摘要:

SUMMARY1. Mechanisms that regulate the cerebral circulation have been intensively investigated in recent years. The role of several vasodilator mechanisms has been examined in the cerebral circulation, including nitric oxide (NO), trigeminal peptides and potassium channels, as well as the potent vasoconstrictor endothelin. These mediators appear to play a role in physiological and pathophysiological responses of the cerebral circulation. In the present review, we will focus on some recent developments in each of these areas.2. Nitric oxide is an important regulator of cerebral vascular tone. Tonic production of NO maintains the cerebral vasculature in a dilated state. NO appears to be an important vasodilator during activation of neurons by excitatory amino acids, somatosensory stimulation and cortical spreading depression. Tonic production of NO appears to be critical in vasodilatation during hypercapnia, although NO may not directly mediate vasodilatation. NO produced by immunological NO‐synthase appears to be important in dilatation following exposure to bacterial endotoxin.3. Calcitonin gene‐related peptide (CGRP), released from trigeminal perivascular sensory nerves in the brain, is an extremely potent dilator of brain vessels. CGRP may limit noradrenaline‐induced constriction of cerebral vessels and contribute to dilatation during hypotension (autoregulation), reactive hyperaemia, seizures and cortical spreading depression.4. Activation of potassium channels leads to hyperpolarization of cerebral vascular smooth muscle and appears to be a major mechanism for dilatation of cerebral arteries. Agents that increase the intracellular concentration of cyclic 3′ 5′‐adenosine monophosphate (cAMP) produce vasodilatation in part by activation of large conductance calcium‐activated potassium channels (BKCa) and ATP‐sensitive potassium channels (KATP). Activation of both KATPand BKCachannels also appears to contribute to vasodilatation during hypoxia. In contrast to KATPchannels, BKCachannels appears to be active under basal conditions, contributing to tonic dilatation of cerebral blood vessels.5. Endothelin is produced in the brain, but its role in the physiological regulation of cerebral blood flow is not known. Endothelin may contribute to the spasm of cerebral arteries following subarachn

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02760.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Components of the renin‐angiotensin system (RAS) are found in the brain; both outside and inside the blood‐brain barrier.2. Almost all of the classical actions of the brain RAS are attributable to angiotensin (Ang) II and mediated by AT1receptors.3. Circumventricular organs (CVO), which lack the blood‐brain barrier, are rich in AngII receptors and monitor circulating AngII levels.In vivobinding studies suggest that the CVO are also accessible to cerebrospinal fluid‐derived AngII.4. The median preoptic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, nucleus tractus solitarius and ventrolateral medulla are inside the blood‐brain barrier and are sites of action of brain AngII. In these nuclei, AngII seems to act as an excitatory neurotransmitter or neuromodulator.5. Actions of AngII in the brain, both inside and outside the blood‐brain barrier, are implicated in the central regulation of blood pressure and sympathetic outflow, release of hypothalamic and pituitary hormones and renal sodium handling.6. Alterations in the activity of brain AngII may be involved in the mechanisms of some types of h

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02761.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The influence of histamine and 5‐hydroxytryptamine (5‐HT) antagonists and agonists on the volume doubling times (Td) of human bronchogenic carcinomas propagated as s. c. xenografts in immunosuppressed mice was examined.2. The H2‐receptor antagonists, cimetidine and ranitidine, increased Td.3. Treatment with the H2‐receptor agonist, 4‐methyl histamine, had no effect on Td.4. Co‐administration of 4‐methyl histamine and cimetidine abolished the effects of cimetidine.5. The 5‐HT2‐receptor antagonists, cinanserin and ketanserin, both increased Td.6. Treatment with the 5‐HT1/2‐receptor agonist quipazine (0.1 mg/kg, reflecting 5‐HT2agonist activity) decreased Td, while a higher dose (10.0mg/kg) had no effect.7. The 5‐HT1/2‐receptor antagonist, methiothepin, decreased Td.8. The 5‐HT uptake inhibitor, fluoxetine, increased Td in one tumour line but not in another, while the 5‐HT releaser/depletor, fenfluramine, increased Td.9. Histamine may stimulate tumour growth through the histamine H2‐receptor, while the dominant effect of 5‐HT is 5‐HT1‐receptor inhibition.10. Tumour growth in some bronchogenic carcin

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02762.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. In the present study the possible relationship between adrenomedullin (AM) and calcitonin gene‐related peptide (CGRP) in the regulation of airway functions in anaesthetized guinea‐pigs was examinedin vivo.2. We found that AM significantly inhibited histamine‐induced bronchoconstriction in a dose‐dependent manner. CGRP or the CGRP receptor antagonist (CGRP [8–37]) alone did not affect pulmonary resistance and pretreatment with CGRP or CGRP [8–37]did not significantly affect histamine‐induced bronchoconstriction. However, AM‐induced broncho‐protection was significantly inhibited by pretreatment with CGRP or CGRP [8–37] in a dose‐dependent manner.3. It is therefore possible that CGRP may be competitive, at least in part, with binding sites of AM in the guinea‐pig airway. Exogenous AM may be useful for the management of bronchial asthma, not only as a potent bronchodilator, but also as a functi

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02763.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The anti‐obesity and anti‐diabetic effects of mazindol were evaluated in obese diabetic yellow KK mice and C57B1 control mice.2. The study compound was fed through a gastric tube at a rate of 1 or 2 mg/kg per day (0.01 mol/L HC1 as control) for 2 weeks. The following parameters were compared in treated and control animals: bodyweight, food intake, white adipose tissue (WAT) weight, brown adipose tissue (BAT) weight and its thermogenesis, noradrenaline (NA) turnover, blood glucose and serum insulin levels and glucose transporter 4 (GLUT4).3. Furthermore, bodyweight loss of mice pair‐fed the same amount of food as the mazindol‐treated mice for 2 weeks was measured.4. Mazindol significantly decreased food intake and significantly increased guanosine‐5′‐diphosphate‐binding in BAT mitochondria and NA turnover in BAT in both yellow KK and C57B1 groups. The amounts of WAT in subcutaneous, mesenteric and retroperitoneal regions and bodyweights were significantly decreased in both groups. Bodyweight loss in mice pair fed with the mazindol‐treated groups was approximately 70% compared with that in the mazindol‐treated groups. Furthermore, mazindol decreased the levels of blood glucose and serum insulin during the glucose overloading test in yellow KK mice, but it did not influence the GLUT4 protein concentration in WAT and muscle.5. These observations suggest that mazindol possesses both an anti‐obesity action, due to the inhibition of appetite as well as the activation of BAT thermogenesis via increased NA turnover in BAT, and an anti‐diabetic action. Consequently, mazindol may be useful for the treatment of obesity as well as non‐insulin‐dependent diabete

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02764.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. The influence of the passive force on the contraction and endothelium‐dependent relaxation in aortae of normotensive Wistar Kyoto (WKY) rats and stroke‐prone spontaneously hypertensive rats (SHRSP) were compared.2. Force changes of endothelium‐intact and ‐removed preparations were measured isometrically by a force‐displacement transducer. Endothelium‐dependent relaxation was observed by applying acetylcholine to the preparation precontracted in the presence of 5×10−7mol/L noradrenaline.3. The preparations showed spontaneously developed tension (tone) that increased with the increase in the passive force. The effect of passive force was greater in preparations from SHRSP. Contraction initiated by noradrenaline was also increased by passive force up to 30 mN, then showed a tendency to decrease.4. Endothelium‐dependent relaxation was depressed as the passive force was increased. Preparations from SHRSP showed impaired endothelium‐dependent relaxation and were influenced by passive force to a lesser degree when compared with preparations from WKY rats.5. Relaxation by sodium nitroprusside was influenced by passive force to a much lesser extent than that by acetylcholine.6. Indomethacin potentiated endothelium‐dependent relaxation and blocked the effect of passive force in both preparations.7. The difference in relaxation and the effect of passive force is primarily caused by the difference in the release of endo‐thelium‐derived contracting factor, which is thought to be a product of the cyclo‐oxygenase pathway of th

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02765.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Endothelium‐derived relaxing factor (EDRF) has been shown to influence arterial tone, but controversial results have been obtained studying veins. The present study was performed to determine the importance of EDRF for the inferior vena cava in the rabbit and whether blockade of the synthesis of EDRF withNG‐nitro‐l‐arginine methyl ester may influence the reactivity of the inferior vena cava to noradrenaline.2. The inferior vena cava was excised in six New Zealand white rabbits and 12 rings were prepared for organ bath studies. Concentration‐response curves were constructed for acetylcholine (10−9‐10−4mol/L) and noradrenaline (10−9‐10−4mol/L) before and following the administration ofNG‐nitro‐l‐arginine methyl ester.3. All rings showed concentration‐dependent relaxation to acetylcholine (mean maximum: 57 ± 9%) following precon‐traction with noradrenaline (EC50: 10−6mol/L). FollowingNG‐nitro‐l‐arginine methyl ester, this dilation was significantly reduced to a mean maximum relaxation of 13 ± 6% (P<0.01).4. Contraction of the inferior vena cava to increasing doses of noradrenaline reached a maximum of 5.8 ± 2.8 g beforeNG‐nitro‐l‐arginine methyl ester (basal tension 1.0 ± 0.5 g).NG‐nitro‐l‐arginine methyl ester did not affect basal tension, but the constrictor response to noradrenaline was enhanced significantly to a maximum of 9.1 ± 3.8 g (P<0.01).5. Although it cannot be ascertained definitively from the present results, it is suggested that EDRF is mediating vasodilation of the inferior vena cava and that this vasoactive agent may also contributes significant

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02766.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Phorbol esters, activators of protein kinase C (PKC), have been widely used to investigate the role of PKC in the regulation of smooth muscle contraction. However, limited studies have so far been made of the sensitivity of the contraction induced by phorbol esters to relaxant drugs. We therefore examined the relaxant effects of the K+channel openers, cromakalim and pinacidil, on the tonic contraction of canine isolated coronary artery rings induced by phorbol 12,13‐dibutylate (PDBu).2. In rings contracted with 10−7mol/L PDBu, cromakalim and pinacidil, as well as nifedipine, produced a concentration‐dependent relaxation. At their maximum effects, both cromakalim and nifedipine caused a partial relaxation, whereas pinacidil produced nearly a full relaxation.3. The relaxant effects of cromakalim and pinacidil were effectively antagonized by the ATP‐sensitive K+channel blocker, glibenclamide (10−6mol/L).4. In the presence of nifedipine, high K+was ineffective while PDBu (10−7mol/L) still induced a tonic contraction. This PDBu‐induced contraction was inhibited by concentrations of cromakalim and pinacidil higher than those needed in the absence of nifedipine.5. In rings partially depolarized with 35mmol/L KCl, the ability of cromakalim to inhibit PDBu‐induced contractions in the presence of nifedipine was completely abolished. Under the same conditions, the relaxant response to pinacidil, unlike cromakalim, was inhibited only partially.6. These results suggest that cromakalim inhibits PDBu‐induced contractions through an opening of K+channels. Pinacidil does so by a mechanism shared with cromakalim as well as by another that is independent of this K+channel opening action. These multiple modes of action may confer on pinacidil a vasorelaxant activity greater than t

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02767.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. We have evaluated the possibility that alterations in lymphocyte β‐adrenoceptor density may be related to changes in the myocardial population in left heart valvular diseases. Receptor density and their binding affinities were estimated using [125I]‐iodocyanopindolol.2. The lymphocyte (LC) β‐adrenoceptor density was 43.4 ± 5.6 fmol/mg protein in the controls (n= 35) and 81% lower in heart valvular patients (n= 86). In myocardial controls (n= 18), the left ventricular (LV) receptor density was 167.2 ± 29.8 fmol/mg protein, right ventricular (RV) density was 123.1 ± 14.6 fmol/mg, left atrial (LA) density was 81.6 ± 10.5 fmol/mg and right atrial (RA) 108.1 ± 14.5 fmol/mg. Compared with this group, the receptor density of the study patients (n= 47) decreased by 67, 43, 24 and 32% in the LV, RV, LA and RA, respectively. The decrease in LC was twice that of the average total myocardial receptor density.3. When patients were classified according to their left ventricular load conditions as having either left ventricular pressure overload (LVP), left ventricular volume overload, mixed lesions (MOL) and no left ventricular overload (mitral stenosis; NOL), the attenuation in LC receptor density reached statistical significance for all four groups, without showing significant difference between the individual groups. In contrast, the decrease in all chambers was predominantly due to volume overload. MOL and NOL exerted intermediate effects that were significant in the LV, while LVP did not contribute to the changes in the LA.4. Accordingly, the reduction in peripheral β‐adrenoceptor density may reflect the extent to which particularly the volume overload exerts its influence on myocardial β‐adrenoceptors in left heart

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02768.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1. Experiments were conducted on cultured renal arterial smooth muscle cells to determine the ability of extracellular ATP to alter cytosolic calcium concentration and to determine the mechanisms by which this effect occurs.2. ATP (100 μmol/L) caused the fluorescence ratio of fura‐2 to increase from a control value of 1.06±0.05 to 2.06±0.13 (P<0.01) before stabilizing at a sustained level of 1.35±0.04 (n= 8;P<0.05).3. Removal of extracellular calcium from the bathing medium resulted in an attenuation of the initial response to 100 μmol/L ATP with cell fluorescence increasing from 1.16±0.18 to 1.44±0.18 ratio units (n= 5). Furthermore, the initial increase in fluorescence ratio rapidly declined to 1.02±0.06, indicating that an influx of extracellular calcium is required to sustain the increase in fura‐2 fluorescence.4. Depletion of intracellular calcium pools with thapsigargin prevented the increase in fura‐2 fluorescence evoked by ATP.5. These data suggest that ATP‐mediated increases in cytosolic calcium in cultured renal arterial smooth muscle cells involve calcium release from the thapsigargin‐sensitive, intracellular pool in conjunction with calcium influx from the ext

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb02769.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY