ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS AND KININ METABOLISM: EVIDENCE THAT ACE INHIBITORS MAY INHIBIT A KININASE OTHER THAN ACE

1. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, and also metabolizes bradykinin-(1–9) to bradykinin-(1–7) and bradykinin-(1–7) to bradykinin-(1–5). Increases in endogenous kinin levels may contribute to the therapeutic effects of ACE inhibitors. 2. ACE inhibitors increase vascular levels of both bradykinin-(1–9) and its ACE cleavage product bradykinin-(1–7), at doses below the threshold for ACE inhibition, leading to the proposal that ACE inhibitors may also inhibit a non-ACE kininase which cleaves both kinin peptides; this non-ACE kininase may be the major pathway of kinin metabolism in the vasculature and some other tissues. 3. In support of this proposal, ACE inhibitors potentiate bradykinin-(1–9) effects at doses which have little or no effect on ACE activity, as indicated by angiotensin I conversion to angiotensin II. ACE inhibitors also potentiate the actions of ACE-resistant kinin analogues, which may be susceptible to metabolism by a non-ACE kininase. 4. Identification and characterization of the putative non-ACE kininase which is inhibited by ACE inhibitors may reveal novel approaches to the tissue-specific modulation of kinin levels.     

Changes in blood pressure and vasoactive hormones during volume expansion in stable patients on chronic haemodialysis

Summary: We studied changes in blood pressure (BP) and plasma hormones (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], endothelin [ET], angiotensin [AII] and renin [PRA]) in four stable haemodialysis patients 48 h after a routine dialysis (basal stat), after volume expansion (4–7% above dry bodyweight) for 4 days then 48 h later following ultrafiltration. Blood pressure rose and plasma AII and PRA values fell with volume expansion and returned to baseline at the end of the study. Endothelin values were unchanged. Plasma ANP and BNP rose similarly in three patients and returned to near baseline levels after ultrafiltration. Sustained volume expansion over 4 days in dialysis patients is associated with an increase in BP, a marked elevation in plasma ANP and BNP but without change in ET.     

SD大鼠肺中降钙素基因相关肽的分布及缺氧对其含量的影响

本研究用免疫细胞化学方法(ABC法)观察了降钙素基因相关肽(CGRP)在SD大鼠肺中的分布,缺氧对肺中神经内分泌细胞内CGRP含餐的影响。结果表明:含CGRP的神经纤维分布在肺血管平滑肌层中及其周围、气管-支气管树的粘膜下层;含CGRP的神经内分泌细胞位于气管一支气管树的上皮层、粘液腺中和肺实质内。缺氧不引起火鼠肺的神经内分泌细胞数目改变,但可使这些细胞内的CGRP含量增加。     

内皮素和降钙素基因相关肽与梗阻性黄疸大鼠门脉压力的关系

目的　通过测定梗阻性黄疸大鼠门静脉血中内皮素和降钙素基因相关肽浓度 ,探讨内皮素和降钙素基因相关肽在梗阻性黄疸鼠门脉压力升高中的作用。方法　建立大鼠梗阻性黄疸模型 ,采用放射免疫法测定门静脉血中内皮素和降钙素基因相关肽的浓度。结果　内皮素在胆道结扎后各时相均明显升高 (P<0 .0 5 ) ,3天达峰值 (186.99± 3 6.0 3 pg/ m l) ,降钙素基因相关肽在胆道结扎后第 1天无明显变化 (2 13 .11± 3 5 .3 8pg/ m l vs 180 .14± 3 0 .66pg/ ml) ,3天后明显升高 ,并与对照组相差明显 (P<0 .0 5 )。梗阻性黄疸组大鼠门脉压力在各时相组均比对照组明显升高 (P<0 .0 5 )但未形成门脉高压。内皮素抗血清治疗可降低内皮素浓度和升高的门静脉压力。结论　梗阻性黄疸时内皮素和降钙素基因相关肽浓度均升高 ,失去内皮素和降钙素基因相关肽的正常平衡并伴有门脉压力的升高     

原发性高血压患者左室肥厚与血浆肾上腺髓质素前体N端20肽的关系

目的:探讨原发性高血压(EH)患者血浆中肾上腺髓质素前体N端20肽(PAMP)与左室肥厚的相互关系。方法:观察62例EH患者血浆PAMP的变化以及与左室重量指数之间的关系。结果:经超声心动图检查显示,62例EH患者中伴左室肥厚者42例,无左室肥厚患者20例。EH伴左室肥厚患者血浆PAMP浓度较无左室肥厚患者明显增高(65·8±12·0)∶(60·8±9·0)ng/L,P<0·05。结论:EH患者血浆PAMP的升高可能为机体的代偿反应,有助于改善患者的预后。     

Urinary excretion of acid-soluble peptides in children with Duchenne muscular dystrophy

In order to investigate the validity of the hypothesis that acid-soluble peptides (ASP) in urinary excreta can be applied as an index of the protein catabolism of the whole body, we measured the urinary excretion of ASP in 46 normal children and in 18 children with Duchenne muscular dystrophy (DMD), in which continuous breakdown of skeletal muscle protein is presumed. The mean value of ASP in the children with DMD was significantly higher than that in normal controls. The concentration of ASP was correlated with that of 3-methylhistidine (3MH), which has been proposed as an index of muscle breakdown. This finding indicates that urinary ASP reflects the catabolism of body proteins. No correlation was observed between the concentration of ASP and that of 1-methylhistidine (1MH), which is used as an objective index of meat and fish ingestion. After the administration of bestatin, an inhibitor of leucine aminopeptidase, for 9 months, the urinary ASP concentration of children with DMD increased markedly. This increase is thought to have been directly caused by the bestatin itself. Urinary ASP is therefore apparently a more conveniently applied index of protein catabolism than is urinary 3MH, which requires the application of several restrictions. However, it should not be applied when the effect of bestatin administration is evident.     

Interaction of glucagon with artificial lipid bilayer membranes

The enhancement of fluorescence emission from the tryptophan residue of glucagon, the quenching of that emission with acrylamide and with 5-doxyl and 16-doxyl stearic acid, circular dichroism spectra, the release of 6-carboxytluorescein, and polarized infrared attenuated total reflection (IR-ATR) spectra were used to study the interaction of glucagon with intact lipid vesicles and flat bilayers. Dimyristoylphosphatidylcholine bound the peptide only below the main transition temperature, thus confirming earlier results of Epand et al. (1977). However, the peptide is also bound by vesicles of unsaturated lipids above their transition temperature, suggesting an influence of lipid area on the binding process. Circular dichroism showed that binding to such vesicles also increases the helix content of glucagon. The IR-ATR study and a comparison with dynorphin-A-(I-13)-tridecapeptide revealed profound differences in orientation of the two peptides. The dichroic ratios and the derived order parameters indicated an isotropic orientation of the helical segments of glucagon, but did not exclude a principal orientation of the molecules lying flat on the nienibrane surface. In contrast, the axis of the dynorphin helix is clearly oriented normal to the interface. The two peptides also differ in their rates of 6-carboxyfluorescein release, suggesting a deeper penetration of the primary amphiphilic helix of dynorphin A-(I-13) than of the secondary amphiphilic helix of glucagon.     

Continuous flow synthesis of peptides using a polyacrylamide gel resin (Expansin™)

The continuous flow syntheses of endothelin 1, proendothelin 2. ATP binding site of the CDC2 kinase 3, and fragment 18-30 of an actin 4, have been performed by using a polyacrylamide gel resin Expansin? (about 0.6 mmol NH₂/g) with the glycolamidic ester handle as labile anchorage. In addition, we report here a method of air oxidation which reduces the formation of side-products related to the formation of intermolecular disulfide bridges.     

Intranasal treatment with ovalbumin but not the major T cell epitope ovalbumin 323–339 generates interleukin-10 secreting T cells and results in the induction of allergen systemic tolerance

BACKGROUND: Nasal administration of major peptide T cell epitopes gives contradictory data on the induction of peripheral tolerance. OBJECTIVE: To compare the prophylactic effect of intranasal treatment (INT) on the development of an allergic response, using either ovalbumin (OVA) or its major T cell epitope OVA 323-339 (OVAp). METHODS: BALB/c mice were treated intranasally with OVA or OVAp and subsequently immunized s.c. with OVA. Anti-OVA-specific antibody, T cell proliferation and cytokine responses were analysed. In an adoptive transfer model using OVAp specific TCR transgenic (Tg) T cells from D011.10 mice, in vivo tracking and characterization of transferred T cells in the cervical, inguinal and bronchial lymph nodes (BLN) and in the spleen were determined by FACS analysis. RESULTS: Prophylactic INT with OVA induced T cell tolerance towards subsequent OVA s.c. immunizations, inhibiting OVA specific T cell proliferation, IgE and IgG1 production, in contrast to INT with OVAp, which was unable to induce tolerance. In vivo analysis of transferred OVA-specific TCR Tg T cells showed that INT with OVA induced a preferential activation of T cells in BLN, as opposed to a broad, systemic activation with OVAp. In vivo, OVAp INT led to faster and more sustained cell division cycles than OVA INT. Ex vivo, tolerance to OVA was associated with the generation of IL-10 secreting CD4(+) T cells in BLN of OVA-treated mice only. CONCLUSION: INT with OVA but not with OVAp led to regional (as opposed to systemic) T cell activation and the induction of IL-10 secreting CD4(+) T cells in BLN, potentially critical steps in the induction of T cell-specific tolerance via the nasal route.