Resiniferatoxin (RTX) has been used to treat interstitial cystitis/bladder pain syndrome (IC/PBS) by desensitizing sensory nerves via the TRPV1 receptors found on nociceptive c-fibres. RTX is usually dissolved in 10% ethanol (v/v) and is delivered intravesically. The aim of this study was to investigate the effects of luminal RTX and its vehicle ethanol, on whole bladder function.

Female C57/BL6J ARC mice (10-12 weeks) were treated intravesically with RTX (50nM), 10% ethanol (Ethanol control) or 0.9% saline (Saline control) for 30 minutes. Twenty-four hours later mice were euthanased and bladders isolated and suspended in gassed Krebs-bicarbonate solution at 37C.  The urethrae were cannulated to allow distension with infused saline and intravescical pressure recording.  Pressure responses to carbachol (muscarinic agonist), isoprenaline (β-adrenoceptor agonist) and electrical field stimulation (EFS) using a range of frequencies applied for 5s every 100s (50V, 0.2ms pulse duration).  Also luminal contents were collected for analysis of ATP and ACh.

Following intravesical treatment, luminal ATP levels increased significantly from 0.45 ± 0.23nM (n=6) at full distension in controls to 5.96±1.39nM in ethanol (p<0.05, n=6) and 8.43 ±1.91nM (p<0.01,n=6) in RTX treated mice (Fig 1A). However, intravesical ethanol or RTX did not significantly affect luminal ACh (Fig 1B).   Efferent nerve evoked contractile responses were significantly enhanced  at all frequencies (Fig 1C) (Response at 20Hz: Control 10.7 ± 2.08 mmHg; Ethanol 24.3 ± 2.76mmHg,p<0.01; RTX 29.0 ± 3.6mmHg, p<0.01, n=6). Similarly, a significant increase in the maximal response to carbachol occurred in both ethanol (46.1 ± 2.49 mmHg, p<0.05, n=6) and RTX treated bladders (46.5 ± 4.99 mmHg, p<0.01, n=6) when compared to control (27.7 ± 2.49 mmHg, n=6) (Fig 1D). No significant alteration to the relaxation response by isoprenaline was observed.

Treatment with RTX causes a number of changes in detrusor and urothelial function including enhanced urothelial ATP release, nerve evoked contractile responses and pressure responses to muscarinic stimulation. Almost identical changes were observed with ethanol alone, the vehicle for RTX.

Intravesical treatment with RTX causes a number of changes in detrusor and urothelial function that may possibly contribute to its clinical effectiveness.  However these effects appear to be produced by the vehicle (ethanol) used for this agent rather than by direct effects of RTX itself.  Thus the vehicle (10% ethanol) for RTX delivery may contribute to its clinical effects on the bladder following intravesical treatment.