Increased adrenergic contractility and decreased mRNA expression of NOS III in aging rat urinary bladders

Abstract

Our objective was to study age-related changes in adrenergic contractility and gene expression profile in the rat urinary bladder. Young (3-month old), adult (10-month old) and senescent (30-month old) male WAG/Rij rats were used. Gene expression profile in the rat urinary bladder was defined using Atlas microarray technology. In vitro contractile responses induced by KCl, phenylephrine (PHE) and norepinephrine (NE) were compared in isolated urinary bladders dissected from young, adult and senescent rats. Among a total of 1176 genes present on the arrays, 15 genes showed an increase in expression and 10 genes a decrease with age. Four genes related to nerve growth factor were upregulated whereas NOS type III was downregulated in aging rats. Intrinsic contractility of isolated rat urinary bladders was not changed between adult and aging rats as judged by the response curves to KCl. In contrast, an age-related increase in the maximal contractile responses to NE, but not PHE, was noticed (13 +/- 1, 48 +/- 2% and 59 +/- 2% at 3, 10 and 30 months, respectively). The alpha1D-adrenoceptor antagonist BMY7378 antagonized NE-induced contractions with low potency in both groups suggesting the involvement of the alpha1A-adrenoceptor subtype. This was confirmed by microarray, which demonstrated mRNA expression for the alpha1A-adrenoceptor subtype only. These results suggest that aging of the urinary bladder is associated with an increase in the maximal contractile response to NE which could be due to NO shortage resulting from downregulation of urothelial NOS III.

Aging differentially modifies agonist-evoked mouse detrusor contraction and calcium signals

“…This pattern is also present in aged rat bladder, which shows a loss of cholinergic innervation (Pagala et al 2001), accompanied by a non contractile up-regulation of muscarinic receptors (Schneider et al 2005) and an increase of the contractile effect of purinergic (Saito et al 1993;Lieu et al 1997;Kageyama et al 2000), α-adrenergic (Suzuki et al 1999;Lluel et al 2003), and serotoninergic (Saito et al 1993;Lieu et al 1997) neurotransmission. While these changes can contribute to bladder overactivity, this is also due to a decrease in the relaxing effect of β-adrenergic receptors (Nishimoto et al 1995) and a reduced expression of mucosal NO synthase III (Lluel et al 2003).…”

The effect of bladder outlet obstruction on α1‐ and β‐adrenoceptor expression and function

“…This finding is in line with a 1A -being the most abundant subtype in the rat bladder at the mRNA level 10 and previous functional studies implicating a 1A -adrenoceptors in rat bladder contraction. 24 While the contractile response to methoxamine was reduced in BOO, the response to A-61,603 was increased. Given the rather similar effects of both agonists on a 1A -adrenoceptors, we cannot fully explain this difference but propose that it may be an artefact related to an overall small magnitude of the contractile responses.…”

Evidence of increased centrally enhanced bladder compliance with ageing in a mouse model

“…collagen and smooth muscle content, and thickness of lamina propria and detrusor, show no prominent changes with ageing [8,9]. However, ageing is associated with changes in nerve density and function, and neurotransmitter sensitivity and receptor density [10][11][12][13], possibly affecting central control over detrusor smooth muscle. The increased bladder compliance in ageing therefore seems more likely to be the result of decreased detrusor muscle activity during filling rather than changes in the passive determinants/ECM.…”