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. 2000 Jul 15;526(Pt 2):397–408. doi: 10.1111/j.1469-7793.2000.t01-1-00397.x

Reduction in renal haemodynamics by exaggerated vesicovascular reflex in rats with acute urinary retention

Chiang-Ting Chien *, Hong-Jeng Yu *, Ya-Jung Cheng †, Ming-Shiou Wu ‡, Chau-Fong Chen †, Su-Ming Hsu §
PMCID: PMC2270022  PMID: 10896728

Abstract

  1. We examined the possibility that a vesicovascular reflex is exaggerated by acute urinary retention, and that the increase in renal vascular resistance caused by this reflex may lead to renal dysfunction. We evaluated the vesicovascular responses to normal micturition (NM, transcystometric condition) and acute urinary retention (isovolumetric condition mimicking complete bladder-outlet obstruction (CBOO) and partial urethral ligation mimicking partial bladder-outlet obstruction (PBOO)) in anaesthetized female Wistar rats.

  2. Acute urinary retention due to CBOO or PBOO provoked a prolonged or increased intravesical pressure, an enhancement in both bladder pelvic afferent and bladder pelvic efferent nervous activity, and an elevation in mean arterial blood pressure.

  3. Single-unit analysis showed that these vesicovascular reflexes were triggered by activation of low-threshold and high-threshold bladder mechanoreceptors, but not by renal uretropelvic mechanoreceptors.

  4. Bladder contraction in CBOO and PBOO conditions and graded increases in bladder volume significantly reduced renal blood flow and cortical microvascular blood flow. The acute urinary retention-induced renal vasoconstriction was mediated by the renal nerve. Renal denervation, but not bilateral ureteral resection, abolished the renal vasoconstriction associated with the vesicovascular reflexes.

  5. These findings indicate that exaggerated activation of bladder afferents exerts a positive feedback effect to increase sympathetic outflow to the kidney further, thereby contributing to significant renal vasoconstriction via a renal nerve-dependent mechanism.

Urine storage and elimination are the two major functions of the urinary bladder. These functions are primarily regulated by pelvic afferent and efferent nerves originating at the sacral level of the spinal cord (Bahns et al. 1987). Afferent nerves innervating the bladder body can respond to mechanical and chemical signals in the bladder (Maggi et al. 1986; Maggi & Meli, 1988; Häbler et al. 1990, 1993; Sengupta & Gebhart, 1994; Moss et al. 1997). During continence, the increased intravesical pressure (IVP) can activate low-threshold mechanosensitive receptors, and evoke sacrolumbar reflexes in lumbar sympathetic neurons to increase bladder capacity (de Groat et al. 1992; Jänig & Koltzenburg, 1992; de Groat, 1999). When these sacral bladder afferents are further activated at a micturition pressure/volume threshold, a parasympathetic-bladder efferent discharge is triggered, leading to micturition and detrusor contraction (de Groat et al. 1992; Chien et al. 2000b).

The bladder afferents also elicit sympathetically mediated vesicovascular reflexes, because increased arterial blood pressure, tachycardia, and vasoconstriction in several vascular beds are often recorded during graded bladder distension associated with bladder-outlet obstruction (BOO) (Häbler et al. 1992; Cheng et al. 1993; Michaelis et al. 1996). Clinically, partial or even complete BOO may develop as a consequence of many conditions, including benign prostatic hyperplasia, bladder neck dys-synergia, carcinoma of the prostate and urethral stricture (Steers & de Groat, 1988; Sarmina & Resnick, 1989; Harrison & Abrams, 1994). BOO may lead to bladder overdistension and increased IVP and, subsequently, to deteriorated renal function (Tammela et al. 1986; Leung et al. 1997). A hydraulic mechanism derived from fluid accumulation and increased uretropelvic pressure (UUP) is generally regarded as the major cause of renal dysfunction in such patients who develop chronic urinary retention (Bishop, 1985; Harrison & Abrams, 1994). However, we suspected that an increase in sympathetic outflow secondary to bladder overdistension also plays a significant role in increased renal vascular resistance and, consequently, renal dysfunction.

This investigation was designed to study the vesicovascular reflex and the associated changes in renal haemodynamics in rats with partial bladder-outlet obstruction (PBOO) or complete bladder-outlet obstruction (CBOO). We examined the mechanisms underlying the changes in renal function induced by bladder distension and determined whether pathological conditions such as acute urinary retention can alter vesicovascular and vesicorenal reflexes. Our results indicate that excessive stimulation of bladder afferents in the overdistended bladder significantly reduces renal haemodynamics by an exaggerated vesicovascular reflex.

METHODS

Experimental models and protocols

A list of abbreviations used in the text is shown in Table 1. For exploring bladder volume and pressure effects on the vesicovascular reflex in pathophysiological conditions, we adopted saline infusion via the bladder dome or urethra during PBOO or CBOO, raising of a fluid-filled container connected to the bladder via a pressure transducer (pressure determination), and injection of a known amount of saline into the urinary bladder (volume determination). An isovolumetric model mimicking CBOO and a transcystometric model with partial urethral ligation mimicking PBOO were employed in this study. A transcystometric condition mimicking normal micturition (NM) was used as a control. First, we measured the IVP, bladder pelvic afferent nervous activity (PANA) and bladder pelvic efferent nervous activity (PENA), as well as the vascular reflex arc of mean arterial blood pressure (BP) in rats with NM, CBOO and PBOO. Second, we confirmed the role of the bladder mechanoreceptor (MRb) or uretropelvic mechanoreceptor (MRu) in evoking the vesicovascular reflex in rats with BOO. We performed single-unit analysis of bladder pelvic afferent and renal afferent fibres in response to increases in IVP and UUP, respectively. Third, to determine whether sympathetically mediated vasoconstriction is generated by BOO, we examined the renal haemodynamics, plasma renin levels (humoral response), as well as adrenal and renal sympathetic nervous activities (neural response) in rats with BOO. It has been reported that renal sympathetic activation can increase renin release into the renal circulation, leading to increased renal vascular resistance (Nakamura & Johns, 1994). Lastly, to evaluate the role of the hydraulic mechanism or vesciovascular reflex in BOO-induced renal vasoconstriction, we examined the effect of bilateral ureteral transection or renal denervation on renal haemodynamics.

Table 1.

List of abbreviations used in the text

NM Normal micturition: transcystometric condition
BOO Bladder-outlet obstruction
CBOO Complete bladder-outlet obstruction: isovolumetric condition
PBOO Partial bladder-outlet obstruction: partial urethral ligation
IVP Intravesicle pressure
UUP Uretropelvic pressure
PANA Pelvic afferent nerve activity
PENA Pelvic efferent nerve activity
BP Blood pressure
MRb Bladder mechanoreceptor
MRbLT Low-threshold MRb
MRbHT High-threshold MRb
MRu Uretropelvic mechanoreceptor
ANA Adrenal efferent nerve activity
RNA Renal efferent nerve activity
RBF Renal blood flow
CMBF Cortical microvascular blood flow
TUF Transurethral filling
AI Angiotensin I
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Surgery

Female Wistar rats weighing 200–250 g were housed at the Experimental Animal Centre of the National Taiwan University at a constant temperature and with a consistent light cycle (light from 0700 to 1800 h). The animal care and experimental protocols were in accord with the guidelines of the National Science Council of the Republic of China (NSC 1997).

On the day of the experiment, rats were anaesthetized with subcutaneous urethane (1.2 g kg−1). Urethane was chosen because it lacks ganglionic blocking properties, and the extrinsic neural input to the bladder is therefore maintained (Santicioli et al. 1985). After induction of anaesthesia, the trachea was intubated to keep the airway patent. All animals were allowed to breathe spontaneously. PE-50 catheters were placed in both the left femoral vein, for administration of supplementary anaesthetic, and the right femoral artery, for continuous arterial BP recording with a pressure transducer (P23 1D, Gould-Statham, Quincy, USA). The maintenance of deep anaesthesia was determined by the persistence of miotic pupils as judged from frequent inspection and by the lack of heart rate and BP fluctuations in the absence of visceral stimuli (Häbler et al. 1992). Body temperature was monitored continuously and maintained in the range 36–38°C with a heat lamp. At the end of the experiments, the animals were killed under deep anaesthesia by intravenous injection of a potassium chloride saturated solution.

NM, CBOO and PBOO

Eight rats were used for establishing the NM and CBOO models. The NM experiment was performed first. The urinary bladder was exposed through a midline incision in the abdomen. A PE-50 tube was inserted through the apex of the bladder dome, 3–4 mm into its lumen. The bladder catheter was connected via a T-tube to an infusion pump (Infors AG, CH-4103, Bottmingen, Switzerland) and a pressure transducer (P23 ID), for recording of IVP. The bladder was filled several times by continuous infusion of 0.9 % saline (0.1 ml min−1) at room temperature and was allowed to drain/micturate repeatedly. The infused volume at the onset of an efficient voiding contraction was defined as the micturition threshold volume of NM.

To induce CBOO in the same rat, we inserted another PE-50 tube into the bladder through the urethra and tied it in place by a ligature around the urethral orifice. The catheter was connected to a separate pressure transducer and an infusion pump via a T-tube connector. Transurethral filling (TUF, 0.1 ml min−1) of 0.9 % saline into the urinary bladder via the urethral catheter was done until rhythmic bladder contractions occurred; the infusion was then stopped and the bladder was maintained under constant-volume conditions. The infused volume at the onset of isovolumetric contractions was defined as the threshold volume of CBOO (isovolumetric condition) (Cheng et al. 1993). Isovolumetric conditions of CBOO were determined for 30 min.

The method for PBOO by urethral ligation was described previously (Steers & de Groat, 1988). Five rats were used for induction of mild and severe PBOO. Before PBOO induction, a PE-50 tube was inserted through the apex of the bladder dome. The bladder catheter was connected via a T-tube to an infusion pump and a pressure transducer for recording of IVP. The bladder was filled several times by continuous infusion of 0.9 % saline (0.1 ml min−1) at room temperature and was allowed to drain/micturate repeatedly as in the NM condition. Subsequently, the urethra was freed from the surrounding connective tissue just cephalad to the pubic symphysis. The urethral calibre was reduced to 1 or 2 mm by tying two 4–0 nylon sutures around the urethra, including extraluminally placed 1 mm (severe PBOO) or 2 mm (mild PBOO) diameter PE tubing. The PE tubing was then removed. Saline infusion was started and mild or severe PBOO was induced.

Three to five contractions from NM, CBOO or PBOO were averaged in each rat. Precontraction pressure was defined as baseline pressure in the three models.

Recording of PANA and PENA

Multifibre PANA and PENA were measured simultaneously in eight rats with NM and CBOO and five rats with mild and severe PBOO. The procedures used for isolation of the left pelvic/bladder nerves and recording of nerve activities were described in detail previously (Chien et al. 2000b). Briefly, two left pelvic nerve branches attached to the urinary bladder surface were isolated and were simultaneously recorded by placement of the intact nerve fibres in parallel with two pairs of thin bipolar stainless steel electrodes. The bladder/pelvic nerves and the electrodes were continuously bathed in a pool of paraffin oil at 37°C to prevent drying. The electrical signals were amplified 20 000-fold, filtered (high-frequency cut-off at 3000 Hz and low-frequency cut-off at 30 Hz) with an AC preamplifier (Grass model P511, Valley View, OH, USA), and continuously displayed on a Gould oscilloscope (1604). The amplified signals were recorded on magnetic tape and fed into a window discriminator 121 (World Precision Instruments, Sarasota, FL, USA) and a Gould integrator amplifier (13-4615-70).

Nerve activity was analysed with an impulse counter designed and built in our laboratories, which was set to count the total number of nerve impulses per unit time (i.e. 1 s in this study) (Chien et al. 1997, 2000a,b). The background activity, which could be caused by the precision of the nerve dissection from surrounding tissue, nerve damage during handling, and the equipment itself, was excluded from the window discriminator by adjustment of the threshold voltage (Chien et al. 2000a). After this adjustment, a standard pulse was generated for every spike that exceeded the threshold level. The neural activity was transformed into total spike number per second.

The bladder/pelvic nerves were cut, and PANA and PENA were assessed by the following criteria. A nerve fibre with PANA was identified by its ability to show increased activity in response to small increments of IVP by saline infusion via the T-tube. A nerve fibre with PENA had minimal activity until a threshold volume/pressure in the bladder was reached which produced a bursting discharge causing a micturition contraction (Steers & de Groat, 1988; Chien et al. 2000b).

Recording of single units of MRb and MRu

We adopted the model of graded increases in IVP or UUP for measuring MRb and MRu activity, respectively (Sengupta & Gebhart, 1994; Chien et al. 1997). Through the use of this model, the IVP or UUP can be maintained at a steady state for certain periods and can be correlated with the activity of two types of receptor, high-threshold and low-threshold. The study was designed to verify the role of mechanoreceptors in the initiation of the vascular reflex.

For single-unit analysis of MRb, eight rats were used. The rats were prepared and a transurethral catheter was inserted as described above. For graded increases in IVP, the transurethral catheter was connected via a pressure transducer to a reservoir containing saline at room temperature. The bladder was distended isotonically by raising the height of the reservoir (Fig. 2A and B). For preservation of bladder afferent input to the central nervous system, only one left bladder/pelvic nerve branch originating from the urinary bladder surface was isolated and was cut close to the major pelvic ganglion.

Figure 2. Responses of arterial BP and MRb to graded increases in IVP and of MRu to graded increases in UUP.

Figure 2

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Activation of MRbHT (A) and MRbLT (B) in response to the increased IVP elicited a significant vasopressor response, whereas activation of renal MRu by increased UPP did not increase BP (C). Insets show MRb/MRu activity on an expanded time scale. D, mean changes in BP (upper panel) and MRb or MRu activity (lower panel) in response to increased IVP (□) or UUP (▪). * P < 0.05 vs. control values at 0 mmHg. This result indicates that MRb, not MRu, is primarily responsible for the vesicovascular reflex.

For single-unit analysis of MRu, six rats were used. After anaesthesia and general surgery, the rat was placed on its right side, and the left kidney was exposed and prepared as previously described (Recordati et al. 1978; Chien et al. 2000a,b). The left ureter was cannulated at the uretropelvic junction with a T-tube connector, which was connected to two saline-filled PE-50 tubes. One of the PE-50 tubes was connected to a Gould pressure transducer (P23-ID) for measurement of UUP, and the other, 60 cm in length, was left open to allow urine to flow out freely or to increase UUP by elevation of the PE-50 catheter. This set-up allowed continuous measurement of UUP and collection of urine (Recordati et al. 1978; Chien et al. 1997, 2000a). One branch of the left renal nerves at the angle between the aorta and left renal artery was carefully isolated from the surrounding tissues for recording of renal nerve activity (Chien et al. 1997).

Under a stereoscopic dissecting microscope (Olympus, SZ-STU2), the afferent nerve bundles from the left bladder/pelvic nerve or renal nerve were then repeatedly split with fine forceps until a single-unit impulse from a dissected nerve filament was apparent on the oscilloscope trace (Chien et al. 1997). The original single-unit signal was recorded on magnetic tape and fed into a window discriminator (WPI 121) and a Gould integrator amplifier (13-4615-70). Single-unit activity was analysed with an impulse counter as described above. Therefore original records and the transformed spikes were displayed simultaneously in this study.

Upon stimulation, an increase in activity of at least 100 % above basal levels was considered to be a prerequisite for verification of a specific type of receptor. If a nerve fibre did not meet this requirement, dissection of the nerve bundle was continued until a single fibre met the criterion. Nerve activity, BP and IVP were stored on a neuro-corder (DR-890, Neuro Data Inc., New York, USA) and displayed on a polygraph (RS3400, Gould Inc.). Bladder afferent fibres were identified on the basis of their extrapolated response thresholds to graded urinary bladder distension: low-threshold afferent fibres (≤ 15 mmHg) and high-threshold afferent fibres (> 25 mmHg) (Sengupta & Gebhart, 1994).

Determination of sympathetic activation in CBOO

The splanchnic sympathetic (efferent) nerves are known to play a role in the bladder distention-induced vesicovascular reflex (Mukherjee, 1957; Medda et al. 1996). In this study, we directly examined the adrenal nerve activity (ANA) and renal nerve activity (RNA) in rats with CBOO. Both nerves are branches of the splanchnic nerves. After surgery, the rat (n= 7) was placed on its right side, and the left adrenal gland and kidney were exposed via a flank incision. Under a stereoscopic dissecting microscope, the innervation from the splanchnic nerve extending towards the left adrenal gland and kidney was carefully identified, isolated from the surrounding tissues, and cut close to the organs. Central cut ends from adrenal and renal efferent fibres were prepared. The multifibre ANA and RNA, as well as BP in response to CBOO were measured.

Simultaneous measurement of single-fibre activity of MRb and multifibre RNA was also performed in five rats with CBOO. The study was designed to verify the role of MRb in evoking a sympathetic activation via RNA. Before the experiment, the urine was completely drained and a transurethral infusion of saline (0.15 ml min−1) for 5–10 min was performed. This amount of saline infusion resulted in bladder contraction in two of the five experiments, The single-fibre activity of MRb and multifibre RNA were then determined simultaneously.

Effects of NM, CBOO and PBOO on renal haemodynamics

Renal blood flow (RBF) is known to be affected during renal sympathetic activation. Renal sympathetic activation can cause vasoconstriction in the cortical area of the kidney (DiBona, 1982; DiBona & Sawin, 1982; Chien et al. 2000a). Thus, we evaluated the effects of the vesicovascular reflex on the RBF and cortical microvascular blood flow (CMBF) in rats with BOO.

For total RBF determination, rats (n= 6, each) were prepared as described for RNA measurement. An electromagnetic flowmeter probe (3 mm, model FN 701D, ClinicFlow II, Carolina Medical Electronics, King, NC, USA) was placed on the left renal artery to measure RBF using a Carolina flowmeter. The CMBF was measured with a Perimed PF3 and a PF303 probe (Stockholm, Sweden) of 1 mm diameter placed over the left kidney surface (Chien et al. 2000a). The laser-Doppler flowmeter (PeriFlux, Perimed) was calibrated such that one perfusion unit was equivalent to 10 mV. CMBF measured in this way represents the product of the velocity of moving blood cells and the concentration of moving blood cells in the volume of tissue under the probe. Thus, the velocity was measured as the magnitude of the frequency shift, whereas the intensity of the signal was proportional to the number of erythrocytes moving within the volume of tissue being illuminated. The PF3 flowmeter allowed the concentration of the moving blood cell component to be extracted from the perfusion, and the CMBF response was continuously recorded on a polygraph (Grass 79D, USA). The CMBF in the premicturition stage was set as 100 % in this study.

Approximately 30 min were allowed to elapse between the end of surgery and the start of experiments. The responses of arterial BP, IVP, RBF and CMBF to BOO were continuously recorded on a Grass model 7 polygraph.

Effect of ureteral transection and renal denervation on CBOO-induced renal vasoconstriction

We examined whether a hydraulic mechanism (ureter mediated) or a vesicovascular reflex (renal nerve mediated), or both, contribute to renal vasoconstriction in rats with CBOO. Three groups of rats were used: group 1 rats (n= 6) underwent sham operation, group 2 rats (n= 6) underwent bilateral transection of the ureters, and group 3 rats (n= 5) underwent bilateral renal denervation. In group 2 rats, the right and left ureters were isolated and cut during surgery. In group 3 rats, renal denervation was performed through a midline abdominal incision, by stripping of the nervous and connective tissue passing to and along the course of the renal artery and vein of both kidneys, and painting these vessels with a solution of 10 % phenol in ethanol (Chien et al. 1995). BP, IVP, RBF and CMBF were measured.

Response of plasma renin activity to CBOO

Renal sympathetic activation is known to increase renin secretion (DiBona, 1982). We examined the response of plasma renin activity in rats with CBOO. The study was intended to examine whether the renin-angiotensin system plays a role in vesicovascular reflex-associated BOO. Renal venous blood was withdrawn from PE-50 tubing inserted into the renal vein for analysis of plasma renin activity. One millilitre of blood was withdrawn at the resting stage and at the bladder contraction stage. One millilitre of blood from a donor rat was injected into the tested rat to compensate for the blood loss. The blood from the resting and contraction courses was sampled twice. Plasma was separated from whole blood by centrifugation immediately after sampling. The plasma renin activity was determined with a radioimmunoassay kit (Gamma Coat, Baxter, Deerfield, IL, USA).

Effects of increased bladder volume on renal haemodynamics

An experimental model with graded increases in bladder volume has been used previously for testing the effect of increased IVP on the vesicovascular reflex (Iggo, 1955; Mukherjee, 1957; Weaver, 1985; Medda et al. 1996). We performed a similar study, and the results were compared with those obtained from the current models of BOO. The study was performed using graded increases of bladder volume by transurethral injection of saline (from 0 to 1 ml) into the urinary bladder. The responses of arterial BP, IVP, RBF and CMBF to graded increases in bladder volume were recorded.

Data acquisition and statistical analysis

All nervous activity was expressed as total number of spikes per second. For comparison of the integrated responses of multifibre PANA and PENA during each contraction between the NM and CBOO conditions of the same rat, total spike number per each micturition cycle, which was defined as extending from the end of the previous micturition contraction to the end of the next micturition contraction, was counted and expressed as PANA per micturition cycle or PENA per micturition cycle (Chien et al. 2000b). All data are presented as means ± standard error of the mean (s.e.m.). Data were subjected to analysis of variance, followed by Duncan's multiple-range test for assessment of the differences among groups. Student's paired t test was used for detecting differences between the transcystometric (NM) and isovolumetric (CBOO) contractions (Table 2). P < 0.05 was considered to indicate statistical significance.

Table 2.

Effects of bladder contractions in NM and CBOO on urodynamics, haemodynamics and neural activity in the same rat

NM(n= 8) CBOO(n= 8)
Amplitude of bladder contractions (mmHg) 34 ± 4 36 ± 4
Duration of bladder contractions(s) 28 ± 3 65 ± 13*
Volume threshold(ml) 0.52 ± 0.10 0.57 ± 0.11
Basal mean arterial pressure (between bladder contractions)(mmHg) 105 ± 5 104 ± 5
Peak mean arterial pressure (during bladder contraction)(mmHg) 112 ± 3 134 ± 7*
Change in mean arterial pressure (during bladder contraction)(mmHg) 7 ± 2 30 ± 3*
Heart rate (between bladder contractions)(beats min−1) 353 ± 20 349 ± 18
Heart rate (during bladder contraction)(beats min−1) 370 ± 22 394 ± 24*
Change in heart rate (during bladder contraction)(beats min−1) 17 ± 4 46 ± 8*
Change in pelvic afferent nerve activity during a micturition cycle(%) 100 ± 0 256 ± 54*
Change in pelvic efferent nerve activity during a micturition cycle(%) 100 ± 0 320 ± 45*
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Values are means ± S.E.M.

*

P < 0·05 when compared to NM.

NM, transcystometric condition; CBOO, isovolumetric condition.

RESULTS

BOO results in an enhanced vesicovascular reflex

The arterial BP, IVP, and PANA and PENA in rats with NM, CBOO and PBOO were recorded simultaneously (Fig. 1). In NM (n= 8), the baseline IVP was around 0 mmHg in the emptying stage and gradually increased upon accumulation of saline in the urinary bladder, causing activation of PANA. When a threshold volume (0.52 ± 0.10 ml) was reached, the PANA reached its peak, and then a bursting PENA was detected. During NM, BP was transiently (for about 15–35 s) elevated in accordance with the abrupt rise in IVP by bladder contraction (Fig. 1A and Table 2). This indicated that an intact vesicovascular reflex arc was present in our experimental model.

Figure 1. Simultaneous recordings of arterial BP, IVP, PANA and PENA during three types of bladder distension.

Figure 1

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A, during NM, BP was transiently elevated in accordance with the abrupt elevation of PENA and IVP by bladder contraction. B, in CBOO, a prolonged isovolumetric contraction was detected. BP was significantly increased in accordance with the rising IVP during bladder contraction. C, an increased frequency of contraction was evident in PBOO. The increased BP was in accordance with the elevated PANA, PENA and IVP.

In CBOO conditions, because of fluid accumulation in the urinary bladder, the baseline IVP hovered around 15 ± 3 mmHg prior to contractions (Fig. 1B). The rats showed a prolonged isovolumetric contraction (65 ± 13 s) as compared with that in NM (28 ± 3 s). Near 3-fold increases in PANA per micturition cycle (256 ± 54 %) and in PENA per micturition cycle (320 ± 45 %) were noted as compared with those in NM conditions (set as 100 %). During CBOO, BP (134 ± 7 mmHg) and heart rate (394 ± 24 beats min−1) were significantly increased in accordance with the rising IVP during bladder contraction (Fig. 1B and Table 2); the mean BP and heart rate in NM contraction were 112 ± 3 mmHg and 370 ± 22 beats min−1, respectively.

Before PBOO induction, the rats had similar responses of baseline IVP, PANA, PENA and BP to those found in NM (Fig. 1C). When mild (Fig. 1C, left panel) or severe PBOO (Fig. 1C, right panel) was induced, the baseline IVP began to rise (from 33 ± 4 to 51 ± 6 mmHg in mild PBOO and from 32 ± 3 to 74 ± 11 mmHg in severe PBOO), as the residual volume in the bladder increased (from 0.21 ± 0.05 to 0.57 ± 0.08 ml in mild PBOO and from 0.19 ± 0.03 to 0.84 ± 0.13 ml in severe PBOO, P < 0.05). The increase in the frequency of contraction was evident in both types of PBOO, (from 0.65 ± 0.07 to 1.1 ± 0.10 contractions min−1 in mild PBOO and from 0.69 ± 0.06 to 1.3 ± 0.09 contractions min−1 in severe PBOO, P < 0.05). Furthermore, increases in PANA per micturition cycle (from 100 ± 0 to 250 ± 35 % in mild PBOO and from 100 ± 0 to 310 ± 40 % in severe PBOO, P < 0.05) and in PENA per micturition cycle (from 100 ± 0 to 285 ± 38 % in mild PBOO and from 100 ± 0 to 320 ± 45 % in severe PBOO, P < 0.05) were noted as compared with those in NM conditions. The concomitant increase in BP (19 ± 3 mmHg in mild PBOO and 36 ± 5 mmHg in severe PBOO) was in accordance with the elevated PANA/PENA and IVP in mild and severe PBOO. After relief from PBOO, the IVP, PANA, PENA and BP immediately returned to levels similar to those in the NM condition.

Enhanced vesicovascular reflex is evoked by MRb but not MRu

We measured the MRb and MRu activity in rats with graded increases in IVP and UPP, respectively. The resting activity of the bladder afferent fibres was recorded when the bladder was empty. Of the 12 single MRb fibres identified in our study, seven were low-threshold MRb (MRbLT) and five were high-threshold MRb (MRbHT). All had resting activity (1.4 ± 0.3 spikes s−1). Graded increases in IVP (from 0 to 40 mmHg) were accompanied by activation in both MRbLT and MRbHT (Fig. 2A and B). Seven single MRu in seven rats were studied; all had spontaneous activity (1.2 ± 0.2 spikes s−1). Graded increases in UUP by elevation of pressure via the uretropelvic catheter to 20 mmHg were accompanied by persistent augmentation in MRu activity (Fig. 2C).

The enhanced MRb (either MRbHT or MRbLT) activity, but not the increased MRu activity, was accompanied by an elevation of BP (Fig. 2D). The BP remained the same or appeared to be slightly decreased by stimulation of MRu (Fig. 2D). These results suggest that the activation of MRb units plays a more significant role than activation of MRu in triggering a vesicovascular reflex.

BOO enhances both adrenal and renal sympathetic activities

As shown in Fig. 3A, the increased IVP (36 ± 3 mmHg) during a bladder contraction consistently enhanced splanchnic ANA (from 100 ± 0 to 195 ± 26 %, P < 0.05) and RNA (from 100 ± 0 to 220 ± 34 %, P < 0.05) in seven rats with CBOO. An increase in IVP to 32 ± 2 mmHg resulted in the activation of MRbHT (from 1.5 ± 0.4 to 5.6 ± 1.1 spikes s−1, P < 0.05), enhanced RNA (from 100 ± 0 to 165 ± 20 %, P < 0.05) and elevated BP (from 112 ± 4 to 145 ± 8 mmHg, P < 0.05) (Fig. 3B). Further elevation of IVP to 45 ± 3 mmHg led to a more significant activation of MRbHT (from 1.5 ± 0.4 to 13 ± 2.2 spikes s−1), and increased RNA (from 100 ± 0 to 245 ± 29 %) and BP (from 112 ± 4 to 163 ± 14 mmHg). Drainage of urine from the urethral catheter abruptly decreased IVP, reduced MRbHT, and consequently led to recovery of RNA and BP to normal levels.

Figure 3. Simultaneous recordings of BP, IVP, RNA, ANA and MRb in rats with CBOO.

Figure 3

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A, an abrupt increase in IVP elicited concurrent activation of RNA and ANA and a vasopressor response. Insets show RNA and ANA on an expanded time scale. B, the vasopressor response starts at an IVP much lower than 35 mmHg. Note the concomitant appearance of MRb activity and RNA activation.

Renal sympathetic activation reduces renal circulation

The effects of NM, PBOO and CBOO on renal haemodynamics (i.e. CMBF and RBF) are demonstrated in Fig. 4. The rising IVP (up to 35 mmHg) by bladder contraction in NM did not significantly influence RBF and CMBF or BP (Fig. 4A, left panel). However, the abruptly increased IVP in rats with PBOO was accompanied by an elevation of BP (by up to 51 ± 7 mmHg) and a reduction of RBF (from 5.0 ± 0.8 to 1.1 ± 0.8 ml min−1, P < 0.05) and CMBF (from 100 ± 0 to 14 ± 12 %, P < 0.05) (Fig. 4A, right panel).

Figure 4. Responses of arterial BP, IVP, CMBF and RBF to NM, PBOO and CBOO.

Figure 4

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A, transcystometric contraction in NM did not influence renal haemodynamics. However, the abrupt increase in IVP was in accordance with a transient increase in BP and decrease in CMBF and RBF in rats with PBOO. B, similarly, isovolumetric contraction in CBOO produced a vasopressor response of BP and a reduction in CMBF and RBF. The degree of vesicovascular response seems to correlate with the magnitude of bladder contraction.

As Fig. 4B shows, the rise in IVP in CBOO (from 14 ± 3 to 34 ± 4 mmHg, P < 0.05) was also accompanied by an elevation of BP (by 25 ± 4 mmHg, P < 0.05) and a reduction in RBF (from 5.4 ± 1.1 to 2.9 ± 0.4 ml min−1, P < 0.05) and CMBF (from 100 ± 0 to 51 ± 10 %, P < 0.05).

Renal denervation, but not ureteral resection, abolishes BOO-induced renal vasoconstriction

As shown in Fig. 5, in group 1 rats with CBOO (n= 6), the baseline IVP was around 14 ± 2 mmHg. When bladder contraction occurred, the IVP was elevated to 32 ± 2 mmHg and the BP was increased by 26 ± 4 mmHg. At the same time, a reduction in RBF (from 5.4 ± 1.4 to 3.2 ± 0.8 ml min−1, P < 0.05) and CMBF (by -43 ± 7 %, P < 0.05) was detected.

Figure 5. Influence of bilateral ureteral transection and renal denervation on vesicovascular reflex in rats with CBOO.

Figure 5

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IVP, BP and plasma renin activity (Renin) were measured before contraction (regarded as baseline, BL; □) and during bladder contraction (BC; ▪). Increased IVP, BP and plasma renin activity, and reduced RBF/CMBF were noted during bladder contraction. This vesicovascular reflex was not evident in rats with renal denervation (RX), but was well preserved in rats with ureteral transection (UX). Note the lack of differences in RBF, CBMF and plasma renin activity between baseline and bladder contraction in rats with renal denervation. The effect of bladder contraction on the elevation of BP was minimized by renal denervation. * BC vs. BL, P < 0.05. † Values in RX group compared to CBOO alone group, or to CBOO with UX group, P < 0.05.

In group 2 rats with CBOO (n= 6), bilateral section of the ureters did not abolish the vesicovascular reflex of hypertension, and reduction in RBF and CMBF (Fig. 5). In group 3 rats with CBOO (n= 5), bilateral renal denervation partly diminished the hypertensive response (increased by only 13 ± 3 mmHg) and completely abolished the renal vasoconstrictive response (Fig. 5).

Renal denervation inhibits the increase of plasma renin activity by CBOO

We measured the plasma renin activity (i.e. amount of angiotensin I, AI) in rats with CBOO. The activity was also measured in CBOO rats that had undergone bilateral ureteral transection or bilateral renal denervation. The plasma renin activity was significantly elevated during bladder contraction in rats with CBOO (7.5 ± 1.6 ng AI ml−1 h−1), and in CBOO rats with bilateral ureteral transection (8.4 ± 2.0 ng AI ml−1 h−1, P < 0.05). However, an increase in plasma renin activity was not evident in the CBOO rats with renal denervation (5.5 ± 1.2 ng AI ml−1 h−1, P > 0.05) (Fig. 5). The baseline value of plasma renin activity in rats before the experiment was 4.9 ± 1.1 ng AI ml−1 h−1.

Graded increases in bladder volume reduce renal haemodynamics

Graded increases in bladder volume (from 0 to 0.25, 0.5, 0.75 and 1.0 ml) by urethral injection of saline were accompanied by graded increases in baseline IVP (from 0 to 5 ± 1, 11 ± 2, 15 ± 3 and 17 ± 4 mmHg) and BP (from 0 ± 0 to 2 ± 1, 11 ± 2, 18 ± 4 and 24 ± 4 mmHg) as well as graded reductions in RBF (from 5.6 ± 1.2 to 5.5 ± 1.3, 3.5 ± 0.8, 3.1 ± 0.7 and 3.0 ± 0.5 ml min−1) and CMBF (from 100 ± 0 to 96 ± 5, 81 ± 9, 58 ± 17 and 49 ± 16 %) (Fig. 6).

Figure 6. Responses of arterial BP, IVP, CMBF and RBF to graded increases in bladder volume.

Figure 6

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Graded increases in bladder volume by injection of saline (from 0.25 to 1.0 ml) into the bladder provoked a stepwise elevation of IVP and BP, and reductions in CMBF and RBF. The rapid initial fall in RBF (not seen in CMBF) can probably be attributed to a movement artifact. Note also that the static increase in baseline IVP was accompanied by an increase in BP and a decrease in CMBF. The degree of vesicovascular response seems to correlate with the magnitude of bladder contraction.

DISCUSSION

In this investigation, the vesicovascular reflex in rats with three types of micturition conditions, NM, CBOO and PBOO, was evaluated. BOO produced an increased bladder volume, elevated baseline IVP, triggered frequent and prolonged contractions and, consequently, generated an exacerbated vesicovascular reflex. The reflex was evidenced by renal vasoconstriction and transiently or persistently elevated BP. The degree of vesicovascular response seemed to correlate with the magnitude of bladder contraction. Furthermore, we demonstrated nearly concomitant activity for PANA/MRb (afferent), PENA (micturition contraction/efferent) and RNA (efferent/sympathetic), and elevation in BP and in plasma levels of renin activity, as well as decreased renal haemodynamics. The bladder afferent activity occurred immediately before parasympathetic or sympathetic efferent activity and the rise in BP. It was noteworthy that the stepwise increases in bladder volume/pressure were accompanied by proportional increases in BP.

Graded or abrupt bladder distension is known to cause a pressor effect (Mukherjee, 1957; Taylor, 1968; Weaver, 1985) and to increase or inhibit sympathetic nervous discharges to different vascular regions in experimental animals (Floyd et al. 1982; Weaver, 1985; Häbler et al. 1992). In cats, for example, graded stimulation of the visceral afferents from the urinary bladder leads to activation of muscle vasoconstrictor neurons supplying skeletal muscle and depression of cutaneous vasoconstrictor neurons supplying hairy skin and a graded increase of the arterial BP (Häbler et al. 1992). Blocking bladder innervation by instillation of procaine before distension, perhaps through desensitization of tension receptors (Iggo, 1955), abolishes the sympathetic and vascular responses (Weaver, 1985). By measurement of single-unit activity, we clearly demonstrated that the exaggerated vasopressor response evoked by acute urinary retention could be ascribed to the excessive activation of both MRbLT and MRbHT receptors. MRbLT activity can be detected in bladders with increased residual volume and with an IVP ≤ 15 mmHg. MRbHT activity was not evident, however, until the IVP was > 25 mmHg. It has been suggested that pelvic nerve fibres with MRbLT that are involved in the physiological regulation of the bladder are myelinated (Aδ-fibre) (Floyd et al. 1982; Bahns et al. 1986, 1987; Häbler et al. 1990; Jänig & Koltzenburg, 1992; Sengupta & Gebhart, 1994), whereas pelvic nerve fibres with MRbHT which are irritated during acute urinary retention, cystitis and inflammatory processes are primarily unmyelinated (C-fibre) (Jänig & Morrison, 1986; Häbler et al. 1990, 1993; Jänig & Koltzenburg, 1992; McMahon & Koltzenburg, 1993) or both myelinated and unmyelinated (C-fibre) (Sengupta & Gebhart, 1994). Pretreatment with capsaicin to desensitize unmyelinated fibres reduced the BOO-induced vesicovascular response by 80 % (Cheng et al. 1993). Our study confirmed that activation of these MRb could decrease renal haemodynamics via a bladder nerve (visceral afferent)-renal nerve (sympathetic efferent)-mediated reflex.

The intact bladder afferent-efferent/sympathetic vesicovascular response is integrated at both the spinal and supraspinal levels (Giuliani et al. 1988; Maggi & Meli, 1988; Cheng et al. 1993) and contributes to splanchnic (Mukherjee, 1957), adrenal (Medda et al. 1996; our present study), external carotid, splenic and renal sympathetic activation (Weaver, 1985; our present study). The enhanced renal sympathetic activity can function in the overall regulation of the kidneys by influencing renal haemodynamics, releasing renin from juxtaglomerular cells (Zanchetti & Stella, 1986), as shown in this study, and by increasing tubular reabsorption of water and sodium (DiBona & Sawin, 1982; DiBona, 1982; Wang & Chen, 1989). These vesicovascular responses leading to decreased RBF and CMBF in the kidney can be abolished by renal denervation, but not by ureteral transection, demonstrating that renal nerves play a potential role in reducing renal haemodynamics during early BOO stages. Alternatively, the increased renal venous plasma renin activity observed during increased RNA and decreased RBF may be due to the decreased RBF per se and not due to an actual increase in the release of renin. The abolition of the increase in renal venous plasma renin activity by renal nerve denervation does not prove that increased renal venous plasma renin activity was mediated by an increase in RNA since renal denervation also abolished the reduction in RBF. In addition, the increased renal venous plasma renin activity may reflect an activation of the macula densa mechanisms in response to the reduced RBF.

Regarding the role of MRb or MRu in triggering a vesicovascular reflex, further activation of MRu by increased UUP to 40 mmHg (a large and non-physiological stimulation) has been reported to elicit inhibitory renorenal reflexes (Stella & Zanchetti, 1991), including a decrease in BP and in contralateral RNA (Kopp et al. 1984; Chien et al. 2000a), which is contrary to our results. We suggest that due to quantitative aspects, not a qualitative difference between MRb and MRu, many more MRb units are activated than MRu units during the acute BOO state. Thus, the increased MRu activity, if present, may play a minor role in the BOO-induced (retrograde) vesicovascular reflex.

In summary, we have demonstrated that bladder distension induced by physiological saline infusion elicits concurrent micturition and vesicovascular reflexes in urethane-anaesthetized rats. An exaggerated vesicopressor reflex is triggered by mechanosensitive bladder afferents during BOO, and results in significant renal vasoconstriction. This vasoconstriction appears to be related to the activation of renal sympathetic nerves. Our results also suggest that the amplified vesicovascular reflex induced by acute urinary retention is mediated by the renal nerves, or at least is dependent on their integrity.

This study has clinical implications. Clinically, in patients with spinal cord injury or benign prostate hypertrophy, and even in healthy subjects when an urge to urinate is felt, isovolumetric contraction of the urinary bladder may increase the BP by exaggerating the sympathetically mediated vesicovascular reflex. This may lead to cardiovascular derangement and might be responsible for nocturnal micturition syncope in some patients.

Acknowledgments

We are very grateful to Professor William C. de Groat for careful reading of the manuscript and for correcting the English. This research was supported by grants from the NSC 88–2314-B-002-363, 89–2314-B-002-148, 89–2320-B-002-123, NHRI-GI-EX89S704L, National Taiwan University Hospital Research Grant (NTUH 89S2003, 88A006 and 89A014), and the Mrs Hsiu-Chin Lee Kidney Research Fund.

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