Pro-inflammatory effect of quercetin by dual blockade of angiotensin converting-enzyme and neutral endopeptidase in vivo.

The effect of the flavonoid quercetin on substance P- and bradykinin-induced plasma extravasation in rat tissues (duodenum, heart, pancreas, trachea and urinary bladder) was studied, and its modulation by endogenous peptidases. Plasma protein extravasation was assayed by extravasated Evans blue dye. Intravenous injection of substance P (1, 3 and 10 nmol/kg) increased the plasma extravasation in a dose-dependent manner in heart, pancreas, trachea and urinary bladder. Bradykinin (3 and 10 nmol/kg, i.v.) increased plasma extravasation in a dose-dependent manner in duodenum, pancreas, trachea and urinary bladder. Pre-treatment with a selected dose of quercetin potentiated the substance P-induced plasma extravasation in heart, pancreas and urinary bladder, and also the bradykinin-induced plasma extravasation in duodenum, heart, trachea and urinary bladder. The selective pharmacological inhibition of neutral endopeptidase and angiotensin-converting enzyme potentiated the substance P- and bradykinin-induced plasma extravasation, respectively; furthermore, treatment with receptor antagonists showed that the mediators involved in the potentiation of plasma extravasation by quercetin are substance P and bradykinin. Analysis of plasma angiotensin-converting enzyme activity demonstrated that quercetin inhibited this enzyme. These results suggest that quercetin potentiates plasma extravasation induced by substance P and bradykinin, and that this may result from inhibition of the degradative enzymes of these peptides.