Bradykinin Contracts Rat Urinary Bladder Largely Independently of Phospholipase C

Abstract

Several receptor systems in the bladder causing detrusor smooth muscle contraction stimulate phospholipase C (PLC). PLC inhibition abolishes bladder contraction via P2Y 6 but not that via M 3 muscarinic receptors, indicating a receptor-dependent role of PLC. Therefore, we explored the role of PLC in rat bladder contraction by bradykinin. The PLC inhibitor U 73, caused a strong and concentration-dependent inhibition of the bradykinin response. Our data support that not only M 3 but also bradykinin receptors cause bladder contraction by a largely PLC-independent mechanism. Both responses strongly involve L-type Ca 21 channels and rho kinase, whereas only the bradykinin response additionally involves the phospholipase A 2 /cyclooxygenase pathway.

Preclinical research strategies for newly approved drugs as reflected in early publication patterns

“…In some cases, this may be explained by the fact that a compound had long been a standard tool in a field prior to actually entering clinical development in the ultimate target indication. An example of this is the bradykinin B2 receptor antagonist icatibant, also known as Hoe 140, which had been available from fine chemical companies for many years before becoming approved for clinical use and which had become a standard tool in the field (Bischoff et al 1998;Sand and Michel 2014).…”

Selectivity of pharmacological tools: implications for use in cell physiology. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

“…For instance, muscarinic or bradykinin receptors in urinary bladder smooth muscle can stimulate phospholipase (PL)C. PLC activation is known to elevate intracellular Ca 2ϩ levels, and elevation of intracellular Ca 2ϩ is known to elicit smooth muscle contraction. Nevertheless, it was found in multiple species that an inhibitor of PLC in a concentration at which it fully suppresses inositol phosphate formation did not attenuate urinary bladder contraction stimulated by muscarinic receptor agonists (172,173) or bradykinin (165). Similarly, ␤-adrenoceptor (AR) stimulation promotes cyclic AMP (cAMP) formation and causes smooth muscle relaxation; both responses are mimicked by the direct adenylyl cyclase stimulator forskolin.…”

Pre‐ and post‐junctional bradykinin B2 receptors regulate smooth muscle tension to the pig intravesical ureter

“…BK immunoreactivity (IR) is present in afferent and efferent neurons innervating the bladder and urethra smooth muscle and in the urothelium, where BK exerts a wide range of biological actions including the ability to contract the detrusor smooth muscle, stimulate sensory nerves, and evoke the release of cyclooxygenase (COX) products . In the rat bladder, BK contraction is produced independently of phospholipase C involving L‐type Ca 2+ channels, as well as by rho‐kinase and phospholipase A 2 /COX dependent mechanisms . BK also modulates the human urothelial phenotype, accelerating stretch‐induced ATP release, release of nerve growth factor, and TRPV 1 channel expression.…”

“…[4][5][6][7] In the rat bladder, BK contraction is produced independently of phospholipase C involving L-type Ca 2þ channels, as well as by rho-kinase and phospholipase A 2 /COX dependent mechanisms. 8 BK also modulates the human urothelial phenotype, accelerating stretch-induced ATP release, release of nerve growth factor, and TRPV 1 channel expression. BK-induced changes in urothelial sensory function might contribute to bladder dysfunction.…”