Abstract
Bradykinin (BK) has been proposed to modulate urinary bladder functions and implicated in the pathophysiology of detrusor overactivity. The present study aims to elucidate the signaling pathways of BK-induced detrusor muscle contraction, with the goal of better understanding the molecular regulation of micturition and identifying potential novel therapeutic targets of its disorders. Experiments have been carried out on bladders isolated from wild-type or genetically modified [smooth muscle-specific knockout (KO): Gαq/11-KO, Gα12/13-KO and constitutive KO: thromboxane prostanoid (TP) receptor-KO, cyclooxygenase-1 (COX-1)-KO] mice and on human bladder samples. Contractions of detrusor strips were measured by myography. Bradykinin induced concentration-dependent contractions in both murine and human bladders, which were independent of secondary release of acetylcholine, ATP, or prostanoid mediators. B2 receptor antagonist HOE-140 markedly diminished contractile responses in both species, whereas B1 receptor antagonist R-715 did not alter BK's effect. Consistently with these findings, pharmacological stimulation of B2 but not B1 receptors resembled the effect of BK. Interestingly, both Gαq/11- and Gα12/13-KO murine bladders showed reduced response to BK, indicating that simultaneous activation of both pathways is required for the contraction. Furthermore, the Rho-kinase (ROCK) inhibitor Y-27632 markedly decreased contractions in both murine and human bladders. Our results indicate that BK evokes contractions in murine and human bladders, acting primarily on B2 receptors. Gαq/11-coupled and Gα12/13-RhoA-ROCK signaling appear to mediate these contractions simultaneously. Inhibition of ROCK enzyme reduces the contractions in both species, identifying this enzyme, together with B2 receptor, as potential targets for treating voiding disorders.
Highlights
Bradykinin (BK) is a nonapeptide pro-inflammatory mediator with a diverse set of functions, including regulation of smooth muscle tone
Bradykinin induced marked, transient contraction in the mouse bladder, it did not reach the level of the response evoked by CCh, a stable analog of ACh, the main physiological mediator of detrusor muscle contraction (Figure 1A)
Bradykinin-induced contractions were dosedependent in human bladders with an EC50 of 5.1 μM and Emax at 42.4% (Figure 1D)
Summary
Bradykinin (BK) is a nonapeptide pro-inflammatory mediator with a diverse set of functions, including regulation of smooth muscle tone. Bradykinin exerts its effects in smooth muscle tissues via two major subtypes of BK receptors: B1 and B2 [7]. Despite their structural similarity, B1 and B2 receptors differ greatly regarding their expression profiles in tissues and their function as well [8]. B2 receptors’ presence is constitutive and predominant under physiological conditions [8, 10]. Expression of both B1 and B2 receptors has been reported in urinary bladder smooth muscle (UBSM), their role and signaling pathways remain to be elucidated [11]. B1 and B2 receptors are members of the seven-transmembrane-domain, type 1 G proteincoupled receptor (GPCR) family, representing a major class of drug targets [10, 12]
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