Mechanisms Mediating the Vasoactive Effects of the B 1 Receptors of Bradykinin

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Abstract
Bradykinin normally exerts its vasodilatory effect via the B 2 receptor (B 2 R), but in this receptor’s absence, the B 1 receptor becomes expressed and activated. To explore the mechanism of B 1 R-mediated vasodilation, 8 groups of B 2 R gene–knockout mice received a 2-week infusion of a B 1 R antagonist (300 μg · kg −1 · d −1 ) or vehicle (groups 1 and 2), B 1 R antagonist or vehicle plus NO inhibition with Nω -nitro- l -arginine methyl ester (groups 3 and 4), B 1 R antagonist or vehicle plus cyclooxygenase inhibition with indomethacin (groups 5 and 6), or B 1 R antagonist or vehicle plus blockade of vasoconstricting prostaglandin (PG) H 2 and thromboxane A 2 (TxA 2 ) with SQ29548 (groups 7 and 8). The B 1 R antagonist produced significant ( P 1 R antagonist to raise blood pressure, as did blockade of the receptors of PGH 2 and TxA 2 . Injection with the B 1 R agonist produced a hypotensive response (12±1.3 mm Hg), which was further accentuated by TxA 2 blockade (21.7±4.1 mm Hg). Analysis of B 1 R 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 TxA 2 receptor gene in renal tissue by quantitative real-time PCR was significantly lower in mice treated with the B 1 R antagonist, consistent with increased levels of agonist for this receptor. The data confirm that the B 1 R becomes markedly expressed in the absence of B 2 R and suggest that it contributes to vasodilation by inhibiting a vasoconstricting product of the arachidonic acid cascade acting via the PGH 2 /TxA 2 receptor.