摘要:

SUMMARY1. Airway inflammation is a signal feature of human asthma, as is bronchial obstruction and the resultant airflow limitation. An obligatory accompaniment to airway inflammation is increased airway microvascular permeability, which in turn is causally related to bronchial oedema. In this review, we have attempted to describe the mechanisms of increased airway microvascular permeability and its relationship to oedema, bronchial obstruction and the hyperreactivity to spasmogenic stimuli which are such common features of asthma.2. It is now clear that bronchial obstruction in chronic asthma can involve bronchial wall oedema and swelling in addition to reversible, elevated airway smooth muscle tone, mucus hypersecretion and airway plugging and potentially permanent structural changes in airway architecture. Inflammatory mediators released in the airway wall in asthma including histamine, platelet‐activating factor, leukotrienes and bradykinin are potent inducers of increased bronchial microvascular permeability and are thus promoters of bronchial oedema, airway wall swelling and reduction in luminal calibre.3. The primary mechanism believed to underlie acute increases in microvascular permeability is contraction of post‐capillary venular endothelial cells, resulting in the formation of gaps between otherwise tightly associated cells. Extravasated plasma distributes to the interstitial spaces in the airway wall, resulting in oedema and swelling, but may also traverse the epithelium and collect in the airway lumen.4. Luminal plasma may compromise epithelial integrity and cilial function and thus reduce mucus clearance. Plasma proteins may also promote the production of viscous mucus and the formation of luminal mucus plugs. Together, these effects can result in or contribute to airway obstruction and hyper‐responsiveness.5. An understanding of such mechanisms can provide insight concerning novel and effective anti‐asthma th

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02028.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. The central nervous system in mammals is able to react to painful stimuli at many levels that are involved in transmission, modulation and sensation of pain. Endogenous opioid peptides and their receptors are located at key points in pain pathways, and response to pain can be modulated by local application of opioids at many sites. Mechanisms of opioid analgesia at peripheral, spinal, medullary and midbrain levels are only incompletely understood; forebrain systems are even less appreciated. Local circuits in the spinal dorsal horn play a critical role in processing nociceptive afferent input and in mediating the actions of descending pain modulating systems.2. The opioid receptors, recently cloned, exert their effects by activating G protein coupled effector systems, such as ion channels and second messenger systems. Although the receptor most commonly associated with pain relief is the μ‐receptor, specific δ‐ and k‐agonists can also mediate antinociception at spinal and supraspinal sites. Acute effects of opioids on target neurons are inhibitory, but excitatory effects have also been reported.3. Noxious stimulation increases neuronal activity and modulates expression of genes, including immediate‐early genes and neuropeptide (i.e. opioid) genes at spinal and supraspinal levels of the somatosensory system. Opioid drugs and endogenously released opioid peptides can modulate signal transduction mechanisms and intracellular processes that lead to alterations in protein phosphorylation and gene expression. These effects of opioids at the cellular level may underlie the mechanisms of pre‐emptive analgesia and neuroplastic changes such as tolerance, dependence, sensitization, hyperalgesia, adaptation, addiction, and modulation of pa

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02029.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. We examined preproendothelin‐1, ETAand ETb receptor mRNA levels in aortic endothelial and smooth muscle cells from cyclosporine (CyA)‐induced hypertensive rats using the reverse transcription polymerase chain reaction method.2. Aortic endothelial preproendothelin‐1 mRNA expression was about 1.5‐fold higher, while that of ETBreceptor mRNA was markedly decreased in CyA‐treated rats compared with those in controls.3. The expression of ETAreceptor mRNA in smooth muscle cells from CyA‐induced hypertensive rats was increased about two‐fold over that in cells from control animals.4. Thus, increased endothelial preproendothelin‐1, and ETa receptor mRNA levels in smooth muscle cells, which are concomitant with the decrease in ETBreceptor mRNA levels in endothelium, may contribute to CyA‐induced hyp

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02030.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. The aim of this study was to evaluate the role of endothelium in mediating the response to acetylcholine in the thoracic aorta and coronary vessels of rats exposed to cigarette smoking. Total serum cholesterol was measured at the beginning and end of the experiment.2. The relaxation response to acetylcholine was significantly impaired in the aortae of rats exposed to cigarette smoking (P<0.05); and the coronary flow during the administration of acetylcholine (0.02 μg/min.) was significantly reduced (P<0.05). The total cholesterol plasma levels increased 31.13% in those exposed to smoke when compared to the controls (P<0.05).3. It is concluded that exposure to cigarette smoking increases total serum cholesterol levels, and also produces primary endothelial dysfunction in aorta rings and coronary vessels

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02031.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. Studies of the effects of garlic on platelet aggregation have produced inconsistent results possibly related to variations in study design and in the garlic preparations used.2. The present study examined the effects on platelet aggregation and serum thromboxane and lyso‐platelet activating factor, of feeding garlic extract to healthy men using a placebo‐controlled, double‐blind design. The effects of the same garlic preparation on platelet aggregationin vitrowere also investigated.3. There were no significant differences in platelet aggregation with adenosine diphosphate, platelet activating factor (PAF) or collagen according to treatment group. Serum thromboxane and IysoPAF also showed no change related to garlic supplements.4.In vitroaggregation with collagen decreased linearly with increasing amounts of garlic extract, but concentrations were higher than those attainablein vivo. Gastrointestinal side effects prevented the use of higher doses of garlic which must be considered to be pharmacological as they exceed changes achievable by dietary modific

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02032.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. This study has defined the positive inotropic responses to the sodium channel modulator BDF 9148 in rats with hypertension, thyroid dysfunction, diabetes or dwarfism. Concentration‐response curves to BDF 9148 and calcium chloride were determined in isolated left atria and left ventricular papillary muscles.2. BDF 9148 increased force of contraction in left ventricular papillary muscles in all disease states with maximal responses comparable to calcium chloride. BDF 9148 potency was significantly decreased in muscles from diabetic rats only.3. BDF 9148 produced similar responses in left atria except from hyperthyroid rats where negative inotropic responses only were measured. This exception confirms that the left atria is an imperfect model for ventricular responsiveness.4. Thus, the increase in force of contraction in the ventricles as a consequence of sodium channel modulation by BDF 9148 is maintained in these disease states unlike responses to α‐or β‐adrenoceptor a

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02033.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. In attempting to consolidate the role of ventricular isomyosins in regulating the contractility of the myocardium, actomyosin ATPase and crossbridge kinetics were obtained at 24°C in chemically skinned isometrically contracting cardiac muscles containing V1and V3isomyosins.2. The ATPase activity was measured at various levels of Ca2+activation by the enzymatic coupling of ATP hydrolysis with the conversion of NADH to NAD+. The crossbridge kinetics were inferred from small‐amplitude perturbations of muscle length and muscle tension, and characterized by the frequency‐domain parameter fmin.3. The ATPase rates of V1and V3muscles obtained at various levels of Ca2+activation were plotted against the corresponding proportional tensions. The ATPasevstension plots were linear with slopes of 4.92 nmol/min‐1per mm per mN and 1.98 nmol/min‐1per mm per mN, respectively for, V1and V3muscles. Individual calculations of ATPase‐to‐tension ratios (nmol/min‐1per mm per mN) gave corresponding averages of 4.98 ± 0.12 (s.e.m.,n =12) and 2.16 ± 0.12 (s.e.m.,n =10). The myosin isoform induced proportional change in tension cost was accompanied by a similar change in fmin(4.1 ± 0.1 Hz and 1.95 ± 0.03 Hz, means ± s.e.m., for V1and V3muscles, respectively).4. The observations and other published kinetic data are discussed in the context of models of crossbridge cycling. It is suggested that the tension economy of V3muscle arises principally from an increase in the fraction of time, during the crossbridge cycle, when the crossbridg

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02034.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. Considerable debate exists as to whether the properties of diaphragm muscles can be modified by training. As the diaphragm is chronically activated during normal respiration, it is of interest to determine whether this muscle is resistant to further modification by exercise. The aim of this study was to investigate the contractile activation characteristics of single skinned muscle fibres from the diaphragm of both CONTROL and TRAINED rats.2. Male rats were subjected to a 20 week high‐intensity endurance exercise training programme that consisted of running on a motorized treadmill, 5 days/week, 90–120 min/day, 27–30 m/min, up a 20° incline. At the conclusion of training, rats were killed with an overdose of ether and costal regions of the diaphragm were removed and stored in a glycerol‐based skinning solution at—20° C.3. Single skinned (membrane‐permeabilized) diaphragm muscle fibres were attached to a sensitive force transducer and activated in Ca2+‐ and Sr2+‐buffered solutions in order to determine relative force‐pCa and force‐pSr characteristics. Fibres were allocated into discrete groups (population I, population II, intermediate, mixed) on the basis of their physiological (contractile) properties.4. Population I (slow‐twitch) fibres from the diaphragm of TRAINED rats exhibited a reduced sensitivity to Ca2+(indicating a rightward shift of the force‐pCa relationship) compared to those diaphragm fibres from CONTROL animals. An increased number of population II (fast‐twitch) fibres were sampled from TRAINED rats, however, training did not affect the activation properties of these fibres.5. The fact that training‐induced alterations in the contractile characteristics did occur in one group of fibres indicates that the intensity of training was sufficient to induce some modifications to the costal fibres of the diaphragm muscle. However, the lack of alterations to the contractile characteristics of the population II (fast‐twitch) fibres may also suggest that the overall properties of the diaphragm are relatively resistant to modification

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02035.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. The association of different patterns of left ventricular hypertrophy and diastolic dysfunction with angiotensin converting enzyme (ACE) genotypes or angiotensinogen dinucleotide repeat alleles were studied in human subjects.2. Three abnormal patterns of hypertrophy (remodelled, eccentric and concentric) were associated with a history of hypertension. The presence of remodelled or concentric hypertrophy was associated with diastolic dysfunction.3. There was no difference between the frequencies of the ACE genotypes in normotensive and hypertensive subjects, in subjects with normal ventricles and those with different patterns of left ventricular hypertrophy, nor in subjects with normal and abnormal diastolic function. Similarly, there was no difference between the relative frequencies of AGT alleles in the same clinical subgroups.4. We conclude that in this population of hospital patients, variants of the ACE and AGT genes do not contribute to the presence of different patterns of hypertrophy or to diastolic dysfunction.

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02036.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SUMMARY1. Gamma‐aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAAagonist, blocks naloxone‐induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA‐mediated, SV should also inhibit naloxone‐stimulated ACTH release.2. We studied five healthy volunteers in randomized, double‐blind, placebo‐controlled afternoon studies with SV 400 mg, given 180 min before i.v. naloxone 125 μg/kg bodyweight. Plasma concentrations of ACTH, cortisol and SV were measured at intervals during the experiments.3. SV had no effect on the mean integrated ACTH and cortisol responses to naloxone; ACTH. 165 ± 21 versus 284 ± 40 pmolmin perL, P=0.08; cortisol: 10.5 ± 1.9 versus 12.8 ± 1.2 nmolmin per L‐3,P= 0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cortisol levels were also not significantly altered by SV (P>0.30). Mean SV levels were not significantly different between SV/nal and SV/placebo studies (P>0.50).4. In conclusion, SV had no effect on naloxone‐induced ACTH and cortisol release in normal humans at the dose and plasma drug concentrations studied. This contrasts with the potent inhibitory effect of alprazolam, and suggests that the effect of SV on the human hypothalamic‐pituitary‐adrenal axis may not be through a GABAA‐mediated mechanism. Alternatively, higher plasma SV levels or more sustained exposure to SV may be necessary to inhibit hyp

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1995.tb02037.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY