Acute ACE inhibition causes plasma extravasation in mice that is mediated by bradykinin and substance P

Costanza Emanueli, Eileen F. Grady, Paolo Madeddu, Michela Figini, Nigel W. Bunnett, Deborah Parisi, Domenico Regoli, Pierangelo Geppetti

Research output: Contribution to journalArticlepeer-review


The use of angiotensin-converting enzyme (ACE) has been associated with the occurrence of adverse effects, including cough and angioneurotic edema. Accumulation of kinins has been suggested to play a major role in these adverse effects of ACE inhibitor, although conclusive evidence for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57B1/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of neurogenic inflammatory mechanisms. Intravenous captopril and enalapril increased the extravasation of Evans blue dye in all tissues examined (trachea, stomach, duodenum, and pancreas). This effect was evident 15 minutes after drug administration. The particulate dye Monastral blue identified the sites of captopril-induced leakage in the microvasculature. Pretreatment with the bradykinin B2 receptor antagonist Hoe 140 or with the tachykinin NK1 receptor antagonist SR 140333 inhibited captopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B2 receptor was disrupted by gene targeting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response induced by captopril. The present findings suggest that ACE inhibition increases kinin levels in tissues and/or plasma. These increased kinin levels increase microvascular leakage in mouse airways and digestive tract via the release of tachykinins from terminals of primary sensory neurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effects of ACE inhibitors.

Original languageEnglish (US)
Pages (from-to)1299-1304
Number of pages6
Issue number6
StatePublished - Jun 1998


  • Angiotensin-converting enzyme
  • Bradykinin
  • Captopril
  • Plasma
  • Substance P

ASJC Scopus subject areas

  • Internal Medicine


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