ACUTE ACE-INHIBITION CAUSES PLASMA EXTRAVASATION IN MICE THAT IS MEDIATED BY BRADYKININ AND SUBSTANCE-P

The use of angiotensin-converting enzyme (ACE) has been associated wit h 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 eviden ce for such a role is lacking. We investigated whether ACE inhibition increases plasma extravasation in mice (Swiss, C57Bl/6J, and J129Sv/Ev strains) via inhibition of bradykinin metabolism and stimulation of n eurogenic 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 1 5 minutes after drug administration. The particulate dye Monastral blu e identified the sites of captopril-induced leakage in the microvascul ature. Pretreatment with the bradykinin B-2 receptor antagonist Hoe 14 0 or with the tachykinin NK1 receptor antagonist SR 140333 inhibited c aptopril-evoked increase in plasma extravasation. In mice in which the gene encoding the bradykinin B-2 receptor was disrupted by gene targe ting, neither bradykinin nor captopril increased plasma extravasation. Pretreatment with Hoe 140 did not reduce the hypotensive response ind uced by captopril. The present findings suggest that ACE inhibition in creases kinin levels in tissues and/or plasma. These increased kinin l evels increase microvascular leakage in mouse airways and digestive tr act via the release of tachykinins from terminals of primary sensory n eurons. Exaggerated kinin production and the subsequent stimulation of peptide release from sensory nerves may be involved in adverse effect s of ACE inhibitors.