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Neuro–Endocrine–Immune Dysfunction in the Chronic Pain Patient
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
With peripheral sensitization, other non-neuronal substances become activated as well. Non-kallikrein, trypsin, and physical trauma activate Factor XII. Bradykinin is synthesized from Factor XII via the kinin-kallikrein system which results in vasodilation, increased vascular permeability, and also sensitizes the primary afferent terminals. Resident mast cells sensitize nociceptors possibly via bradykinin release.4
Central bradykinin receptors in the SHR and blood pressure
Published in H. Saito, Y. Yamori, M. Minami, S.H. Parvez, New Advances in SHR Research –, 2020
The detection of bradykinin sensitive sites in the medulla suggests the existence of functional kinin-kallikrein neurotransmitter system in the brain. However evidence of such a system is conflicting: kallikrein encoding mRNA and kallikrein activity and kallikrein like immunofluorescence were detected in the pituitary pineal gland and hypothalamus and to a leser extent in other brain areas (Chao et al., 1983,1987). Relatively large amounts of bradykinin (Perry and Snyder, 1984) or kinin like immunoreactive material (Correa et al., 1979) were found in hypothalamus while low amounts of bradykinin were detected in other brain regions including the medulla. The mismatch between the localization of bradykinin receptors and the effects of bradykinin and other components of the kinin kallikrein system in the brain does not satisfy the criterion of co-localization of the effector molecules and the receptors. These considerations infirm a role for bradykinin as a central synaptic neurotransmitter. However the central kininergic system in the brain may represent a typical example of volume transmission, a mode of neuronal communication in the brain in which the effector molecule reaches receptors via diffusion by extracellular fluid pathways (Agnati et al., 1986; Bjelke et al., 1994). The cerebrospinal fluid circulation from the third and lateral ventricle to the fourth ventricle could convey bradykinin from the periventricular regions of the hypothalamus, where the presence of bradykinin was identified (Correa et al., 1979), in the fourth ventricle. Bradykinin has been detected in cerebrospinal fluid and its presence there related to cardiovascular functions (Thomas et al., 1984; Yang et al., 1989). Another possibility which should be considered is that the bulbar receptors may be stimulated by kinins coming from the arterial circulation. The localization of the receptors in superficial structures of the dorsal medial and dorsal lateral medulla, less than half a millimeter deep from the medullary surface (Fior et al., 1993), would favor access from cerebrospinal fluid or from arterial circulation. Early experiments have shown that pressor effects may be produced by bradykinin administration in the cerebral circulation via injection in the carotid or paravertebral arteries of cats, rats or dogs. The blood barrier function is reduced in the fourth ventricular region and the vascular actions of bradykinin itself which include vasodilation, increase of vascular permeability (Devilier et al., 1989) and reduction of the blood-brain barrier function (Unterberg et al., 1984; Raymond et al., 1986) would promote its own passage in to the brain. If circulating kinins are capable of stimulating central receptors a negative feedback system may be envisioned by which high levels of circulating bradykinin could reach the bulbar receptors and trigger pressor responses counteracting the systemic hypotensive action of the peptide.
Angiotensin-converting enzyme inhibitor induced angioedema: not always a class effect? A case report and short narrative review
Published in Current Medical Research and Opinion, 2021
Guillaume Becker, Fabien Rougerie, Amelia-Naomi Sabo, Marie-Caroline Dalmas, Estelle Ayme-Dietrich, Laurent Monassier
Many pathophysiological mechanisms for the onset of angioedema have been proposed. Understanding these mechanisms is crucial, as it provides a classification and leads to effective diagnosis and therapeutic approaches. Angioedema is usually classified according to the mediator involved and the presence of skin symptoms. Because of increased vascular permeability, various vasoactive mediators such as histamine or bradykinin have been suggested1. These mediators can be released by basophils or mast cells, generated during the activation of the kinin–kallikrein system, or produced by still unknown mechanisms. Whatever the mechanism, it results in plasma extravasation to the surrounding tissues. Three main categories of angioedema can be identified: (i) angioedema with urticaria (histamine- or immune-mediated); (ii) angioedema mediated by bradykinin without urticaria; and (iii) so-called idiopathic angioedema2. Consequently, angioedema caused by the activation of the immune system and the release of vasoactive mediators by mast cells responds to treatments based on antihistamines, glucocorticoids and epinephrine.
Hereditary angioedema: examining the landscape of therapies and preclinical therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2019
Perhaps, there is no other rare disorder for which such an abundance of different therapies would be available or under development. Among others, this might be explained by the underlying pathophysiology of HAE – that is, activation of the kinin-kallikrein system may be an important factor in the etiology of other disorders. Unraveling the genetic background of HAE might identify new therapeutic targets, such as plasminogen and angiopoietin 1. Moreover, further genes with yet uncharacterized roles have been implicated in the pathophysiology of HAE – these also might become possible targets. On the other hand, notwithstanding the remarkable progress achieved in drug development, a medicinal product capable of preventing the onset of angioedema attacks with absolute certainty is still not available. However, this would be the greatest expectation from a new agent, inasmuch it is impossible to predict in advance the occurrence of HAE attacks. Fortunate for the ongoing scientific effort, this subject has its scientific community and forum, the activity of which contributed significantly to the progress of drug research. The C1-INH Deficiency and Angioedema Workshop (http://www.2019.haenetworkshop.hu/) – an event held every 2 years in Budapest, Hungary since 1999 – has attracted a special mix of proactive participants, including academic researchers, laboratory professionals, clinicians, and the delegates of patient organizations – this creates an excellent opportunity for cooperation in research. Because HAE is an orphan disease, it is indispensable to ensure the availability of blood samples and patients in sufficient numbers for the purposes of basic research and of clinical studies. The International Patient Organization for C1-Inhibitor Deficiencies (https://haei.org/) and the HAE Global Registry (https://it.hae.cloud-r.eu/) provide much help in this respect. The expansion of the range of new therapeutic targets will open up new perspectives in the management of HAE. The ultimate goal is to introduce the interventions designed to influence these targets into clinical application and verify their usefulness in practice – because, as the saying goes, ‘the proof of the pudding is in the eating.’