Platelet-Activating Factor and Kinin-Dependent Vascular Leakage as a Novel Functional Activity of the Soluble Terminal Complement Complex

AbstractThe infrequent occurrence of septic shock in patients with inherited deficiencies of the terminal complement components experiencing meningococcal disease led us to suspect that the terminal complement complex is involved in vascular leakage. To this end, the permeabilizing effect of the cytolytically inactive soluble terminal complement complex (SC5b-9) was tested in a Transwell system measuring the amount of fluorescein-labeled BSA (FITC-BSA) leaked through a monolayer of endothelial cells. The complex caused increased permeability to FITC-BSA after 15 min as opposed to the prompt response to bradykinin (BK). The effect of SC5b-9 was partially reduced by HOE-140 or CV-3988, two selective antagonists of BK B2 and platelet-activating factor receptors, respectively, and was completely neutralized by the mixture of the two antagonists. Also, DX-88, a specific inhibitor of kallikrein, partially inhibited the activity of SC5b-9. The permeabilizing factor(s) released after 30 min of incubation of endothelial cells with SC5b-9 caused a prompt leakage of albumin like BK. Intravital microscopy confirmed both the extravasation of circulating FITC-BSA across mesenteric microvessels 15 min after topical application of SC5b-9 and the complete neutralization by the mixture of HOE-140 and CV-3988. SC5b-9 induced opening of interendothelial junctions in mesenteric endothelium documented by transmission electron microscopy

Kallikrein‐kinin system as the dominant mechanism to counteract hyperactive renin‐angiotensin system

The renin-angiotensin system (RAS) generates, maintains and makes worse hypertension and cardiovascular diseases (CVDs) through its biologically active component Angiotensin II (Ang II), that causes vasoconstriction, sodium retention and structural alterations of the heart and the arteries. A few endogenous vasodilators, kinins, natriuretic peptides and possibly angiotensin (1-7), exert opposite actions and may provide useful therapeutic agents. As endothelial autacoids, the kinins are potent vasodilators, active natriuretics and protectors of the endothelium. Indeed, the kallikrein-kinin system (KKS) is considered the dominant mechanism for counteracting the detrimental effects of the hyperactive RAS. The two systems, RAS and KKS are controlled by the angiotensin-converting enzyme (ACE) that generates Ang II and inactivates the kinins. Inhibitors of ACE can reduce the impact of Ang II and potentiate the kinins, thus contributing to restore the cardiovascular homeostasis. In the last 20 years, ACE-inhibitors (ACE-Is) have become the drugs of first choice for the treatments of the major CVDs. ACE-Is not only reduce blood pressure, as Sartans also do, but by protecting and potentiating the kinins, they can reduce morbidity and mortality and improve the quality of life for patients with CVDs. This paper provides a brief review of the literature on this topic.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Pharmacology of the Kallikrein-Kinin system

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AGONISTI PIENI E PARZIALI ED ANTAGONISTI DEL RECETTORE PER NOCICETTINA/ORFANINA FQ AD ELEVATA POTENZA\u201d

La prsente invenzione riguarda peptidi analoghi di nocicettina/orfanina FQ (N/OFQ) in grado di modulare l'attivit\ue0 del recettore del peptide N/OFQ (recettore NOP), composizioni farmaceutiche che li contengono e loro impiego nel trattamento di dsfunzioni, condizioni o stati patologici in cui \ue8 coinvolto lo stesso recettore

Highly potent full and partial agonists and anatagonists of the nociceptin/orphanin FQ receptor

The present invention relates to nociceptin/orphanin FQ (N/OFQ) peptide analogs capable of modulating the activity of the N/OFQ peptide receptor (NOP receptor), pharmaceutical compositions comprising said peptide analogs and their use for treatment of dysfunctions, phatological conditions or phatological states involving said receptor

Identificazione di un agonista parziale del recettore per il neuropeptide S

La presente invenzione riguarda la sintesi di una molecola di natura peptidica in grado di modulare l’attività del recettore per il neuropeptide S, le composizioni farmaceutiche che la contengono e il loro impiego nel trattamento di disfunzioni, condizioni o stati patologici in cui lo stesso recettore è coinvolto

Highly potent full and partial agonists and anatagonists of the nociceptin/orphanin FQ receptor

The present invention relates to nociceptin/orphanin FQ (N/OFQ) peptide analogs capable of modulating the activity of the N/OFQ peptide receptor (NOP receptor), pharmaceutical compositions comprising said peptide analogs and their use for treatment of dysfunctions, phatological conditions or phatological states involving said receptor