川芎嗪与左旋精氨酸对急性心肌梗死大鼠的心肌保护作用

目的比较川芎嗪(TMP)与川芎嗪和左旋精氨酸(L—arg)联合疗法对急性心肌梗死(AMI)大鼠的心肌保护作用,并探讨其作用机制。方法采用垂体后叶素(pituitrin,Pit)尾静脉注射复制大鼠AMI模型,设立正常对照组、模型组、TMP治疗组、TMP与L—arg联合治疗组,用免疫组化法观察心肌梗死时P-选择素、E-选择素的表达情况,并测定血清肌酸激酶(CK)、肌钙蛋白T(TnT)及心肌组织髓过氧化物酶(MPO)的浓度。结果模型组与正常对照组比较,血清CK、TnT浓度、心肌组织MP0浓度有明显升高(P<0．01),P-选择素、E-选择素的表达明显上调(P<0．01);TMP治疗组、联合治疗组分别与模型组比较,上述各指标均下降,联合治疗组下降更为明显(P值均<0．05)。结论TMP与L—arg合用可通过多种环节抑制黏附分子的表达和降低白细胞的浸润,对治疗AMI有显著协同作用。     

Alpha1 adrenoreceptors mediate the stimulatory effects of oestrogen on stress-related hypothalamic-pituitary-adrenal activity in the female rat

Variation in challenge-induced adrenocorticotropin hormone (ACTH) release over the oestrous cycle occurs in response to fluctuations in circulating concentrations of oestrogen and progesterone. However, how these ovarian steroids interact to regulate the principal ACTH cosecretagogues, corticotropin-releasing hormone (CRH) and arginine vasopressin is not understood. Here, we measured median eminence CRH and vasopressin content in intact cycling female rats, and in ovariectomized (OVX) females steroid-replaced in a manner that approximates the relative release patterns of oestrogen and progesterone seen over the oestrous cycle. Intact cycling females showed significantly higher median eminence CRH and vasopressin concentrations during proestrous and oestrous compared to the diestrous phase. In OVX rats, a single 10 micro g injection of oestrogen failed to mimic this increase in median eminence CRH and vasopressin. However, this dose significantly elevated CRH and vasopressin content in OVX rats previously exposed to diestrous concentrations of oestrogen and progesterone. Moreover, oestrogen priming enhanced restraint-induced depletion of CRH and vasopressin from the median eminence, but only against a background of low oestrogen and progesterone replacement. Oestrogen-induced elevations in median eminence vasopressin (but not CRH) content were reduced by peripheral administration of the alpha1 adrenoreceptor antagonist prazosin. Finally, plasma ACTH concentrations following central injection of the alpha1 receptor agonist, phenylephrine, were significantly higher in rats during proestrous compared to diestrous. These results indicate that the stimulatory effect of oestrogen on both the expression and stress-induced release of ACTH cosecretagogues is exerted only against a background of low oestrogen and progesterone levels, and is mediated, in part, via the alpha1 adrenoreceptor.     

Age-dependent cardiovascular, renal and endocrine responses to furosemide in conscious lambs

1. The present study was performed to investigate some of the physiological responses to furosemide during postnatal maturation. 2. In 1- (n = 8) and 6-week old (n = 10) conscious, chronically instrumented lambs at least 3 days after surgery, three experiments were performed at intervals of 24-48 h and in random order. Various parameters of cardiovascular and endocrine function, as well as cumulative urinary flow rates, were measured before and after intravenous injection of 0 mg/kg (experiment one), 0.25 mg/kg (experiment two; low dose) and 5 mg/kg (experiment three; high dose) furosemide. 3. After high-dose furosemide, mean venous pressure decreased and there was a transient increase in mean arterial pressure in lambs aged 6 weeks. At 1 week of age, heart rate increased after high-dose furosemide and renal blood flow decreased. After high-dose furosemide, plasma renin activity increased in both groups of lambs, although the effects were greater in 1-week-old lambs. Plasma levels of arginine vasopressin increased after high-dose furosemide in lambs aged 1 but not 6 weeks. Cumulative urinary flow rate responses to furosemide were similar in 1- and 6-week-old lambs. 4. These data provide new information that cardiovascular and endocrine responses to furosemide are developmentally regulated.     

Urinary aquaporin-2 levels in healthy volunteers

SUMMARY:   Renal water handling is regulated by the release of arginine vasopressin (AVP) and the subsequent insertion of aquaporin 2 (AQP2) in the apical membrane of collecting duct cells. This in turn increases the membrane permeability to water and the passive reabsorption of water down the concentration gradient present in the medulla. Aquaporin 2 can be detected in the urine under conditions of antidiuresis. We wish to validate an assay for urinary AQP2. Fourteen volunteers participated in studies of water loading and water deprivation followed by the administration of 1-deamino-8- d -arginine vasopressin (dDAVP). Urine osmolality was measured by vapour pressure osmometry. Urinary AQP2 was measured by using a chemiluminescent assay. Baseline correlations between serum AVP levels, urinary osmolality and urinary AQP2 levels were not significant. Following the administration of dDAVP, a positive correlation between urine osmolality and urinary AQP2 was evident ( r  = 0.762). For specific conditions where renal water retention is stimulated via AVP, urinary AQP2 measurements provide a reproducible measurement of the renal actions of AVP.     

Corticotropin and cortisol response to maximal exercise testing in central diabetes insipidus

BACKGROUND: It is known that arginine vasopressin (AVP) has a stimulatory effect on corticotropin (adrenocorticotropic hormone; ACTH) and cortisol secretion especially during stress. The present study was designed to investigate the effect of stress on ACTH and cortisol levels in patients with central diabetes insipidus (DI) with endogenous AVP deficiency receiving AVP therapy, and to determine whether these children need steroid replacement during stress. METHODS: Seven patients with a median age of 12 years (range 7-13 years) with idiopathic central DI on appropriate Desmopressin (DDAVP) therapy (group 1) and seven healthy controls with a median age of 15 years (range 13-20 years; group 2) were included in the study. Acute stress was produced in all children by treadmill exercise, assessed by maximal oxygen consumption and heart rate. ACTH and cortisol levels were determined before and after exercise. RESULTS: In group 1, median ACTH level after exercise (28.3 pg/mL) was not different from the median value (24.0 pg/mL) before exercise. However, median cortisol level (10.5 microg/dL) was significantly increased (14.9 microg/dL; P < 0.05) with exercise. In group 2, cortisol (median 9.3 microg/dL) and ACTH levels (median 6.3 pg/mL) were significantly increased after exercise (15 mug/dL and 13.6 pg/mL, respectively; P < 0.05). There was no significant difference between the groups with respect to cortisol levels before and after exercise, but the stimulated ACTH levels after exercise were higher in patients with DI than in the controls (P < 0.05). A positive correlation was observed between total daily DDAVP dose and cortisol level after exercise (r(s)= 0.786, P < 0.05). CONCLUSIONS: Cortisol response during acute stress is normal in children with DI and these patients do not need extra steroid treatment during stress. In contrast, the normal cortisol response obtained by increased ACTH levels in these patients indicates an increased sensitivity of corticotroph cells.     

L-精氨酸治疗心绞痛

目的：研究Ｌ＿精氨酸片对冠心病心绞痛的疗效及其安全性。方法：对６８例冠心病心绞痛病人分为２组,Ｌ＿精氨酸组３８例（男性２４例,女性１４例,年龄６０ａ±ｓ９ａ）和安慰剂组３０例（男性１８例,女性１２例,年龄６２ａ±９ａ）,以双盲对照法给Ｌ＿精氨酸或安慰剂片（淀粉）各４片（０．２５ｇ／片）,ｐｏ,ｔｉｄ,共４ｗｋ。结果：Ｌ＿精氨酸组临床与心电图总有效率依次为９５％和７４％;安慰剂组依次为６３％和４０％,２组组间比较,依次为Ｐ＜０．０１和Ｐ＜０．０５。Ｌ＿精氨酸能降低血压、降低心肌氧耗及降低血脂（Ｐ＜０．０１或＜０．０５）。未见明显不良反应。结论：Ｌ＿精氨酸片是安全有效的治疗心绞痛的药物。     

Analogs of arginine vasopressin modified in position 3 with (R)-α- hydroxymethylphenylalanine

Abstract: This study describes the synthesis and some pharmacological properties of three new analogs of arginine vasopressin (AVP) substituted in position 3 with (R)-α-hydroxymethylphenylalanine ([R]-HmPhe). All new peptides were tested for vasopressor and antidiuretic as well as uterotonic activity. None of the 3 analogs showed any pressor activity and their uterotonic activity was negligible. Only analog [Mpa¹,(R)-HmPhe³]AVP exhibited significant antidiuretic activity.     

Pharmacological chaperones: a new twist on receptor folding

Protein misfolding is at the root of several genetic human diseases. These diseases do not stem from mutations within the active domain of the proteins, but from mutations that disrupt their three-dimensional conformation, which leads to their intracellular retention by the quality control apparatus of the cell. Facilitating the escape of the mutant proteins from the quality control system by lowering the temperature of the cells or by adding chemicals that assist folding (chemical chaperones) can result in proteins that are fully functional despite their mutation. The discovery that ligands with pharmacological selectivity (pharmacological chaperones) can rescue the proper targeting and function of misfolded proteins, including receptors, might help to develop new treatments for ‘conformational diseases’.