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    • In a recent series of studies from

    2023-11-01

    In a recent series of studies from our laboratory, to characterize the contractile systems within the rat Cy5 NHS ester(Et) wall, three conditions were identified that led to detrusor activity: spontaneous micro-contractions, electrical field stimulated (EFS) contractions and muscarinic agonist induced contractions (Gillespie et al., 2015a; Gillespie et al., 2015b; Gillespie et al., 2015c). It was shown that the micro-contractile activity was sensitive to isoprenaline and that this mechanism was mediated via β1-adrenoceptors, while the EFS and muscarinic agonist induced contractions were less affected (Gillespie et al., 2015a; Gillespie et al., 2015b; Gillespie et al., 2015c; Persyn et al., 2016). It has been argued that the system generating micro-contractions is different from those involving muscarinic agonists and nerves and possibly involves the network of interstitial cells that surround the muscle bundles (Gillespie et al., 2015a; Gillespie et al., 2015c). Thus, there appears to be different systems operating in the bladder wall that can lead to contraction and that these different systems underpin different physiological processes. The system involving micro-contractions appears to be sensitive to adrenergic agonists. However, although the pharmacology of this system has been characterized, its physiological role and particularly the source of the catecholamines involved in its regulation are not obvious. The vmat-IR interstitial cells also demonstrate β1AR-IR. The expression of β-adrenoceptors on interstitial cells has also been suggested to occur in the human bladder (Limberg et al., 2010). A role for interstitial cells in the generation of phasic contractile activity in the bladder wall has been suggested previously (Hashitani and Lang, 2010; Hashitani et al., 2004) and that it is under neural control (McCloskey, 2010). It has therefore been hypothesized that the inhibition of the micro-contractile activity by isoprenaline, demonstrated via a β1-adrenoceptor mechanism (Gillespie et al., 2015b), is mediated through an interstitial cell network (Gillespie et al., 2015a). The present observations illustrate that the β1-adrenoceptors are primarily expressed on the interstitial cell network, providing evidence for a role of the interstitial cells in the β1-adrenoceptor mediated regulation of micro-contractile activity. Evidence for such a mechanism has been found in the gastro-intestinal tract in which the interstitial cells of Cajal are known to have a pacemaker activity and are involved in the regulation of gastro-intestinal tract motility (Sanders, 1996). It has been found that noradrenaline inhibits the pacemaker currents through the activation of β1-adrenoceptors in cultured interstitial cells of Cajal from murine small intestine (Jun et al., 2004). Since a population within the interstitial cell network that expresses vmat-IR and possibly releases catecholamine, has been observed in the present study, it is worth speculating that this is the source of the physiological signal that modulates micro-contractile activity in the lateral wall of the bladder. It must be stressed that the localization of receptors and their ability to function based on immunohistochemical data is fraught with complications. The technique relies heavily on the selectivity of antibodies in the species under investigation. In the present study, the antibodies were chosen as they had been characterized (see manufacturer's data sheets and bibliography) and have suggested structural insights that seem to support the functional responses found in our previous series of experiments (Gillespie et al., 2015a; Gillespie et al., 2015b; Gillespie et al., 2015c). In addition, the removal of immunoreactivity using blocking peptides suggests a strong degree of antibody specificity. The present data are suggestive of a catecholaminergic autocrine system linked to the control of micro-contractile activity. Co-localization of the β1-AR and vmat on individual interstitial cells has been observed in the current study. The existence of autocrine systems operating in the bladder within the interstitial cell network has already been suggested in the guinea pig in relation to prostanoid signaling. Exogenous prostaglandin modulates micro-contractile activity in the guinea pig bladder (de Jongh et al., 2007). It was subsequently shown that the interstitial cells, surrounding the smooth muscle bundles, express the prostanoid synthesizing enzyme COX1 and express prostaglandin receptors (EP1 and EP2) (Rahnama'i et al., 2012; Rahnama'i et al., 2011).