There is a significant unmet need for new therapeutic interventions for Detrusor hyperactivity with impaired contractile function (DHIC), which is the most common cause of incontinence in institutionalized elderly people. DHIC is defined by the non-voiding contractions or detrusor hyperactivity (DH) during bladder filling together with detrusor underactivity (DU or the IC component of DHIC) during voiding. Existing therapy with antimuscarinics is grossly inadequate owing to their adverse effect on the IC/DU component of DHIC, which has serious consequences. This T1 translational proposal in response to PAR-18-177 will use a combination of FDA approved drugs to investigate a novel mechanistic treatment paradigm, which simultaneously targets the myogenic origin of DH and the cholinergic deficiency for the origin of IC/DU component in DHIC. The main driver for the myogenic origin of DH is the spontaneous depolarization of detrusor smooth muscle (DSM), which precedes the spontaneous Ca2+ influx via high voltage-gated Ca2+ channels (L-type VGCC). Importantly, instead of depolarization of DSM, G-protein signaling of M3 receptor drives the Ca2+ influx via L-type VGCC for bladder emptying; so, the severity of myogenic DH can be reduced without worsening the IC/DU component by modulating the spontaneous depolarization of DSM initiated by low voltage T-type VGCC. Most importantly, T- type VGCC antagonists are not approved yet, but the activation of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels suppresses the T-type VGCC activity. HCN channels are densely expressed in mammalian bladder and approved antiepileptic drug, Lamotrigine (at 1/8th of its antiepileptic dose) exerts a tonic constraint on detrusor excitability via activation of HCN channels. Therefore, goal of Specific Aim 1 is to demonstrate that DH component of the DHIC phenotype in 28 months old Fischer 344 rats is functionally linked to the age-related decline in bladder expression of HCN channels and approved HCN blocker, Ivabradine blocks the Lamotrigine mediated improvement of DH component in DHIC. Another approved drug, Acotiamide reduced the post-void residual urine volume in a pilot study on DU patients. Since Acotiamide acts by antagonism of prejunctional M4 receptors and acetylcholinesterase, the goal of Specific Aim 2 is to examine whether Acotiamide counters the cholinergic deficiency to improve the IC/DU component of DHIC and whether its combination with Lamotrigine improves the IC/DU as well as DH components of the DHIC phenotype in aged rats. A multidisciplinary team of researchers and clinical experts will employ awake cystometry, single unit afferent recordings combined with bladder wall tension (spontaneous and nerve evoked) and voltage- sensitive and Ca2+ sensitive dye imaging of rat bladder wall to dissect the mechanism of action of this novel treatment paradigm. Since mouse bladder predominantly expresses HCN1 subtype and rat bladder mimics the predominant e...