Background: We recently reported that murine and cavian heart mast cells are a unique extrarenal source of renin. Ischemia/reperfusion releases this renin leading to local angiotensin formation and norepinephrine release. As mast cells are a primary target of hypersensitivity, we assessed whether anaphylactic mast cell degranulation also results in renin and norepinephrine release. Methods: Hearts isolated from presensitized guinea pigs were challenged with antigen. Results: Cardiac anaphylaxis was characterized by mast cell degranulation, evidenced by β-hexosaminidase release and associated with renin and norepinephrine release. Mast cell stabilization with cromolyn or lodoxamide markedly attenuated the release of β-hexosaminidase, renin and norepinephrine. Renin inhibition with BILA2157 did not affect mast cell degranulation, but attenuated norepinephrine release. Conclusions: Our findings disclose that immediate-type hypersensitivity elicits renin release from mast cells, activating a local renin-angiotensin system, thereby promoting norepinephrine release. As renin is stored in human heart mast cells, allergic reactions could initiate renin release, leading to local angiotensin formation and hyperadrenergic dysfunction.

Keywords:
Angiotensin II, Immediate-type hypersensitivity, Mast cell degranulation, Mast cell-derived renin, β-Hexosaminidase, Norepinephrine, Cardiac anaphylaxis, Renin inhibitor
1.
Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R: Mast cells: a unique source of renin. Proc Natl Acad Sci USA 2004;101:13607–13612.
2.
Mackins CJ, Kano S, Seyedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R: Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 2006;116:1063–1070.
3.
Schwartz LB: Mast cells: function and contents. Curr Opin Immunol 1994;6:91–97.
4.
Graver LM, Robertson DA, Levi R, Becker CG, Weksler BB, Gay WA: IgE-mediated hypersensitivity in human heart tissue: histamine release and functional changes. J Allergy Clin Immunol 1986;77:709–714.
5.
Levi R: Cardiac anaphylaxis: models, mediators, mechanisms and clinical considerations; in Marone G, Lichtenstein LM, Condorelli M, Fauci AS (eds): Human Inflammatory Disease, Clinical Immunology. Toronto, Decker, 1988, pp 93–105.
6.
Rubin LE, Levi R: Protective role of bradykinin in cardiac anaphylaxis. Coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms. Circ Res 1995;76:434–440.
7.
Feigen GA, Prager DJ: Experimental cardiac anaphylaxis. Physiologic, pharmacologic and biochemical aspects of immune reactions in the isolated heart. Am J Cardiol 1969;24:474–491.
8.
Schwartz LB, Austen KF, Wasserman SI: Immunologic release of β-hexosaminidase and β-glucuronidase from purified rat serosal mast cells. J Immunol 1979;123:1445–1450.
9.
Seyedi N, Mackins CJ, Machida T, Reid AC, Silver RB, Levi R: Histamine H3-receptor-induced attenuation of norepinephrine exocytosis: a decreased protein kinase A activity mediates a reduction in intracellular calcium. J Pharmacol Exp Ther 2005;312:1–9.
10.
Simoneau B, Lavallee P, Anderson PC, Bailey M, Bantle G, Berthiaume S, Chabot C, Fazal G, Halmos T, Ogilvie WW, Poupart MA, Thavonekham B, Xin Z, Thibeault D, Bolger G, Panzenbeck M, Winquist R, Jung GL: Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999;7:489–508.
11.
Bani D, Nistri S, Mannaioni PF, Masini E: Cardiac anaphylaxis: pathophysiology and therapeutic perspectives. Curr Allergy Asthma Rep 2006;6:14–19.
12.
Dostal DE, Baker KM: The cardiac renin-angiotensin system – conceptual, or a regulator of cardiac function? Circ Res 1999;85:643–650.
13.
Bader M, Peters J, Baltatu O, Müller DN, Luft FC, Ganten D: Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research. J Mol Med 2001;79:76–102.
14.
Reid AC, Mackins CJ, Seyedi N, Levi R, Silver RB: Coupling of angiotensin II AT1 receptors to neuronal NHE activity and carrier-mediated norepinephrine release in myocardial ischemia. Am J Physiol Heart Circ Physiol 2004;286:H1448–H1454.
15.
Boehm S, Kubista H: Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol Rev 2002;54:43–99.
16.
Levi R, Seyedi N, Schaefer U, Estephan R, Mackins CJ, Tyler E, Silver RB: Histamine H3-receptor signaling in cardiac sympathetic nerves: identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway. Biochem Pharmacol 2007;73:1146–1156.
17.
Levi R, Smith NCE: Histamine H3-receptors: a new frontier in myocardial ischemia. J Pharmacol Exp Ther 2000;292:825–830.
18.
Mest H-J, Pönicke K, Heinroth-Hoffmann I, Meissner N, Giessler C: Relevance of mediators to cardiac parameters of isolated anaphylactic guinea-pig heart. Prostaglandins Leukot Essent Fatty Acids 1995;53:21–29.
19.
Danser AHJ, van Kesteren CAM, Bax WA, Tavenier M, Derkx FHM, Saxena PR, Schalekamp MADH: Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts: evidence for renin binding. Circulation 1997;96:220–226.
20.
Catanzaro DF: Physiological relevance of renin/prorenin binding and uptake. Hypertens Res 2005;28:97–105.
21.
Campbell DJ: Circulating and tissue angiotensin systems. J Clin Invest 1987;79:1–6.
22.
Lindpaintner K, Ganten D: The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circ Res 1991;68:905–921.
23.
Perskvist N, Edston E: Differential accumulation of pulmonary and cardiac mast cell-subsets and eosinophils between fatal anaphylaxis and asthma death. A postmortem comparative study. Forensic Sci Int 2007;169:43–49.
24.
Criqui MH, Lee ER, Hamburger RN, Klauber MR, Coughlin SS: IgE and cardiovascular disease. Results from a population-based study. Am J Med 1987;82:964–968.
25.
Marone G, Bova M, Detoraki A, Onorati AM, Rossi FW, Spadaro G: The human heart as a shock organ in anaphylaxis. Novartis Found Symp 2004;257:133–149.
26.
De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T: International union of pharmacology. 23. The angiotensin II receptors. Pharmacol Rev 2000;52:415–472.
27.
Kounis NG, Grapsas ND, Goudevenos JA: Unstable angina, allergic angina, and allergic myocardial infarction. Circulation 1999;100:156e.
28.
Fujita Y, Chikamitsu M, Kimura M, Toriumi T, Endoh S, Sari A: An anaphylactic reaction possibly associated with an intraoperative coronary artery spasm during general anesthesia. J Clin Anesth 2001;13:221–226.
29.
Goldhaber-Fiebert S, Grecu L: Postoperative ST-segment elevation: was vasospasm caused by anaphylaxis or by its treatment with epinephrine? Ann Allergy Asthma Immunol 2006;97:449–453.
30.
Del Furia F, Querceto L, Testi S, Santoro GM: Acute ST-segment elevation myocardial infarction complicating amoxycillin-induced anaphylaxis: a case report. Int J Cardiol 2007;117:e37–e39.
31.
Huang M, Pang XZ, Letourneau R, Boucher W, Theoharides TC: Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in apolipoprotein E knockout mice. Cardiovasc Res 2002;55:150–160.
32.
Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier DE, Yanagisawa MM, Tsai M, Galli SJ: Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature 2004;432:512–516.
33.
Dugina TN, Kiseleva EV, Glusa E, Strukova SM: Activation of mast cells induced by agonists of proteinase-activated receptors under normal conditions and during acute inflammation in rats. Eur J Pharmacol 2003;471:141–147.
© 2007 S. Karger AG, Basel
2007
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.