Influence of sildenafil on blood oxygen saturation of the obstructed bladder

There is growing evidence that ischemia of the bladder wall contributes to the initiation of bladder dysfunction. Several studies have shown effects in obstructed bladder that can be interpreted as long term results of hypoxia [1]. Furthermore, there is an increasing interest in the nitric oxide (NO) pathway as a potential pharmacological target to treat lower urinary tract symptoms.

Phosphodiesterase 5 (PDE5) is involved in the NO pathway and it has been immunolocalized both in the detrusor muscle cells and in the vascular endothelium [2]. PDE5 inhibitors were found to improve several functional aspects of bladder dysfunction in human and animal studies [2‐10]. The mechanisms behind this have not been fully elucidated yet, but it can be assumed that PDE5 inhibitors influence detrusor muscle cell action directly but also indirectly through enhancement of tissue microcirculation of the bladder tissue [11]. In a previous study we have shown in a Guinea pig model of bladder outlet obstruction (BOO) that the oxygen saturation is significantly lower in the obstructed bladder compared to sham operated bladder, both during the voiding and filling phase [12].

During bladder filling the saturation in the normal Guinea pig bladder is around 90%. At the end of bladder filling and during voiding there is a marked decrease in saturation. Shortly after voiding the saturation returns to its high pre-voiding value.

The obstructed bladder is characterized by a significantly lower saturation both during voiding and filling. This decrease in saturation is more pronounced when detrusor overactivity occurs during the filling phase [12].

In contrast, in Guinea pigs with BOO treated with SC the bladder saturation both during filling and voiding remains as high as in the sham operated animals. This maintenance of a high saturation level is accompanied by normal bladder compliance and less overactivity. Maintaining bladder compliance and damping detrusor overactivity might be explained by direct smooth muscle cell action of the PDE5 inhibitor SC. However, the maximum voiding pressure and the contractility of SC-treated obstructed bladder increase at least as much as in the saline treated obstructed bladder. This phenomenon can not be explained by a direct muscle relaxing effect of SC alone. Possibly the maintenance of an almost normal bladder function in animals with BOO treated with SC is an effect of enhanced bladder microcirculation rather then a direct effect on muscle cells. Obstructed bladders treated with SC have a higher saturation level.. Muscle cells acting aerobically can produce force more efficiently than the same amount of muscle cells acting under anaerobic circumstances. As a consequence, the increased contractility and voiding pressure that are needed to overcome the obstruction need less muscle mass and the bladder wall increases less in size resulting in less muscle hypertrophy. This may partly explain the better compliance and the lower bladder weight that was observed in the SC treated obstructed bladder. Low saturation may excite nerve endings in the bladder wall, leading to overactivity and higher muscle tone. Maintenance of a high saturation could prevent this nerve action and may result in better bladder compliance. In support of this is our finding that SC treated obstructed bladder shows less overactivity.

Similar effects of PDE5 inhibitors on bladder function have been found with in vitro muscle strip tests in a rat model of BOO [18, 19]. The carbachol induced contractile force of bladder strips tested in vitro is reduced by BOO. Vardenafil treatment during the obstructive period diminishes this in vitro loss of carbachol induced contractility [18]. Muscle strips from sham operated rats that received vardenafil showed an increased contractility as compared to normal rat bladder strips [19]. In our experiments, we noticed a trend for increased contractility of the whole bladder in the sildenafil treated sham operated animals but this was only significant at week 8. This might be explained by a slight increase of bladder saturation during detrusor contraction. Furthermore, in the sildenafil treated sham operated animals the bladder weight was lower compared to sham + saline group. Thus, possibly the unobstructed bladder also benefits from optimal saturation.

In our experimental setup we did not determine a tissue marker for hypoxia such as glycogen or hypoxia-inducible factor 1 (HIF-1). In a previous study we demonstrated that the presence of glycogen deposits in the bladder wall correlates well with loss of bladder function in both Guinea pigs and humans [20, 21]. Furthermore, we demonstrated in another study [12] that the glycogen content of the bladder wall was increased in obstructed Guinea pigs in comparison with sham operated animals. The same study revealed a good correlation between DPS measurements and glycogen deposits in the bladder wall. Therefore, we did not expect any further relevant information from tissue markers in this experimental setup and determination of glycogen deposits were not done on a regular basis.

There is evidence that oxidative stress is a key feature in the initiation and progression of voiding dysfunction [1]. Although the data are preliminary, they correlate with a mechanism where bladder dysfunction in BOO is initiated by bladder pressure related ischemia and reperfusion injury. With the present model it is not obvious if the effect is just a matter of better flow due to vessels smooth muscle relaxation or due to preservation of microvasculature or stimulation of angiogenesis. Future experiments with DPS-measurements of blood volume per cross-sectional area and measurements of vessel diameters might answer these questions.

The mechanism of increased pressure and overactivity reducing saturation that in turn reduces bladder function by impeding aerobic muscle action and by excitation of bladder nerves poses a self enhancing loop. Direct actions on the saturation part in this loop like with the PDE5 inhibitor sildenafil citrate used here may disrupt this loop and thereby might prevent the loss of bladder function that otherwise occurs.

In a normal bladder BOS is high in the filling phase and drops slightly during voiding. In an obstructed bladder the loss of bladder function is accompanied by a significant decrease in BOS during voiding and filling. Treatment of obstructed bladders with SC maintains normal BOS during filling and voiding resulting in high bladder compliance and less DO. This supports the hypothesis that maintaining the microcirculation of the bladder wall results in better bladder performance without significant loss of bladder function. Measurement of BOS and interventions focussing on tissue microcirculation may have a place in the evaluation/treatment of various bladder dysfunctions.