摘要:

Summary—Preconditioning the heart with brief episodes of ischemia paradoxically increases its resistance to subsequent ischemic episodes, and markedly limits infarct size. Although preconditioning is now considered as the most powerful antiischemic intervention known, its beneficial effects are short‐lived since they are lost if the reperfusion period after preconditioning is extended past 2–3 h. There is, however, some evidence of a delayed phase of protection, manifest 24 h after the initial preconditioning stimulus, associated with a decrease in infarct size, a prevention of postischemic contractile dysfunction (stunning) and a reduction in endothelial injury. The delayed beneficial effects of preconditioning resemble those induced by prior heat stress, and might be related to the expression of stress proteins (heat shock proteins or HSP). Evidence for a role of HSP derives from observations showing that brief ischemia is a potent stimulus for HSP expression. Moreover, transfection of isolated cells with HSP or overexpression of HSP in transgenic mice renders the myocytes more resistant to ischemia. Once produced, HSP are believed to facilitate protein synthesis, stabilize newly formed proteins and repair denatured ones. Alternatively, delayed preconditioning may be mediated by antioxidant enzymes such as superoxide dismutase or catalase, which are also upregulated by ischemia, and this could lead to a lesser production of oxygen‐derived free radicals during reperfusion. Indeed, in isolated myocytes, prevention of hypoxia‐induced expression of superoxide dismutase (using an antisense oligonucleotide) abolished the delayed protective effect of preconditioning. Importantly, recent in vivo evidence suggests that the delayed protection may be mediated by adenosine, through activation of A1‐receptors, and by stimulation of protein kinase C. Finally, although the exact mechanisms by which preconditioning induces delayed protection are still mostly unknown, the fact that the expression of protective proteins such as HSP can be induced by many other means than ischemia suggests that it is possible to pharmacologically stimulate this expression and thus possibly mimic the endogenous protective pathway. This could lead to the development of new pharmacological interventions which induce delayed myocardial protection in clinical situations such as angioplasty, coronary bypass surgery or even in patients at high risk of

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00595.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The aims of this review are to present a brief overview of growth hormone (GH) physiology and to summarize the studies of GH treatment in adults. Special attention has been paid to randomized controlled trials. Studies have revealed a partial deficiency of GH secretion in the elderly. GH secretion on the average declines by 14% with each decade in normal adults after 20 years of age. Aging has a central effect on the GH secretion and peripheric effect on insulin‐like growth factor 1 (IGF‐1) through changes in the body composition. GH administration may attenuate several important decrements in body composition and in function associated with aging. GH may also have very potent anabolic effects in surgical situations. Short‐term side‐effects of GH therapy include edema, carpal tunnel syndrome and arthralgia. A number of agents such as oral GH‐releasing peptides (GHRPs) increase GH secretion; they may be an alternative to GH treatment in the future. Further studies of GH replacement are needed, examining issues such as dosage, tolerance and efficacy before the widespread use of GH in the elderly i

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00596.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—Locomotor effects of modafinil were analysed and compared in various strains of mice and rats. A stimulation of locomotor activity was evidenced in all tested strains of mice: Swiss CD1, BALB/c, DBA2, C3H, B6CBAF1/JICO, Nude CD1 and in all tested strains of rats: Long Evans, Sprague Dawley, Wistar. In mice, from 10 mg/kg intraperitoneal, a precocious stimulant effect was observed. The drug seems to operate in its native form on the mouse brain since its intracerebroventricular administration (from 15 μg/mouse) elicited a stimulation of locomotion. In rats, the effective doses were higher (from 40 mg/kg ip); the effects of modafinil mainly oppose to the decrease in locomotion (habituation) which normally occurs in control animals. In addition, it was observed that administration of modafinil in rats habituated to their environment induced a recovery of locomotor activi

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00597.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—It has been suggested that activation of muscarinic M2receptors is one of the components of the functional antagonism between muscarinic and β‐adrenoceptor agonists in canine and guinea pig tracheal smooth muscle. The aim of the present study was to determine in the guinea pig trachea the importance of this component according to the magnitude of the acetylcholine‐induced contraction. Cumulative concentration‐response curves for isoprenaline were obtained in the absence or presence of the muscarinic M2receptor antagonist methoctramine (3 × 10−7M) in tracheal rings under basal tension or precontracted by acetylcholine 2 × 10−7, 3 × 10−6and 10−4M, giving contractions of 25, 50 or 75%, respectively, of the maximal tension induced by acetylcholine 3 × 10−3M. In the absence of methoctramine, acetylcholine induced a concentration‐dependent shift of the concentration‐response curves of isoprenaline (‐log EC50of isoprenaline are 8.09 ± 0.07, 7.85 ± 0.08, 7.38 ± 0.12 and 6.49 ± 0.12,n= 6 for basal tension and for acetylcholine concentrations of 2 × 10−7, 3 × 10−6and 10−4M, respectively). In the presence of methoctramine, the basal ‐log EC50of isoprenaline was unmodified, whereas the acetylcholine‐induced shifts of concentration‐response curves of isoprenaline were abolished for low levels of contraction (25%) and significantly reduced to 50 and 75% levels of contraction. Under similar conditions, acetylcholine‐induced shifts of concentration‐response curves of isoprenaline were unmodified by the muscarinic M1receptor antagonist pirenzepine (10−7M). These results suggest that the inhibitory effect of M2receptors on β‐adrenoceptor agonists effects is important for low contraction levels induced by acetylcholine, and that this effect becomes le

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00598.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The study was undertaken to characterize the effects of porcine galanin (pGal) and some of its analogues on rat gastric fundus muscle strips. pGal, galantide (M15) and pGal(1–14)‐[Abu8]SCY‐I evoked reproducible concentration‐dependent contractions in concentrations of 1–300, 3–1,000 and 100–3,000 nM, respectively, with EC50values of 13, 70 and 187 nM. Hill's coefficient for pGal is 1.03, indicating an interaction of one pGal molecule with one receptor, fulfilling criteria of classical receptor theory. For M15 and pGal(1–14)‐[Abu8]SCY‐I, Hill's coefficients are significantly different from 1, namely 0.73 and 1.56, so that one drug molecule may not interact with one receptor. The stimulatory effects of pGal were not modified by dibenamine 10 μM or glybenclamide 1 or 10 μM. Diltiazem 0.1, 1 and 10 μM, papaverine 0.1, 10 μM or dibutyryl cAMP (dib cAMP) 100 and 300 μM, blocked the contraction to pGal in a concentration‐dependent manner, indicating an important role for the influx of extracellular calcium ions and regulation by cAMP the pGal‐evoked contraction. Diltiazem, dibutyryl cAMP and papaverine were not competitive antagonists of pGa

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00599.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—Serotonin (5‐HT) is present in the gastrointestinal tract and is probably one of the compounds responsible for diarrhea in patients presenting with carcinoid syndrome. Intraperitoneal administration of L‐5‐hydroxytryptophan (L‐5‐HTP) at doses of 25 to 100 mg/kg dramatically increase defecation in mice. In this new paradigm, counting fecal boli deposited is simple and the appraised or inhibition of diarrhea induced by ip 25 mg/kg of L‐5‐HTP is very clear, with a good reproducibility of scores. L‐5‐HTP needs to be metabolized into 5‐HT to be active; benserazide, an inhibitor of decarboxylase, antagonized the diarrhea induced by 5‐HT. Among the 5‐HT antagonists used in interaction with 5‐HT, only those of the 5‐HT3type (ondansetron, granisetron, tropisetron) and, to a lesser extent 5‐HT2type (ritanserin), decreased the diarrhea induced by 5‐HTP. The 5‐HT4receptor agonists from the benzamide family (metoclopramide and zacopride) increased defecation in mice but the effect faile

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00600.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The effects of S 12370 (2‐[4‐benzhydryloxypiperidinoethyl]isoxindole), were studied in vitro. In guinea pig isolated tracheal rings, S 12370 induced a similar competitive inhibition of the contractile responses produced by acetylcholine, histamine and serotonin. However, it did not affect the contractions induced by leukotriene D4(LTD4), substance P and U 46619, a stable analogue of thromboxane A2. S 12370 induced a concentration‐dependent inhibition of the cholinergic component of the contraction induced by electrical field stimulation, whereas it did not influence the sustained nonadrenergic noncholinergic (NANC) excitatory response observed in guinea pig isolated bronchi. S 12370 did not influence the relaxations induced by prostaglandin E2, isoprenaline and salbutamol, and did not modify the nonadrenergic noncholinergic inhibitory response induced by electrical field stimulation. In isolated left atria, the negative inotropic effect of acetylcholine was competitively inhibited by S 12370. In binding experiments, S 12370 exhibited similar affinity for M1, M2, M3, M4muscarinic receptors and also recognized 5‐HT2serotonin and H1histamine receptor subtypes. In ovalbumin‐sensitized animals, the contractile response of isolated tracheal rings produced by exposure to the allergen was not influenced by S 12370. Tracheal rings from sensitized animals preexposed in vitro to the allergen developed a hyporesponsiveness to β‐adrenoceptor stimulation. S 12370 prevented the inhibitory effect caused by ovalbumin immune sensitization in the relaxation to isoprenaline. In rat polymorphonuclear neutrophil (PMN) cells, S 12370 up to 10−5M did not inhibit the arachidonic acid metabolism. These results suggest that in guinea pig tracheal smooth muscle, S 12370 is a competitive inhibitor of muscarinic, serotonin and histamine receptors and can modulate the β‐adrenergic dysfunction induced by immune sensitization. S 12370 may present some therapeutic interest in inflammat

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00601.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na+‐H+ exchange, against veratrine‐induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration‐dependent protective effects against veratrine‐contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50= 20.1(7.6–27.0) μM,n= 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na+‐H+ exchange blockade by a high concentration of amiloride (100 μM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmaxsignificantly at 10 μM (166.7 ± 21 vs 154.7 ± 20 V/s, P<0.05,n= 6) without any effect on resting potential or action potential duration. High concentrations (100 μM) of HOE 694 further decreased Vmaxand increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na+‐H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1‐ty

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00602.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The increase in renin secretion and the induction of the converting enzyme (ACE) observed during treatment by ACE inhibitors (CEIs) could result in increased angiotensin II (ang II) synthesis when the treatment is stopped. The object of this study was to compare changes in the components of the renin‐angiotensin system with changes in arterial pressure in hypertensives, following the cessation of long‐term ramipril treatment. Twenty hypertensives, treated for at least three months with ramipril, in monotherapy for the last three weeks, were randomly allocated to two parallel groups and received for fifteen days, on a double‐bind basis, either a placebo (withdrawal group W,n= 12) or ramipril at the previous doses (treated group T,n= 8). Blood pressure was measured using four different techniques. The active renin (AR), angiotensinogen, angiotensin I (ang I), angiotensin II (ang II) and aldosterone plasma concentrations were measured, as was plasma angiotensin I converting enzyme (ACE) activity in vitro (colorimetric and fluorimetric method) and in vivo (the ang II/ang I ratio). The biological effects of cessation of long‐term ramipril treatment in hypertensives were a decline in AR and angiotensin I concentrations, an increase in ACE activity and no significant changes in angiotensinogen, angiotensin II and aldosterone levels. Fifteen days after withdrawal, the different parameters of the renin‐angiotensin system appear to have returned to basal value. A slow rise in blood pressure was also observed but no rebound increase was noted during the 15 days neither in angiotensin II levels nor in blood pressure. Following the cessation of prolonged ramipril treatment, in vivo converting enzyme inhibition disappears slowly, probably on account of the slow tight binding inhibitor properties of ramiprilat, the active metabolite of this CEI. The gradual decline in AR plasma levels, together with the prolonged ACE inhibition as measured in vivo by the ang II/ang I ratio, explains the absence of a rise in ang I

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00603.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—This study compares cyclosporine (CsA) concentrations in whole blood from patients receiving bone marrow (n= 10), renal (n= 48), heart (n= 50) or liver (n= 50) transplants, as measured by monoclonal antibody flurorescence polarization immunoassay (FPIA) and specific125I‐radioimmunoassay (RIA). The FPIA overestimated CsA by an average of 25%. Results were higher for all indications: FPIA/RIA ratios were 1.17 for bone marrow, 1.23 for renal and 1.27 for both heart and liver transplants, and these values were significantly different from 1.0. The percentage of overestimation was higher at low CsA concentrations (≤ 100 μg/L) than at high CsA concentrations (≥ 400 μg/L). In all indications, results by both methods correlated well (r>0.96) but slopes and intercepts were different from 1.0 and 0.0, respectively, and these parameters varied greatly between the grafted populations. These findings obtained with the two methods could not be attributed to matrix effect because the mean FPIA/RIA ratio for spiked control samples was 1.0. The discrepancy between the FPIA and RIA could be explained by the lower specificity of the monoclonal antibody contained in the FPIA kit. These results suggest that FPIA is not as accurate as RIA and that the two methods are not interchangeable in CsA level me

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00604.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY