Search

Abstract: In a previous paper we showed that bradykinin (BK), interacting with its B2 receptor, inhibits proximal tubule Na+-ATPase activity but does not change (Na+ +K+)ATPase activity. The aim of this paper was to investigate the molecular mechanisms involved in B2-mediated modulation of proximal tubule Na+-ATPase by BK. To abolish B1 receptor-mediated effects, all experiments were carried out in the presence of (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu), des-Arg9-[Leu8]-BK (DALBK), a specific antagonist of B1 receptor. A dual effect on the Na+-ATPase activity through the B2 receptor was found: short incubation times (1–10 min) stimulate the enzyme activity; long incubation times (10–60 min) inhibit it. The stimulatory effect of BK is mediated by activation of phosphoinositide-specific phospholipase C β (PI-PLCβ)/protein kinase C (PKC); its inhibitory action is mediated by Ca2+-independent phospholipase A2 (iPLA2). Prior activation of the PI-PLCβ/PKC pathway is required to activate the iPLA2-mediated inhibitory phase. These results reveal a new mechanism by which BK can modulate renal sodium excretion: coupling between B2 receptor and activation of membrane-associated iPLA2. [Copyright &y& Elsevier]

This paper describes the solution conformation of the vasoactive peptide hormone des-Arg9-bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe). 1. By ¹H-NMR spectroscopy we studied des-Arg9-bradykinin and its fragments bradykinin-(1-5), bradykinin-(1-6) in aqueous solution as a function of pH (titration) and in dimethylsulfoxide solution at two ionic states (cation and neutral ion species). 2. The preferred solution conformation which is most strongly stabilized in dimethylsulfoxide in the neutral ion species includes a distorted β-turn II involving the N-terminal sequence of Pro²-Pro²-Gly4-Phe5 and most likely a C7-type bend in the C-terminal part Ser-Pro-Phe. 3. A complete series of analogous ([Alan]des Arg9-bradykinin, with n = 1, 2 . . . 8) was then investigated by circular dichroism and ¹H-NMR spectroscopy in order to study the conformational role played by cach residue and to delineate the local and the long-range effects on conformation brought about by the Xaa→Ala substitutions. Chosen spectral parameters (circular dichroic spectra, chemical shift variations and vicinal coupling constants) characteristics of the preferred solution conformation of the native sequence of des-Arg9-bradykinin are followed from analogue to analogue. The important conformational role of the arginine-1 side chain and its positive charge and the spatial proximity of the N-terminal and C-terminal groups, i.e. the folded structure of the peptide can be inferred from these data. 4. A comparison of the biological activities of the analogues with the conformative pertubatins caused by the chemical alterations shows des-Arg9-bradykinin conformation and receptor affinity to be equally sensitive to single-residue substitutions. The correct orientation of the arginine-1 side chain, the precise geometry of the turn involving residues 2-5 and of the C-terminal Pro-Phe sequence are of primary importance. [ABSTRACT FROM AUTHOR]

In a previous paper, we have shown that bradykinin (Bk) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulate arachidonic acid release from HEL-30 keratinocytes along a Bk-B2 receptor G-protein-coupled pathway or a protein kinase C-dependent mechanism, respectively. Here we show a cytosolic PLA2 (cPLA2) to be responsible for this effect. This enzyme exhibited a marked acyl-group specificity towards arachidonic acid. It was activated by Ca++ in micromolar concentrations and partially translocated from the cytoplasmic to the membrane fraction upon Ca++ treatment. Translocation was also observed upon treatment of cells with either Bk or TPA. However, only with Bk was a corresponding increase of the cytoplasmic Ca++ level observed, whereas TPA-induced translocation occurred at basal Ca++ concentrations. Indirect evidence for a G protein to be involved in Bk- but not TPA-dependent cPLA2 activation was provided using non-hydrolyzable GTP derivatives. It is concluded that keratinocyte cPLA2 plays a critical role in the initiation by exogenous and endogenous factors of the eicosanoid cascade in skin. [ABSTRACT FROM AUTHOR]

Reports of Chagas disease are increasing in non-endemic populations across the globe. Apart from vector eradication and prevention efforts by public health organizations, current pharmacological interventions are sparse and show important side effects. In this issue of the BJP, Andrade et al. elegantly demonstrate a new pharmacological paradigm whereby Trypanosoma cruzi host cell invasion requires significant cross-talk between receptors for kinins and endothelins. It is shown, for example, that acting via both ETA and ETB receptors, endothelin-1 (ET-1) cooperates with the (TLR2/CXCR2/B2 kinin receptor) complex to activate inflammatory processes in response to invading trypomastigotes. This study by Andrade et al. prompts, however, several important questions, summarized in this Commentary, such as the putative role of chymase-dependent production of ET-1, the contentious protective role of ACE inhibitors in Chagasic patients, the unexplored role of de novo formed B1 receptors for kinins triggered by cytokines and the putative role of compartmentalized calcium pools in host cell invasion by trypomastigotes. LINKED ARTICLE This article is a commentary on Andrade et al., pp. 1333-1347 of this issue. To view this paper visit [ABSTRACT FROM AUTHOR]

In order to evaluate the utility of copper surfaces as spray initiators for mass spectrometric ionization sources, it is necessary to establish how efficient and reproducible the methodology is. To do this, a superhydrophobic and bare copper surface were used to ionize the singly and doubly charged peptides, bradykinin and leucine-enkephalin spiked with substance P as an internal standard, respectively. Both treated and bare copper surfaces were cut to 90, 60, and 30° angles. Calibration curves were constructed for both peptides on a superhydrophobic surface using covalently bonded trichloro(1H, 1H, 2H, 2H-perflourooctyl)silane-treated copper, and bare copper surface. The highest sensitivity for all peptides was observed using a 30 or 60° tip with the silane-treated copper. Limits of detection and quantitation for the 60° silane-treated surface for bradykinin were 6.01 × 10−3 μM and 2.00 × 10−2 μM respectively, with a R2 of 0.9959. Limits of detection and quantitation for the 30° silane-treated surface for leucine-enkephalin were 3.28 × 10−2 μM and 1.09 × 10−1 μM respectively, with a R2 of 0.9993. Image 1 • Copper surfaces were used as spray initiators similar to paper spray ionization. • Surfaces are reusable, have fixed geometry, and can be functionalized, and require minimal solvent to initiate a spray event. • Metalspray ionization was used to test sensitivity between bare copper and modified copper surfaces. • Copper was functionalized with trichloro(1 H , 1 H , 2 H , 2 H -perflourooctyl)silane to create a superhydrophobic surface. • Superhydrophobic surface displayed greater sensitivity and lower limits of quantitation compared to bare copper surface. [ABSTRACT FROM AUTHOR]

Summary Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass. AT1-B2 receptor aggregation was inhibited by beta-arrestin-mediated downregulation. Importantly, symptoms of preeclampsia were prevented by transgenic ARRB1 expression or a small-molecule drug. Because AT1-B2 heteromerization was found to occur in human placental biopsies from pregnancies complicated by preeclampsia, specifically targeting AT1-B2 heteromerization and its downstream consequences represents a promising therapeutic approach. Graphical Abstract Highlights • The beta-arrestin-biased agonist, TRV027, targets AT1-B2 and prevents preeclampsia • AT1-B2 enhances the vascular sensitivity to angiotensin II and mechanical stimulation • Increased vascular AT1-B2 in pregnant mice is a sufficient cause for preeclampsia • Transgenic ARRB1 counteracts preeclampsia symptoms by downregulation of AT1-B2 This paper provides a mechanistic understanding of the causes of preeclampsia and uses the newly gained insights to explore treatment for the condition. [ABSTRACT FROM AUTHOR]

While the role of the brain kallikrein-kinin system in the development of various pathological processes, such as oedema formation following brain injury or induction of central hypertonia has generated major interest, the possible role of this system in nociceptive processing has received little attention. In their present paper, Mortari et al. (2007) show that bradykinin B2 receptor activation in the brain by the bradykinin analogue, Thr6-bradykinin, isolated from the venom of the social wasp, Polybia occidentalis potently reduces acute, noxious heat-evoked reflex responses in naive rats. The unknown underlying mechanism of this powerful antinociceptive effect reminds us that the supraspinal antinociceptive system is still a “black box” in many aspects and awaits thorough investigation.British Journal of Pharmacology (2007) 151, 721–722; doi:10.1038/sj.bjp.0707274; published online 29 May 2007 [ABSTRACT FROM AUTHOR]

A conference paper on the role of extracellular products of the mastitis-inducing pathogens, Escherichia coli (EC), and Staphylococcus aureus (SA) in the activation of bovine milk kallikreins is presented. The study indicated that the presence in milk of the pathogens is associated with elevated bradykinin (BK) levels. It showed that both EC and SA directly activate BK formation in milk by activating synthetic tissue- and plasma-kallikreins-like activity in the milk.

A conference paper about the role of gap junctions in the bradykinin-induced relaxation of the bovine pulmonary supernumerary arteries is presented. It discusses on how the assessment was made with the use of fresh bovine lungs including the different phases the tissue underwent. Further, it revealed that gap junctions does not contribute to the bradykinin-induced relaxation of bovine supernumerary arteries instead it involved in the mediation with nitric acid.

A conference paper about the non-cholinergic component of the bronchoconstrictor response to bradykinin (BK) is presented. It investigates the involvement of leukotrienes, tachykinins and the peptidases, angiotensin converting enzyme and neutral endopeptidase. It shows that the bronchoconstrictor response to BK is not mediated by leukotrienes or tachykinins.

A conference paper about the selectivity of the ascorbate blockade in the ciliary vascular bed and the occurrence of the blockade in the porcine left anterior descending coronary artery is presented. It reveals that bradykinin induces concentration-dependent and endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilatation. It concludes that ascorbate-induced blockade of EDHF-mediated vasodilatation in the bovine ciliary circulation appears to be selective.

A conference paper about the ability of large pulmonary arteries to utilize an endothelium-derived hyperpolarizing factor (EDHF) after removing nitric oxide or inhibiting guanylyl cyclase is presented. It discusses the effect of potassium channel blockers on the concentration response curve for bradykinin-induced relaxation. It concludes that bradykinin induces relaxation in this study.

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT[sub1]RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT[sub1]RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT[sub1]RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies. [ABSTRACT FROM AUTHOR]