Overactive bladder (OAB) is a highly prevalent disease that increases with age [¹]. Its impact on the quality of life is similar to that of hypertension and diabetes and is more serious than that of depression [²]. For these reasons, OAB has an important position in the international drug industry. Although OAB patients show many variable symptoms, the central symptom of OAB is urgency [³,⁴], which is closely related to detrusor overactivity (DO) during the filling phase in cystometry [^5-7]. It was reported that 83% of patients with DO showed urgency, and 64% of patient with urgency showed DO [⁷]. Thus, it is important to observe DO objectively in clinical and research studies of OAB. Recently, we investigated nonvoiding contractions in awake animal models by simultaneous registrations of intravesical pressure (IVP) and intraabdominal pressure (IAP) [⁸].

Anticholinergic therapy is the first-line treatment option for patients with OAB, owing to the parasympathetic activation of the detrusor contractions [⁵]. Anticholinergic drugs suppress the involuntary detrusor contractions through competition with acetylcholine for the muscarinic receptors during both the storage and the voiding phase [³,⁹,¹⁰]. However, it is known experimentally that these drugs have no effects on voiding contraction and residual volume, because the amount of acetylcholine released during the voiding phase is much more than those of anticholinergic drugs [¹⁰]. However, in clinical studies, some patients complained of straining voiding, increased residual volume, and sometimes acute urinary retention. This suggests that anticholinergics may have an influence on detrusor contractions during the voiding phase [¹¹]. Up to now, there has been no experimental evaluation of the effect of anticholinergics during the voiding phase in awake rats by simultaneous registrations of IVP and IAP.

The objective of this study was therefore to perform simultaneous registrations of IVP and IAP to evaluate the effects of propiverine 1 and 3 mg/kg on DO during the filling phase and on abdominal straining during the voiding phase in awake rats with intravesical prostaglandin E₂(PGE₂) instillation.

OAB is known to include various different pathophysiologic mechanisms [¹³,¹⁴]. Recently, among those mechanisms, special attention has been given to the sensory and afferent mechanisms [¹⁰,¹⁴]. Research on the new generation of OAB drugs is focused on the inhibition of afferent firing before the generation of a detrusor contraction during the filling phase, whereas the present anticholinergic drugs suppress the afferent firing after the generation of DO [¹⁴].

The intravesical PGE₂ instillation method, one of the OAB models, induces DO by the indirect activation of afferent nerves in the bladder as well as the direct activation of detrusor muscle. Prostanoids are endogenous signaling molecules that are distributed in both human and rat bladder. When the bladder is injured or stimulated, the prostanoids activate capsaicin-sensitive afferents. Then, tachykinins are released from the afferents, which lower the threshold for afferent firing, and, finally, stimulate the detrusor to induce overactivity [^15-17]. Experimentally, the tachykinins initiate a micturition reflex by stimulating NK1,NK2 receptors, and intravesical prostanoids can induce DO in cystometry in vivo [¹⁴,¹⁶,¹⁷]. In our study, the cystometric features of OAB patients were successfully generated by intravesical prostanoids in rats, which showed increased BP, TP, and MP and decreased BC, MV, and MI.

The detrusor contraction is mainly caused by stimulating muscarinic receptors, and the M3 subtype in particular is believed to have the most major action for detrusor contraction [⁹,¹⁸]. In general, anticholinergic drugs inhibit involuntary detrusor contraction during the storage phase, but they do not significantly affect contractions during the voiding phase, because the quantity of acetylcholine is several dozen times higher than that during the storage phase [¹⁰]. In the present study, propiverine significantly decreased BP only, the basal tension of the bladder, in the intravesical PGE₂ group and showed no effect on MP, BC, VV, or MI. This might be partly related to the accumulation of continuously infused intravesical prostanoids in this rat model. However, we know that there were some effects of the propiverine, because this group showed no differences in pressure or volume parameters compared with the control group, unlike the intravesical PGE₂ only instillation group.

If we look at the effects by different concentrations of propiverine on the PGE₂-instilled state of rat bladder, propiverine 3 mg/kg decreased BP by DP but not by IVP, whereas propiverine 1 mg/kg showed no decrease in BP by either IVP or DP. This suggests that the higher dose of propiverine decreased the basal tension of the detrusor. This is not in accordance with previously reported studies, in which the investigators did not observe any difference in BP, but only in MP. We suspect that the reason for this is the difference in animal models. Our study is the first observation of propiverine effects in the animal model of prostanoid-induced OAB [⁵,¹¹]. The volume parameters were significantly decreased after PGE₂ instillation and increased to the levels of control rats after propiverine injection. This suggests that propiverine inhibits the effects of PGE₂, regardless of concentrations of propiverine. Also, DO was not seen in control rats, but was shown in PGE₂-instilled animals. The propiverine showed no effects on the frequency or pressure of DO, which is in contrast with the conventional concept for anticholinergic drugs. We conclude that the propiverine did not have any effect on the DO in animal models of prostanoid-induced OAB. This is supported by the fact that some anticholinergic drugs for OAB show no effects in some patients [⁵,¹⁸,¹⁹].

The side effects of anticholinergic drugs are well known and described through clinical and basic research. However, straining voiding, which is a complaint from some people taking anticholinergic medication, has not been well investigated in previous reports [¹⁹,²⁰]. This symptom is a straining of the abdomen to void because of feeling difficulty in voiding or a sense of residual urine and could be related to urinary retention [²¹]. In the present study, we checked the grade of straining during the voiding phase by using our models. There were no differences in abdominal straining on MP between the control rats and the PGE₂-induced OAB model. Straining was not increased after infusion of propiverine 1 mg/kg but was significantly increased after infusion of propiverine 3 mg/kg. This suggests that in the OAB model, taking a higher dose of anticholinergic drugs showed more straining during voiding. This finding may be associated with acute urinary retention and dysuria, which are among the complications of anticholinergic drugs. According to the study by Elisa et al, which was based on patient information collected by general practitioners in the United Kingdom [²¹], increased risk of voiding difficulty and acute urinary retention were observed in patients administered anticholinergic drugs, and these patients should be closely monitored during the first 30 days of treatment for signs or symptoms of urinary retention. Therefore, the presence and significance of these symptoms need to be taken into consideration when elucidating the side effects of anticholinergic drugs in future research.

Propiverine improved pressure and volume-related parameters in an OAB model induced by intravesical PGE₂, showing that propiverine can inhibit the activation of bladder contractions and possibly providing experimental evidence for decreased urgency symptoms after administration of propiverine in patients. Furthermore, propiverine also decreased the DO frequency. However, a higher concentration of propiverine induced straining voiding, suggesting the need for clinical studies of the side effects of anticholinergic drugs, which are still unknown.

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (KRF-2008-521-E00085).