2%) were cleared fromHelicobacter pylori (HP)after CBS treatment. In conclusion, the high relapse rate observed in CBS treated patients may be related to the high percentage of patients withHPinfection in the tested group and support the hypothesis that lack of efficacy of CBS in preventing DU recurrence is related to its poor era

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1995.tb00296.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY