Mechanisms mediating the vasoactive effects of the B1 receptors of bradykinin.

Bradykinin normally exerts its vasodilatory effect via the B2 receptor (B2R), but in this receptor's absence, the B1 receptor becomes expressed and activated. To explore the mechanism of B1R-mediated vasodilation, 8 groups of B2R gene-knockout mice received a 2-week infusion of a B1R antagonist (300 microg x kg(-1) x d(-1)) or vehicle (groups 1 and 2), B1R antagonist or vehicle plus NO inhibition with Nomega-nitro-L-arginine methyl ester (groups 3 and 4), B1R antagonist or vehicle plus cyclooxygenase inhibition with indomethacin (groups 5 and 6), or B1R antagonist or vehicle plus blockade of vasoconstricting prostaglandin (PG) H2 and thromboxane A2 (TxA2) with SQ29548 (groups 7 and 8). The B1R antagonist produced significant (P<0.05) blood pressure increases of 17.7+/-3.1 mm Hg in group 1 and 10.4+/-3 mm Hg in group 3, whereas their vehicle-treated respective control groups 2 and 4 had no significant blood pressure changes. Indomethacin abolished the capacity of the B1R antagonist to raise blood pressure, as did blockade of the receptors of PGH2 and TxA2. Injection with the B1R agonist produced a hypotensive response (12+/-1.3 mm Hg), which was further accentuated by TxA2 blockade (21.7+/-4.1 mm Hg). Analysis of B1R gene expression by reverse transcription-polymerase chain reaction (PCR) in cardiac and renal tissues revealed marked expression at baseline, with further upregulation by 1.5- to 2-fold after various manipulations. Expression of the TxA2 receptor gene in renal tissue by quantitative real-time PCR was significantly lower in mice treated with the B1R antagonist, consistent with increased levels of agonist for this receptor. The data confirm that the B1R becomes markedly expressed in the absence of B2R and suggest that it contributes to vasodilation by inhibiting a vasoconstricting product of the arachidonic acid cascade acting via the PGH2/TxA2 receptor.