A number of diseases and pathologies are associated with both urinary incontinence and erectile dysfunction (ED), including diabetes, benign prostate hyperplasia, hypertension, and hyperlipidemia. The co-occurrence of urinary bladder and erectile dysfunction suggests the existence of mechanistic commonalities. One such point of convergence is the large conductance Ca2+-activated K+ (BK) channel, as evidenced by the fact that targeted disruption of the pore-forming BKa-subunit leads to overactive detrusor, urinary incontinence, and ED. A second potential common denominator is the NO/cGMP/PKG pathway, which regulates BK channel function directly as well as indirectly through calcium signaling elements that modulate BK channel function. The NO/cGMP/PKG pathway is nearly universally associated with smooth muscle (SM) relaxation. Yet, in contrast to corpus cavernosum (CC) SM, where nitrergic signaling through the PKG pathway is a well-established mediator of SM relaxation and erectile function, the role of NO in urinary bladder (UB) SM is an unsettled issue.
In Aim 1, UBSM and CCSM will be investigated at the molecular and cellular levels to establish the potential of NO/cGMP/PKG signaling to regulate SM function, with an emphasis on the role of the BK channel pathway. BK channel function and PKG regulatory mechanisms in intact bladder and corpus tissue will be addressed in Aim 2, which will also consider the role of the cGMP-specific phosphodiesterase, PDE5, and Ca2+-sensitive chloride currents (ClCa) as potential contributors to tissue-specific differences in NO sensitivity. Finally, Aim 3 seeks to integrate the findings of Aim 1 and 2 and address the roles of the BK channel and cGMP/PKG pathways in regulating function during bladder filling using an ex vivo whole bladder model. Additionally, the role of these pathways in regulating intracavernous pressure and urodynamic properties during bladder filling will be addressed in vivo.The clinical success of the cGMP-specific phosphodiesterase-5 (PDE5) inhibitor sildenafil (Viagra) and related compounds in treating erectile dysfunction demonstrates a clear role for the cGMP-dependent protein kinase (PKG) pathway in regulating corpus cavernosum smooth muscle relaxation and erectile function. Despite the existence of both neuronal and urothelial sources of NO in the urinary bladder, and evidence for the expression of NO-responsive cGMP/PKG signaling pathway components in myocytes, the significance of the cGMP/PKG pathway in bladder physiology remains an unsettled question. The large conductance, calcium activated potassium (BK) channel, which has a central role in relaxing smooth muscle in the lower urinary tract, is a target of the PKG pathway, and represents a promising therapeutic target in the treatment of sildenafil-resistant ED and urinary incontinence.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Vermont & St Agric College
Schools of Medicine
United States
Zip Code
Harraz, Osama F; Longden, Thomas A; Hill-Eubanks, David et al. (2018) PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells. Elife 7:
Gomes, Carolina Cavalieri; Gayden, Tenzin; Bajic, Andrea et al. (2018) TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw. Nat Commun 9:4572
Harraz, Osama F; Longden, Thomas A; Dabertrand, Fabrice et al. (2018) Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion. Proc Natl Acad Sci U S A 115:E3569-E3577
Koide, Masayo; Moshkforoush, Arash; Tsoukias, Nikolaos M et al. (2018) The yin and yang of KV channels in cerebral small vessel pathologies. Microcirculation 25:
Hawkins, Virginia E; Takakura, Ana C; Trinh, Ashley et al. (2017) Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe. Elife 6:
Longden, Thomas A; Dabertrand, Fabrice; Koide, Masayo et al. (2017) Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci 20:717-726
Villalba, Nuria; Sackheim, Adrian M; Nunez, Ivette A et al. (2017) Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase. J Neurotrauma 34:192-203
Heppner, Thomas J; Hennig, Grant W; Nelson, Mark T et al. (2017) Rhythmic Calcium Events in the Lamina Propria Network of the Urinary Bladder of Rat Pups. Front Syst Neurosci 11:87
Tykocki, Nathan R; Bonev, Adrian D; Longden, Thomas A et al. (2017) Inhibition of vascular smooth muscle inward-rectifier K+ channels restores myogenic tone in mouse urinary bladder arterioles. Am J Physiol Renal Physiol 312:F836-F847
Capone, Carmen; Dabertrand, Fabrice; Baron-Menguy, Celine et al. (2016) Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. Elife 5:

Showing the most recent 10 out of 56 publications