Detrusor Underactivity as an HCN-Mediated Failure of Resilience in Aging

Sympathetic relaxation of the bladder wall permits low pressure urine storage and allows central regulation of afferent sensitivity to volume. Impaired regulation of volume sensitivity has been linked to symptoms of underactive bladder and cystometric detrusor underactivity. Hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels) are mediators of sympathomimetic-induced detrusor relaxation in young mouse bladder tissue, however in bladder strips from old female mice, HCN blockade enhanced age-diminished isoproterenol-induced relaxation. We therefore hypothesized that loss of HCN would compromise cystometric function and enhance sympathomimetic responses in old mice. Male HCN1 KO mice (20-22 mo) and their WT littermates underwent pressure-flow cystometry under urethane anesthesia to assess urinary performance at the level of the autonomic nervous system in the absence of cortical control. Following cystometry, bladders were harvested and pharmacomyography was performed on bladder strips to determine tissue-level changes in the absence of CNS input. All mice responded to continuous-fill cystometry by establishing regular filling/voiding cycles. HCN KO mice function showed discrete changes in volume sensitivity vs. WT. Bladder strip studies showed minimal response to isoproterenol regardless of HCN status, and no significant differences in response to carbachol based on HCN status. We conclude that HCN status impacts the brainstem-bladder reflexic control over urine storage/voiding, but not by regulating bladder wall tensions during filling. The absence of HCN influence on the loss of end-organ responsiveness to sympathetic control in old mice points to an increasing dependency on central control mechanisms with aging.

Electrical activity of the isolated nerve-urinary bladder strip preparation of the rabbit

The electrical activity of single cells of the smooth muscle of the isolated pelvic nerve-bladder strip preparation of the rabbit has been recorded by means of KCl-filled glass capillary microelectrodes. It was found that increasing the tension on the muscle either by stretching or by the addition of carbachol (3 µg/ml) to the bathing fluid causes a concomitant depolarization of the cell membrane. Spontaneous electrical activity and that elicited by stimulation of the nerve were similar and consisted of slow waves of depolarization of a 3–5 sec duration and spikes superimposed upon the depolarization phase of the slow wave. The spikes varied from 5 to 35 mv with no overshoot. Excitability of cells varied from one in which no response to tetanic stimulation of the nerve was seen to one which exhibited a series of spikes to a single shock. It was shown that slow waves and spikes could occur out of phase with the dominant activity of the whole muscle. Latency to a single shock to the nerve was found to be quite consistent for the same cell. However, a marked variation in latency was found among different cells of the same preparation.