It is well known that high concentrations of carbon monoxide (CO) are toxic and affect the human physiological conditions such as oxygen delivery insufficiency of systemic organs and neural disturbances. But, today, CO is also recognized as an endogenous gaseous signaling molecule related to neuromodulator, tissue homeostasis maintenance, cytoprotection, vasomodulation, anti-inflammation and anti-apoptosis [1].
CO is formed during degradation of haem to biliverdin by haem oxygenase (HO) in the body including the lower urinary tract and the brain. There were a few reports showing roles of endogenous CO in the micturition reflex, especially as a relaxation factor in the urethral smooth muscle [2]. On the other hand, roles of CO in the brain in regulation of the micturition reflex remains unclear. In this study, to elucidate roles of brain endogenous CO in regulation of the micturition reflex, we investigated effects of centrally administered CORM-3 (a CO donor) and ZnPP (a non-selective inhibitor of HO) on the rat micturition reflex.

Urethane anesthetized (0.8 g/kg, ip) male Wistar rats (350-450 g) were used. A catheter was inserted into the bladder from the bladder dome to perform continuous cystometry. Two hours after the surgery, intravesical instillation of saline at 12 ml/h was started to evaluate intercontraction intervals (ICI) and maximal voiding pressure (MVP). One hour after the start of cystometry, CORM-3 (1 or 10 nmol/rat), ZnPP (10 or 30 nmol/rat) or vehicle was intracerebroventricularly administered. In some rats, CORM-3 (10 nmol/rat) or ZnPP (30 nmol/rat) was intravenously administered through a catheter inserted into the femoral vein. Evaluations of ICI and MVP were continued 120 min after the administration. We also performed single cystometry (saline instillation rate at 12 ml/h) in some rats. After 4-5 times of single cystometry, ZnPP (30 nmol/rat) was intracerebroventricularly administered, then single cystometry was continued for 30 min after the administration. Next, effects of intracerebroventricular pretreatment with CORM-3 (10 nmol/rat) on intracerebroventricularly administered ZnPP (30 nmol/rat)-induced responses were investigated.

Intracerebroventricularly administered CORM-3 dose-dependently prolonged ICI and intracerebroventricularly administered ZnPP dose-dependently shortened ICI (Fig. A and B), without affecting MVP (data not shown). On the other hand, intravenously administered CORM-3 or ZnPP showed no significant effect on ICI or MVP (data not shown). Intracerebroventricularly administered ZnPP significantly reduced single-voided volume (Vv) and bladder capacity (BC) without affecting post-voiding residual volume (Rv) or voiding efficiency (VE) (Table). Intracerebroventricularly administered ZnPP-induced ICI shortening was cancelled by intracerebroventricular pretreatment with CORM-3 (Fig. C).

CORM-3-induced ICI prolongation was induced by intracerebroventricular, but not intravenous, administration, indicating that exogeneous CO derived from CORM-3 centrally suppressed the micturition reflex. ZnPP-induced ICI shortening was induced by intracerebroventricular, but not intravenous, administration, and intracerebroventricularly administered ZnPP induced reduction in Vv and BC without altering Rv or VE. These results suggest that ZnPP-mediated inhibition of HO in the brain may induce frequent urination through reduction in endogenous CO production. In fact, supplementation of CO by intracerebroventricular pretreatment with CORM-3 cancelled the intracerebroventricularly administered ZnPP-induced ICI shortening, indicating that brain endogenous CO play a suppressive role in regulation of the micturition reflex.

Endogenous CO in the brain centrally suppresses the micturition reflex in rats. Thus, brain endogenous CO could be a novel therapeutic target for patients who cannot obtain sufficient therapeutic effects from conventional medications on lower urinary tract dysfunctions.

Queiroga CS, Vercelli A, Vieira HL. Carbon monoxide and the CNS: challenges and achievements. Br J Pharmacol. 2015; 172: 1533-1545.
Naseem KM, Mumtaz FH, C.S.Thompson CS, et al. Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide, Eur J Pharmacol. 2000; 387:329-335.

Continence 2S2 (2022) 100209
DOI: 10.1016/j.cont.2022.100209