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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 15, 2005; DOI: 10.1124/jpet.105.088005

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Received for publication April 15, 2005.
Revised September 13, 2005.
Accepted for publication September 13, 2005.

Expression of metallopeptidases and kinin receptors in swine oropharyngeal tissues: effects of ACE inhibition and inflammation

Marie Eve Moreau 1, Pascal Dubreuil 2, Giuseppe Molinaro 1, Miguel Chagnon 3, Werner Muller-Esterl 4, Yves Lepage 3, Francois Marceau 5, Albert Adam 1*

1 Faculte de pharmacie, Universite de Montreal 2 Faculte de medecine veterinaire, Universite de Montreal 3 Departement de mathematiques et de statistique, Universite de Montreal 4 Institute of Biochemistry II, Johann Wolfgang Goethe University School of Medicine 5 Centre Hospitalier Universitaire de Quebec, Centre de recherche

* Address correspondence to: E-mail: albert.adam{at}umontreal.ca

Abstract

Angiotensin I-converting enzyme inhibitors (ACEi) cause both chronic and acute side effects, including rare but potentially life-threatening angioedema (AE). The main hypothesis to be tested in this study was that metallopeptidases and kinin receptors are present in oropharyngeal tissues and that their expression is modulated by ACEi and inflammation. Novel real-time polymerase chain reaction analysis was developed and allowed the relative quantification of tissue's gene expression for neprilysin, membrane-bound aminopeptidase P (mAPP) and both B1 and B2 kinin receptor subtypes in tongue, parotid gland and laryngeal tissue (areas especially involved in the gravest clinical forms of AE) and in kidney in a porcine model (single injection or 7-day ACEi oral treatments applied, or lipopolysaccharide (LPS) injected as a positive inflammatory control). The results provide evidence of the expression and activities of kininases in oropharyngeal tissues in the swine. ACEi treatment modulated the expression of neutral endopeptidase and aminopeptidase P mRNA, but the corresponding enzyme activities and that of angiotensin I-converting enzyme (ACE) were generally stable in tissues. The 7-day ACEi treatment upregulated both kinin receptor's mRNAs in the oropharynx, and the B1 receptor mRNA in the lingual vascular endothelium (immunohistochemistry). The inhibition of ACE in plasma is responsible for an accumulation of bradykinin and des-arginine9-bradykinin (des-Arg9-BK) generated during activation of the contact system with glass beads. The expression of critical components of the kallikrein-kinin system in the oropharyngeal tissues supports the role of kinins in ACEi-induced AE.


Key words: ACE inhibitor, angioedema, kinin receptors, metallopeptidases, oropharyngeal tissues, swine




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