The renal nerves are the communication link between the central nervous system and the kidney. In response to multiple peripheral and central inputs, efferent renal sympathetic nerve activity is altered so as to convey information to the major structural and functional components of the kidney, the vessels, glomeruli, and tubules, each of which is innervated. At the level of each of these individual components, information transfer occurs via interaction of the neurotransmitter released at the sympathetic nerve terminal-neuroeffector junction with specific postjunctional receptors coupled to defined intracellular signaling and effector systems. In response to normal physiological stimuli, changes in efferent renal sympathetic nerve activity contribute importantly to homeostatic regulation of renal blood flow, glomerular filtration rate, renal tubular epithelial cell solute and water transport, and hormonal release. Afferent input from sensory receptors located in the kidney participates in this reflex control system via renorenal reflexes that enable total renal function to be self-regulated and balanced between the two kidneys. In pathophysiological conditions, abnormal regulation of efferent renal sympathetic nerve activity contributes significantly to the associated abnormalities of renal function which, in turn, are of importance in the pathogenesis of the disease.

Neural Control Of Renal Function

Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.

https://pharmrev.aspetjournals.org/content/pharmrev/57/1/27.full.pdf

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Peripheral and central mechanisms of cutaneous hyperalgesia.

1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies

During the annual meeting in Glasgow, July 1990, the Executive Committee of the European Academy of Allergology and Clinical Immunology (EAACI) decided to transform the Subcommittee on Skin Tests to the Subcommittee on Allergen Standardization and Skin Tests. Furthermore, the business meeting of this Subcommittee decided to produce a revised version of the 1989 Position Paper on skin tests used in type I allergy skin testing and include in the new version a chapter on “Allergen standardization by in vitro and in vivo methods”, replacing the chapter on “Biologic standardization”. The new chapter includes a general description of factors which affect the potency and composition of allergen extracts and a second part focusing on standardization of allergenic extracts used for skin testing. The subcommittees on immunotherapy, provocation tests, and in vitro tests are responsible for preparing position papers on the Academy’s view on standardization of allergens for immunotherapy, in vivo provocation tests, and in vitro tests, respectively. When outlining Chapter4, we have been in contact with these subcommittees. This position paper does not cover skin tests used for the study of immune complex diseases and delayed-type hypersensitivity. The different chapters of the position paper on Allergen standardization and skin tests have been worked out by members of the Steering Committee of the Subcommittee on Allergen Standardization and Skin Tests. Draft chapters were circulated to all members and other interested parties and were discussed during a special session at the annual meeting in Zurich in May 1991. The final version was discussed and approved by the subcommittee and then by the EAACI Executive Committee during the Congress held in Paris in May 1992. During recent years, methods and goals for allergen standardization have been the subject of intense discussions within the Academy, and among authorities and industries, and, recently, the EC regulatory authority has approved directives and guidelines for registration of allergenic preparations in Europe. These directives and guidelines will soon be implemented by member countries. There is an international system for allergen standardization and a number of WHO/IUIS International Standards (IS), labeled in arbitrary International Units (IU). The Academy stresses the importance of assessing the potency of allergenic preparations, intended for all types of use, in IU, giving the method for calibration of potency against these IS, in order to allow comparison of different materials used in scientific investigations and to give an idea of the difference in potency between materials prepared by different manufacturers. The Academy also promotes the use of biologically relevant units suitable for labeling commercially available extracts used for diagnosis, since such units allow better and more reliable diagnosis of sensitization and atopic disease. A number of company-specific units have been launched: some of these units are equivalent to units prescribed by authorities; that is, the Nordic Biological Unit (BU/ml) and the US Allergy Unit (AU/ ml). Other units are less well documented. For scientific purposes, it is essential that wellstandardized extracts or pure allergenic components of such extracts be used. Methods of skin testing vary among regions and also among medical specialties. At present, the skin prick test method using a lancet with 1-mm tip is the method of choice for routine diagnosis, especially among pediatricians. In contrast to results obtained by laboratory methods, skin test results are often presented without giving any details of the potency of the allergen preparation used, the method of testing, or reproducibility in the hands of the investigator. This fact reduces the value of most published studies using skin tests. It is our hope that the recommendations in this position paper on the performance, evaluation, and use of skin tests in diagnosis, standardization, and epidemiologic studies, will be followed by European allergologists and, especially, by editors of scientific journals. Finally, we hope that this edition of the position paper will stimulate scientific work within the field. Sten Dreborg Anthony Frew July 1992

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1398-9995.1993.tb04756.x

Position Paper: Allergen standardization and skin tests

Competitive antagonists of bradykinin

Autoradiographic studies localize [3H]bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. [3H]Bradykinin labeling is also observed over myocardial/coronary visceral afferent fibers. The localization of [3H]bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions.

The substitution of the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin with an aromatic amino acid or the D-configuration converts bradykinin agonists into a bradykinin antagonist. The invention further includes additional modifications at other positions within the novel 7-position modified bradykinin antagonists which increase enzyme resistance, antagonist potency and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of the mammal and human body in which an excess of bradykinin or related kinins are produced or injected as by bites into the body.

Raymond J. Vavrek

Papers

Competitive antagonists of bradykinin

Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions.

Bradykinin antagonist peptides

Antinociceptive effects of bradykinin antagonists.

Induction of histamine release from human skin mast cells by bradykinin analogs.