Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Jan;298(1):F118-24.
doi: 10.1152/ajprenal.00281.2009. Epub 2009 Oct 28.

Differential vulnerabilities of urethral afferents in diabetes and discovery of a novel urethra-to-urethra reflex

Zhongguang Yang  1 , Paul C Dolber, Matthew O Fraser
Affiliations

Differential vulnerabilities of urethral afferents in diabetes and discovery of a novel urethra-to-urethra reflex

Zhongguang Yang et al. Am J Physiol Renal Physiol. 2010 Jan.

Abstract

Urethral reflexes are important regulators of micturition, and impairment of urethral afferent neuronal function may disrupt coordinated bladder and urethral activity, thereby contributing to voiding dysfunction in lower urinary tract disorders. Chemical stimulation by intraurethral irritant solution perfusion was used to determine whether urethral afferent neuronal function is altered in diabetes mellitus (DM). Sprague-Dawley rats were studied 10 wk after streptozotocin injection to induce DM or vehicle alone. Escalating doses of capsaicin (0.1-30 microM) or acetic acid (0.01-1%; AA) were perfused intraurethrally while recording isovolumetric bladder activity, urethral perfusion pressure, and electromyography of the external urethral sphincter (EUS-EMG). Some rats were additionally treated with alpha-bungarotoxin, hexamethonium, or bilateral transection of the sensory branches of the pudendal nerves (PudSNx). Intraurethral capsaicin inhibited bladder contractions in six out of seven control rats but not in any of six DM rats. Low-frequency oscillations (LFOs) of intraurethral pressure were observed in five out of six control rats with capsaicin-induced bladder inhibition. In contrast, intraurethral AA inhibited bladder contractions and enhanced tonic EUS-EMG activity in six out of six control and five out of six DM rats. LFOs occurred in four out of six control and three of five DM rats with AA-induced bladder inhibition. Chemically induced bladder inhibition and LFOs were not prevented by alpha-bungarotoxin but were eliminated by PudSNx and hexamethonium. Finally, LFOs were followed by phasic EUS activity. These findings show that DM affects urethral afferent neurons differentially, compromising those expressing TRPV1 receptors. Urethral smooth muscle LFOs are neurogenically mediated and induce EUS activity, revealing the existence of a hitherto undescribed reflex pathway: a smooth-to-striated muscle urethra-to-urethra reflex.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
The isolated bladder-urethra preparation. The double-lumen urethral catheter consisted of external PE-160 tubing for urethral perfusion and internal PE-50 tubing for recording urethral perfusion pressure (UPP). A cone-shaped plug fashioned from a 200-μl Eppendorf pipette tip and serving as the tip of the double-lumen urethral catheter was seated in the bladder neck to separate the urethra from the bladder functionally. Separate PE-50 tubing was used for bladder filling and pressure recording.
Fig. 2.
Fig. 2.
Response of bladder contractions and urethral activity to intraurethral administration of capsaicin in a control rat. Each panel shows isovolumetric bladder pressure (top), UPP (middle), and electromyography of the external urethral sphincter (EUS-EMG, bottom) recordings. A: cessation of bladder contractions and micturition-associated urethral relaxations and high-frequency oscillations (HFOs) following intraurethral administration of capsaicin (CAP). Note the appearance of urethral low-frequency oscillations (LFOs) following cessation of bladder activity. B and C compare, with different time bases, HFOs and LFOs, respectively. Numeric comparisons are found in Table 2.
Fig. 3.
Fig. 3.
The temporal relationship of HFOs and LFOs to associated EUS-EMG activity. Although HFOs (left) are caused by preceding high frequency bursts of EUS activity, LFOs (right) precede and thus apparently cause bursts of EUS activity. Note the marked difference in time scale.
Fig. 4.
Fig. 4.
Different responses of bladder contractions and urethral activity to intraurethral administration of capsaicin in control rats and rats with diabetes mellitus (DM). Intraurethral capsaicin inhibited isovolumetric bladder contractions in control rats but not in DM rats. LFOs were seen only in control rats.
Fig. 5.
Fig. 5.
Responses of bladder contractions and urethral activity to intraurethral administration of dilute acetic acid (AA) in control and DM rats. AA inhibited isovolumetric bladder contractions in both controls and DM rats. LFOs were seen in both the control (left) and DM (right) rat after bladder contractions ceased.
Fig. 6.
Fig. 6.
Effect of neuromuscular blockade by α-bungarotoxin on the responses to capsaicin in control and DM rats. α-Bungarotoxin was administered iv before iu administration of capsaicin. α-Bungarotoxin blocked EUS-EMG activity but did not alter the effects of capsaicin on smooth muscle activity in either control or DM rats. Once again, capsaicin inhibited bladder contractions and resulted in subsequent LFOs in control rats (left), but not in DM rats (right).
Fig. 7.
Fig. 7.
Effect of neuromuscular blockade by α-bungarotoxin on the responses to dilute acetic acid in control and DM rats. α-Bungarotoxin was administered iv before iu administration of acetic acid. α-Bungarotoxin blocked EUS-EMG activity but did not alter the effects of acetic acid on smooth muscle activity in either control or DM rats. Once again, acetic acid inhibited bladder contractions and resulted in subsequent LFOs in both control rats (left) and DM rats (right).
Fig. 8.
Fig. 8.
Pudendal afferent signaling is essential for intraurethral capsaicin-induced inhibition of bladder contraction. Bilateral transection of the sensory branches of the pudendal nerves (PudSNx) caused loss of inhibition of bladder contractions induced by intraurethral capsaicin (30 μM) in control rats (left) and was without effect in DM (i.e., capsaicin was still unable to inhibit bladder activity; right). These data support a role for pudendal afferents in conferring the capsaicin effect of bladder activity inhibition.
Fig. 9.
Fig. 9.
Pudendal afferent signaling is essential for intraurethral acetic acid-induced inhibition of bladder contraction. After PudSNx, acetic acid did not inhibit bladder contractions in control rats (left) or DM rats (right) as it had previously in pudendal intact animals, again indicating that such inhibition was mediated via the sensory branch of the pudendal nerve.
Fig. 10.
Fig. 10.
Role of autonomic efferent innervation in the genesis of LFOs. Intravenous administration of hexamethonium (Hex) at a dose that blocks autonomic ganglionic transmission (25 mg/kg) eliminated the LFOs in a control rat following intraurethral capsaicin.
See this image and copyright information in PMC

References

    1. Alm P, Zygmunt PK, Iselin C, Larsson B, Uvelius B, Werner S, Andersson KE. Nitric oxide synthase-immunoreactive, adrenergic, cholinergic, and peptidergic nerves of the female rat urinary tract: a comparative study. J Auton Nerv Syst 56: 105–114, 1995 - PubMed
    1. Andersen JT, Bradley WE. Early detection of diabetic visceral neuropathy. An electrophysiologic study of bladder and urethral innervation. Diabetes 25: 1100–1105, 1976 - PubMed
    1. Andersson KE. Bladder activation: afferent mechanisms. Urology 59: 43–50, 2002 - PubMed
    1. Avelino A, Cruz F. TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications. Naunyn-Schmiedeberg's Arch Pharmacol 373: 287–299, 2006 - PubMed
    1. Chang HY, Cheng CL, Chen JJ, Peng CW, de Groat WC. Reflexes evoked by electrical stimulation of afferent axons in the pudendal nerve under empty and distended bladder conditions in urethane-anesthetized rats. J Neurosci Methods 150: 80–89, 2006 - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources