Effects of tramadol on rat detrusor overactivity induced by experimental cerebral infarction

OBJECTIVE: Cerebrovascular disease, such as stroke, frequently results in incontinence by reducing suprapontine micturition control. Intraluminal occlusion of the middle cerebral artery (MCA), which produces detrusor overactivity, has been introduced as a useful model of stroke-induced lower urinary tract dysfunction. Recently, the effective analgesic tramadol, was found to possess inhibitory actions on normal rat micturition. The current study aimed to examine the potential effect of tramadol on rat detrusor overactivity due to cerebral infarction. METHODS: In female Sprague-Dawley rats, cerebral ischemia was induced by occlusion of the MCA and the urinary bladder was catheterised. Three days later, continuous cystometry was performed in awake animals and the effects of tramadol given intravenously were studied. RESULTS: In cerebral infarcted rats, bladder capacity was lower (48+/-9%) and micturition pressure higher (76+/-21%) than in control rats. Tramadol 5 mg x kg(-1) given i.v., increased bladder capacity (59+/-29%) and threshold pressure (47+/-32%) to values similar to those in control rats. However, micturition pressure was not significantly altered. Tramadol induced diuresis in some, but not all, cerebral infarcted rats. CONCLUSION: Tramadol normalised detrusor overactivity in MCA-occluded rats. The drug might have a treatment potential in patients with detrusor overactivity after stroke.     

Effects of tolterodine on afferent neurotransmission in normal and resiniferatoxin treated conscious rats

PURPOSE: The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters. MATERIALS AND METHODS: The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine. RESULTS: In resiniferatoxin treated animals (0.3 mg kg-1 subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 microg kg-1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 microg kg-1 tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 microg kg-1 apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment. CONCLUSIONS: Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding.     

Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats

PURPOSE: Using baclofen (Sigma-Aldrich, Steinheim, Germany), a gamma-aminobutyrate B (GABA(B)) receptor agonist, and CGP62349 (AstraZeneca R & D M?lndal, Sweden), a GABA(B) receptor antagonist, in a rat model of conscious micturition we addressed certain questions, including whether there is a tonic GABA(B) receptor influence on normal bladder function, how baclofen affects normal and C-fiber activated micturition, and where the sites of GABA(B) receptor action are. MATERIALS AND METHODS: Nonanesthetized female Sprague-Dawley rats were used. The bladder was catheterized and other catheters were placed intravenously, intrathecally or intracerebroventricularly. At 3 days the rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Overactivity caused by C-fiber activation was induced by intravesical oxyhemoglobin. Drugs were given intravenously, intrathecally or intracerebroventricularly. Micturition parameters were recorded and compared before and after drug administration. RESULTS: Baclofen at doses of 0.5 microg. intrathecally and 0.3 microg. intracerebroventricularly increased bladder capacity and threshold pressure. Overflow incontinence developed in 4 of 7 rats after 0.5 microg. baclofen intrathecally and in 5 of 7 after 1 microg. baclofen intracerebroventricularly. CGP62349 at a dose of 30 microg. intrathecally and intracerebroventricularly had a stimulatory effect on micturition, which was attenuated by baclofen. While intravenous baclofen at 1 mg. (-1)kg. was devoid of effects, intravenous baclofen at 4 mg. kg. (-1)tended to decrease micturition pressure, bladder capacity and micturition volume. Infusion volume decreased significantly, demonstrating a diuretic effect, which was abolished by pretreatment with subcutaneous desmopressin at 25 ng. kg. (-1). CGP62349 at 2 mg. kg. (-1) intravenously had a stimulatory effect on micturition, which was inhibited by baclofen. Intravesical oxyhemoglobin at 250 microM. induced bladder overactivity, which was attenuated by baclofen at 4 mg. kg. (-1) intravenously and abolished by baclofen 0.5 microg intrathecally. CONCLUSIONS: In the normal rat stimulation of GABA(B) receptors, mainly in the central nervous system, inhibits micturition. Antagonism of GABA(B) receptors stimulates micturition, suggesting that the receptors are under tonic GABAergic influence. Baclofen intrathecally attenuated oxyhemoglobin induced detrusor overactivity, suggesting that the inhibitory actions of GABA(B) receptor agonists in the spinal cord may be useful for controlling micturition disorders caused by C-fiber activation in the urothelium and/or suburothelium.     

Urodynamic effects of a novel EP(1) receptor antagonist in normal rats and rats with bladder outlet obstruction

PURPOSE: Prostaglandin E(2) and its EP(1) receptor were suggested as endogenous modulators of bladder function in the normal physiological state and under pathophysiological conditions. We investigated if the new EP(1) receptor antagonist PF-2907617-02 would influence the regulation of normal micturition in rats, and if it affects bladder function in animals with partial bladder outlet obstruction. MATERIALS AND METHODS: The study was performed in normal female Sprague-Dawley rats and in rats with moderate, experimentally induced bladder outlet obstruction 2 weeks in duration. All animals underwent continuous cystometry in the awake state. PF-2907617-02 was given intravenously at doses of 0.1 and 1.0 mg/kg(-1) in normal rats, and at 1.0 mg/kg(-1) in bladder outlet obstructed animals. In a group of normal rats detrusor overactivity was produced by intravesical instillation of prostaglandin E(2). RESULTS: In normal rats PF-2907617-02 (1 mg/kg(-1)) significantly increased bladder capacity, micturition volume and the micturition interval but it had no effect on other urodynamic parameters. The lower dose of PF-2907617 (0.1 mg/kg(-1)) showed no effect. Intravesical prostaglandin E(2) (50 muM) induced detrusor overactivity. The antagonist significantly decreased the stimulatory effects of prostaglandin E(2) at 0.1 and 1.0 mg/kg(-1). In obstructed animals PF-2907617-02 significantly increased the micturition interval but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions. CONCLUSIONS: EP(1) receptor is involved in initiation of the micturition reflex in normal rats and in animals with bladder outlet obstruction. It may also contribute to the generation of detrusor overactivity after bladder outlet obstruction. Thus, EP(1) receptor antagonists may have potential as treatment for detrusor overactivity in humans.     

Central acute D2 stimulation worsens bladder function in patients with mild Parkinson's disease

PURPOSE: The different roles of D1 and D2 dopamine receptors in LUT behavior have been demonstrated in animal studies. In particular D2 selective agonists and D1 selective antagonists seem to produce a reduction of the bladder capacity in conscious rats. This finding has never been confirmed in human studies. Thus, in this study we investigated the role of D1 and D2 agonists/antagonists on LUT behavior in patients with PD. MATERIALS AND METHODS: A total of 87 patients with mild PD were evaluated. Patients were evaluated with urodynamic studies (cystometry followed by a pressure flow study with perineal floor electromyography) performed in off status and after oral administration of 250 mg of LD. In 70 patients a third urodynamic evaluation was conducted in one of the following conditions: after simultaneous administration of 250 mg oral LD and 60 or 120 mg oral domperidone (D2 peripheral antagonist); after simultaneous administration of 250 mg oral LD and 25, 50 or 150 mg intramuscular L-sulpiride (D2 central and peripheral antagonist). Several urodynamic parameters were evaluated and results obtained in different conditions compared. RESULTS: LD alone worsened detrusor overactivity: in particular, a reduction of first urinary sensation, involuntary detrusor contraction threshold (reflex volume) and bladder capacity was observed. L-sulpiride (central and peripheral D2 antagonist) coadministration counteracted the worsening in a dose dependent manner. Domperidone (peripheral D2 antagonist) coadministration failed to determine the same counteraction. CONCLUSIONS: According to our results, a central acute D2 stimulation seems to be responsible of a reduction of bladder capacity with worsening of detrusor overactivity in patients with mild PD.     

Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats

Apomorphine, given subcutaneously (s.c.), induces erection and bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system. In paraplegic patients, apomorphine was reported to cause bladder overactivity. This suggests that apomorphine may have a spinal site of action also for stimulation of erection. The present study was initiated to evaluate the effect of apomorphine on erectile function in spinalized rats. Apomorphine (100 microg/kg, s.c.) was given to awake, unrestrained male Sprague-Dawley rats (300 g) with or without spinal cord injury, made at the Th 8 level 2 weeks before the experiment. Intracavernous pressure changes from baseline were evaluated as time to first response to apomorphine (TFR; sec), number of phasic pressure changes in the first 30 min (PP30), duration (D; sec) of the phasic pressure changes, the amount of increase in tonic peak pressure (TPP; cmH2O), and burst peak pressure (BPP; cmH2O). Blood pressure (cmH2O) was recorded via an intra-arterial catheter. Apomorphine, 100 microg/kg, caused no significant differences in TFR (217.8 vs 271.2), PP30 (6.4 vs 6.5), D (38.9 vs 37.6.), TPP (51.0 vs 54.0) and BPP (128.9 vs 160.4) between normal (n=8) and spinalized rats (n=6). However, blood pressure decreased significantly more in spinalized than in normal animals (17.7 vs 43.3; P<0.05). The results suggest that both in normal rats, and in rats with spinal cord injury, apomorphine given s.c., can produce erection. This finding supports the use of apomorphine for treatment of erectile dysfunction in paraplegia patients. However, due consideration should be given to possible decreases in blood pressure.     

Tramadol has no effect on cortical renal blood flow--despite increased serum catecholamine levels--in anesthetized rats: implications for analgesia in renal insufficiency

Tramadol is an analgesic that inhibits norepinephrine (NE) reuptake. Although NE released from renal sympathetic nerves causes renal hypoperfusion, the effects of tramadol on renal hemodynamics have not been well characterized. We investigated the effects of tramadol on renal blood flow (RBF), mean arterial blood pressure (MAP), and heart rate (HR) by using a laser Doppler flowmeter, both in normal anesthetized rats and in rats with experimentally-induced nephritis secondary to anti-Thy 1.1 antibody administration. We also studied the effects of tramadol on serum NE levels. Tramadol increased MAP and decreased HR without changing RBF in normal rats at clinical doses. Serum NE levels increased up to 176% of control after a 2 mg/kg bolus injection of tramadol. Continuously infused, increasing doses of tramadol (0.5-4 mg.kg(-1).h(-1)) did not affect MAP, HR, or RBF. Tramadol also increased MAP and decreased HR without changing RBF in rats with experimentally induced renal insufficiency. These findings suggest that a bolus injection of tramadol does not alter RBF, although it causes a decrease in HR and an increase in MAP and serum NE in both normal rats and in rats with renal insufficiency. These results suggest that tramadol may have little effect on RBF during the postoperative period. IMPLICATIONS: A bolus and continuous injection of tramadol does not alter renal blood flow (RBF) in normal rats. A bolus injection of tramadol has little effect on RBF in rats with experimentally induced renal insufficiency. These results suggest that tramadol would be a safe analgesic for maintaining RBF during the postoperative period.     

A method for producing overactive bladder in the rat and investigation of the effects of GABAergic receptor agonists and glutamatergic receptor antagonists on the cystometrogram

PURPOSE: We induced radio frequency (RF) lesions in the neuronal pathway leading from the forebrain to the pontine micturition center (PMC) to produce a rat model of bladder overactivity. We studied the effects of gamma-aminobutyric acid agonists (diazepam and baclofen) and glutamate receptor antagonists (MK-801 maleate and GYKI52466 [1-(4-aminophenyl-D-4-methyl-7,8 methylenedioxy-5H-2,3-benzodiazepine] hydrochloride) on the cystometrogram and developed a possible explanation of the neuronal mechanisms underlying RF lesion induced bladder overactivity. MATERIALS AND METHOD: Seven-week-old male Sprague-Dawley rats were anesthetized with sodium pentobarbital and RF lesions were produced in the nuclei basalis. Five days later bladder contractions were induced by infusing fluid into the bladder and cystometrograms were measured in conscious rats. RESULTS: The micturition interval (MI) in rats subjected to RF lesioning was significantly shorter than that in sham operated control rats. Diazepam (0.1 and 1 mg/kg intraperitoneally), baclofen (1 mg/kg intravenously) and MK-801 (0.1 and 1 mg/kg intravenously) did not change or shortened MI in control rats but it prolonged MI in lesioned rats. GYKI52466 (0.5 and 1 mg/kg intravenously) weakly prolonged MI in lesioned rats. CONCLUSIONS: We consider that RF lesioning causes interruption of the inhibitory GABAergic neurons that lead from the forebrain to the PMC. This results in the activation of N-methyl-D-aspartate receptors in the PMC that are involved in the facilitation of voiding.     

Comparison of intravenous patient-controlled analgesia with tramadol versus morphine after microvascular breast reconstruction

Tramadol is a weak centrally acting analgesic and it might provide efficacious postoperative pain relief with minimal sedative effects in the use of intravenous patient-controlled analgesia (PCA). Sixty women scheduled to undergo microvascular breast reconstruction under standard general anaesthesia were enrolled in a study on the performance of patient-controlled analgesia with tramadol or morphine with special emphasis on drug- and technique-related side-effects. Seven patients were re-operated within the same day, leaving 25 patients in the tramadol group and 28 in the morphine group for comparison. When postoperative pain occurred, loading doses of either 10 mg tramadol or 1 mg morphine intravenous increments were administered in a double-blind fashion until the pain control was judged to be satisfactory by the patient. After that the patients received tramadol or morphine by a PCA apparatus (lockout 5 min, tramadol 450 microg kg-1, morphine 45 microg kg-1 bolus). In addition, all patients received 500 mg paracetamol rectally, three times a day. The potency ratio of tramadol to morphine was found to be between 8.5 : 1 (loading) and 11 : 1 (PCA). There was neither a significant difference between the groups in the overall satisfaction of the analgesic medication nor in the visual analogue and verbal rate scales for pain. Women in the tramadol group had more nausea and vomiting during the administration of loading doses (P < 0.05) and more patients in the tramadol group (7) than in the morphine group (3) (NS) wanted to discontinue the PCA therapy before the end of the study due to nausea. Sedation or blurred vision prevented the performance of the psychomotor tests in 22 and 32% of the tramadol and morphine patients, respectively. The remaining patients performed similarly in the Digit Symbol Substitution Test. In women receiving intravenous PCA for analgesia after microvascular breast reconstruction tramadol and morphine provided comparable postoperative analgesia with similar sedative effects. However, tramadol was associated with a disturbingly high incidence of nausea and vomiting.     

Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats

To clarify the role of dopamine D1 and D2 receptors in the volume-induced micturition reflex, conscious, female rats were investigated cystometrically before and after intravenous administration of SKF 38393 (a selective D1 receptor agonist), SCH 23390 (a selective D1 receptor antagonist), quinpirole (a selective D2 receptor agonist), and remoxipride (a selective D2 receptor antagonist). The effect of quinpirole was also investigated in the presence of remoxipride. Intravenous administration of SKF 38393 (0.01-3.0 mg/kg) did not affect any cystometric parameters investigated. On the other hand, SCH 23390 (0.1-1.0 mg/kg i.v.) reduced bladder capacity and micturition volumes and increased the micturition pressure in a dose-dependent manner. Quinpirole (0.01-0.1 mg/kg) given intravenously, dose-dependently decreased bladder capacity and micturition volumes. Pre-treatment with remoxipride (1.0 mg/kg i.v.) significantly attenuated the effect of quinpirole (0.1 mg/kg i.v.). Remoxipride (0.1-1.0 mg i.v.) itself did not cause any significant changes in the cystometric parameters. These results suggest that in conscious rats, D1 receptors tonically inhibit the micturition reflex and that D2 receptors are involved in facilitation of the micturition reflex. It may be speculated that detrusor hyperreflexia associated with Parkinson's disease results from activation failure of D1 receptors and that administration of D2 receptor agonists might worsen the condition.     

Peripheral relaxant activity of apomorphine and of a D1 selective receptor agonist on human corpus cavernosum strips

Apomorphine is used in the erectile dysfunction therapy and its action has been ascribed to the stimulation of central dopamine receptor. At the present stage, very little is known about the peripheral action of apomorphine on human corpus cavernosum (HCC). We have investigated the peripheral action of apomorphine and the role of dopamine receptors in HCC. We here demonstrate that both D1 and D2 receptors were expressed in the HCC, D1 receptors were two-fold more abundant than D2 and that both receptors were mainly localized on the smooth muscle cell component. Apomorphine in vitro exerted an anti-alpha1 adrenergic activity in human cavernosal strips since it prevented contraction induced by phenylephrine (PE), but not by U46619 or endothelin. Apomorphine elicited endothelium-independent and concentration-dependent relaxation of the strips contracted by PE, U46619 or endothelin. The EC50 values (microM) for apomorphine, in the presence and absence of endothelium, were 51.0+/-16 and 16.0+/-14, 120+/-19 and 150+/-18, 59.0+/-15 and 140+/-50 on PE-, U46619- or endothelin-induced contraction, respectively. Selective dopamine receptor agonist A-68930 (D1-like), but not quinpirole (D2-like), caused concentration-dependent relaxation of the cavernosal strips, which was partially prevented by endothelium removal or by treatment with an inhibitor of nitric oxide (NO) synthase. In conclusion, we show that (1) apomorphine has a peripheral relaxant direct effect as well as an antiadrenergic activity, (2) HCC possesses more D1-like (D1 and D5) than D2-like (D2, D3 and D4) receptors, (3) both D1- and D2-like receptors are mainly localized on smooth muscle cells and (4) the relaxant activity is most probably mediated by D1-like receptor partially through NO release from endothelium.     

Recent evidences in the pharmacological mechanisms of the tramadol

Tramadol [(1R, 2R) and (1S, 2S)-2-dimethyl-amino-methyl-1-(3-methoxyphenyl) -cyclohexanol hydrochloride] has been used clinically. It binds to micro-opioid receptors with lower affinity than morphine, which suggests that the antinociceptive action of tramadol may not be due to opioid receptor binding. Several lines of evidence have shown that tramadol inhibits the reuptake of monoamines, as do antidepressant drugs such as desipramine. Tramadol inhibits the reuptake of NE and serotonin. The mechanisms of action of tramadol have not been well understood. Recently, some evidences in the mechanisms of action of tramadol have been published. Tramadol inhibits the muscarinic receptor, serotonin receptor, and nicotinic acetylcholine receptor ion-channel, suggesting these receptors might be related to the mechanisms of action of tramadol. In this review, the mechanisms of action of tramadol were reviewed form these findings. Tramadol does not alter renal blood flow (RBF) in normal rats. This suggests that tramadol would be a safe analgesic maintaining RBF during the postoperative period. It would be necessary to study the effects of tramadol on orphan G-ptotein coupled receptor which is related to the pain.     

Analgesia for adenotonsillectomy in children and young adults: a comparison of tramadol, pethidine and nalbuphine

A prospective, double-blind, randomized, controlled study was undertaken to compare the perioperative analgesic and recovery characteristics of equipotent doses of tramadol, pethidine and nalbuphine (3.0 mg kg-1, 1.5 mg kg-1 and 0.3 mg kg-1 respectively) with placebo (saline 0.02 ml kg-1) given at induction of anaesthesia in 152 ASA 1 children and young adults undergoing tonsillo-adenoidectomy. Premedication (temazepam and diclofenac), induction and maintenance of anaesthesia (thiopentone, atracurium, nitrous oxide and isoflurane), with controlled ventilation, were standardized. Variables monitored were heart rate (HR) and systolic arterial pressure (SAP) during surgery, time to recovery of spontaneous respiration at the termination of anaesthesia and restlessness, time to awakening, sedation and emesis in the recovery unit. Increases in HR or SAP > 33% of baseline during surgery were treated with esmolol 2.0 mg kg-1 intravenously (i.v.) and restlessness during recovery was treated with the same opioid i.v. given with an aesthesia, or pethidine i.v. in the placebo group. With placebo, there was a high requirement for esmolol during surgery and for pethidine in the recovery ward. Tramadol did not reduce the rate of intra-operative treatment with esmolol, but reduced the tramadol requirement during recovery (P < 0.05). Pethidine and nalbuphine reduced the intra-operative esmolol requirement more significantly (P < 0.025 and P < 0.005 respectively) and the need for treatment during recovery with opioids (P < 0.005 each). The time to recovery of spontaneous respiration at the end of anaesthesia was only delayed by pethidine. Other recovery variables were similar, except that restlessness-pain scores were reduced by tramadol (P < 0.02), pethidine (P < 0.005) and nalbuphine (P < 0.005). These results suggest that pethidine 1.5 mg kg-1 and nalbuphine 0.3 mg kg-1 given with induction of anaesthesia provide better analgesia during and after tonsillo-adenoidectomy than does tramadol 3.0 mg kg-1. The delay to recovery of spontaneous respiration with pethidine suggests a greater safety profile of nalbuphine and tramadol.     

Intravesical adenosine triphosphate stimulates the micturition reflex in awake,freely moving rats

PURPOSE: Adenosine triphosphate (ATP) (Sigma Chemical Co., St. Louis, Missouri) is known to contract animal as well as human detrusor muscle and recent investigations have shown an involvement of ligand gated purinergic-1 receptors in detrusor contraction. In addition, ligand gated purinergic-3 receptors have been demonstrated on suburothelial sensory nerves (C-fibers) and may be involved in distention induced initiation of the micturition reflex. We tested the hypothesis that ATP given intravesically can stimulate afferent nerves and initiate the micturition reflex. MATERIALS AND METHODS: Continuous cystometry was performed in conscious, freely moving, normal female Sprague-Dawley rats. Cystometric parameters were evaluated before and after drug administration. RESULTS: Instilled intravesically ATP (10 mM.) induced bladder overactivity in 6 animals with a mean increase in voiding pressure plus or minus standard error of 73 +/- 9 to 107 +/- 9 cm. water (p <0.01), mean baseline pressure increase of 5.32 +/- 0.58 to 12.71 +/- 1.01 cm. water (p <0.01) and mean bladder capacity decrease of 1.13 +/- 0.25 to 0.75 +/- 021 ml. (p <0.01). Lower concentrations had no significant effect. The effects of ATP were abolished by pretreatment with the ganglion blocker hexamethonium (40 mg./kg. ), nitric oxide synthase substrate L-arginine (Sigma Chemical Co.) (200 mg./kg. ) and neurokinin-2 receptor antagonist 123 (S)-N-methyl-N 123 4-(acetylamino-4-phenyl piperidone)-2-(3,4-dichlorophenyl) butyl 125 benzamide (Molecular Probes, Leiden, The Netherlands) (4 nmol.) given intravenously, the ligand gated purinergic-3 antagonist 2'-(or 3')-O-(trinitrophyl)adenosine 5'-triphosphate (50 microM./kg.) given intravenously and the k channel opener ZD6169 given intravesically.(ATP). CONCLUSIONS: ATP given intravesically can induce bladder overactivity, probably by stimulating suburothelial C-fibers. The data suggest that several mediators and mechanisms are involved in mechano-afferent transduction in the bladder.     

Dopaminergic mechanisms controlling urethral function in rats

AIMS: To investigate the role of dopamine receptor subtypes in the control of urethral activity. METHODS: Simultaneous recordings of intravesical and urethral perfusion pressure (UPP) were performed in rats under urethane anesthesia. Changes in coordinated activity of the bladder and urethral sphincter were examined following intravenous (i.v.), intrathecal (i.t.), or intracerebroventricular (i.c.v.) administration of dopamine D1- and D2-like receptor agonists (SKF38393 and quinpirole, respectively) and antagonists (SCH23390 and remoxipride, respectively). RESULTS: Quinpirole (0.03, 0.1, and 0.3 mg/kg i.v.) dose-dependently decreased baseline urethral pressure to 45.33 +/- 5.8, 33.7 +/- 3.3 (P < 0.05, n = 6), and 27.7 +/- 3.3 cm H(2)O (P < 0.05, n = 5) from the control value (46.0 +/- 4.0 cm H(2)O), respectively. i.c.v. injection of quinpirole (1 microg) decreased baseline urethral pressure to 33.6 +/- 5.0 cm H(2)O (P < 0.05, n = 4) from the control value (51.4 +/- 4.9 cm H(2)O) in contrast to the insignificant effects of i.t. administration of the drug (3 microg). The decrement of baseline pressure induced by quinpirole (0.1 mg/kg i.v.) was suppressed by alpha-bungarotoxin (BGT), a neuromuscular blocking agent. SCH23390 (1 and 3 mg/kg, i.v.) dose-dependently decreased the frequency of high frequency oscillation (HFO) of the urethral sphincter. SKF38393 or remoxipride did not have significant effects on any parameters of bladder and urethral activity. CONCLUSIONS: These results indicate that activation of D2-like dopamine receptors at a supraspinal site can suppress activity of the striated muscle urethral sphincter. Thus, decreased urethral resistance induced by D2 dopamine receptor activation might aggravate urge incontinence symptoms often seen in patients with Parkinson's disease (PD).     

Pro-erectile effect of systemic apomorphine: existence of a spinal site of action.

PURPOSE: Apomorphine exerts pro-erectile effects by acting on neurons in the paraventricular nucleus of the hypothalamus. In spinal cord injured rats we assessed whether apomorphine also directly activates the spinal autonomic and somatic neurons controlling penile erection MATERIALS AND METHODS: Intracavernous and blood pressure was monitored in groups of 10 anesthetized rats to quantify intracavernous pressure increases elicited after intravenous apomorphine. We determined the number and duration of increases, percent of maximum intracavernous pressure/mean diastolic blood pressure using the formula, maximum intracavernous pressure/diastolic blood pressure x 100, area under the intracavernous pressure curve/diastolic blood pressure and sum of the area under the curve/diastolic blood pressure. RESULTS: Of 2, 10, 50 and 250 microg./kg. intravenous apomorphine 50 microg./kg. induced significant pro-erectile effects and was subsequently used. In spinal cord injured rats 50 microg./kg. intravenous apomorphine significantly increased median maximum intracavernous pressure/diastolic blood pressure x 100 compared with vehicle injection (56 versus 27 seconds, p <0.001), area under the curve/diastolic blood pressure (21 versus 12 seconds, p = 0.07) and the sum of area under the curve/diastolic blood pressure (132 versus 32 seconds, p = 0.01). These pro-erectile effects of apomorphine were prevented by 50 mg./kg. hexamethonium intravenously or bilateral transection of the pelvic nerves. They were not affected by 3 mg./kg. of the peripheral D1/D2 antagonist domperidone intraperitoneally. In spinal cord injured rats subcutaneous pretreatment with 0.2 mg./kg. of the D1 antagonist SCH23390 significantly enhanced apomorphine induced erections, as indicated by an area under the curve/diastolic blood pressure of 23 to 30 seconds (p = 0.003), whereas they were not changed by 25 mg./kg. of the D2 antagonist sulpiride intraperitoneally. Under the same conditions 1 mg./kg. of the central D1/D2 antagonist haloperidol intraperitoneally only reduced the number of responding rats to 5 versus 10 of 10. CONCLUSIONS: In spinal cord injured rats systemic apomorphine elicits erection by acting at the spinal cord level. This finding suggests that systemic apomorphine elicits penile erections via spinal and supraspinal targets.     

Co-administration of an α(1) -blocker improves the efficacy and safety of antimuscarinic agents in rats with detrusor overactivity

Objective: To investigate the efficacy and safety of a combination treatment with α₁‐blockers and antimuscarinics for detrusor overactivity in rats. Methods: Rats with detrusor overactivity caused by a cerebral infarction were divided into four groups that received an i.v. administration of tamsulosin (0.1–1000 µg/kg); solifenacin (0.01–0.3 mg/kg); combined low doses of tamsulosin (0.008, 0.1 µg/kg) and solifenacin (0.01 mg/kg); or solifenacin (0.1, 0.3, 1.0 mg/kg) at 1‐h intervals during the continuous administration of tamsulosin (0.01 µg/kg/h). Results: Both tamsulosin alone and solifenacin alone significantly increased bladder capacity in cerebral infarcted rats, but these effects were reduced in rats pretreated with resiniferatoxin. The combined low dose of tamsulosin and solifenacin resulted in a significant increase in bladder capacity compared to mono‐administration of 0.01 mg/kg solifenacin (68.8 vs 19.8% of control value, respectively). In the group receiving solifenacin at 1‐h intervals, solifenacin dose‐dependently decreased bladder contraction duration and a significant reduction in bladder contraction pressure (by 35.0% of control value) was found at the highest dose (1.0 mg/kg). However, no reduction in bladder contraction duration was found even at the highest dose of solifenacin when co‐administered with tamsulosin. Conclusion: α₁‐blockers and antimuscarinic agents have an additive ameliorative effect on detrusor overactivity when co‐administered at low doses. α₁‐blockers prevent the reduction in bladder contraction duration induced by a high‐dose administration of antimuscarinic agents.     

Intravesical analgesia for ambulatory urologic procedures: a histopathological study

Background and objective: Local anesthetics and morphine have been reported to be useful for painful diagnostic procedures in the bladder. Tramadol has the potential for use as an intravesical analgesic. However, intravesical use of tramadol has not been described widely. Methods: This study was approved by the Animal Ethical Committee of Akdeniz University and performed with standard guidelines for care and use of laboratory animals. In this study we tested the histopathological effects of intravesical tramadol versus saline in 20 adult rats. The control group received intravesically 1 ml saline. Tramadol 50 mg (1 ml) was administered intravesically in the other group. Two hours later, all animals were sacrificed and their bladders were excised. Tissue samples were evaluated macroscopically and microscopically. The data were analyzed with χ² and Fisher’s χ² tests. Results: In all the specimens in the control group epithelial edema was seen. This finding may be explained by insertion of intravesical catheter and tissue trauma. Haemorrhagic necrosis of epithelium was observed in four cases only in the tramadol group. This finding demonstrated severe epithelial destruction. However, there was no statistically significant difference when compared with the control group. Conclusion: The technique of topical tramadol anesthesia may be very simple, useful and safe for bladder biopsies and cautery in many cases. However, the number of cases examined in this preliminary study after bladder instillation of tramadol was small. For this reason, the results obtained in this study regarding the histopathological effects of tramadol on the bladder, should be further investigated.     

Combined treatment with a β3‐adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats

Aims

This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the β₃‐adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs).

Methods

Thirty‐two female 10‐week‐old SHRs were fed an 8% NaCl‐supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the β₃‐ARs and M₃‐MRs expressed within the urinary bladders were analyzed.

Results

Just after transfer from RT to LT, vehicle‐, solifenacin‐, and mirabegron‐treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress‐induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination‐treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M₃‐MR and β₃‐AR mRNA. The tissue distribution of M₃‐MRs was similar to that of the β₃‐ARs.

Conclusions

This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress‐induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026–1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.