Effects of isoproterenol and butylscopolamine on the friction between an artificial stone and the intraureteral wall in anesthetized rabbits

PURPOSE: We evaluated the effects of the nonselective beta-adrenoceptor agonist isoproterenol and the nonselective muscarinic antagonist butylscopolamine on ureteral wall tension, namely friction between an artificial stone and the intraureteral wall, in anesthetized rabbits. MATERIALS AND METHODS: The relaxing effect of the drugs on the KCl induced tonic contraction was examined in isolated rabbit ureters. The effect of the drugs on the applied force needed for the artificial stone to pass at a constant speed through the ureter, called sliding force, was evaluated in anesthetized rabbits. RESULTS: In a concentration dependent manner isoproterenol but not butylscopolamine reduced the KCl induced contraction in isolated ureter (mean pD2 7.35 +/- 0.06). Intravenous administration of 1 and 10 microg./kg. isoproterenol significantly decreased the friction between the artificial stone and intraureteral wall in anesthetized rabbits with sliding force at 15 minutes after drug administration decreased by 54.5% and 63.6%, respectively. In contrast, 100 and 1,000 microg./kg. butylscopolamine intravenously had no evident effect on ureteral wall tension. CONCLUSIONS: Our results strongly suggest that ureteral smooth muscle relaxation by beta-adrenergic stimulation reduces ureteral wall tension, thereby, diminishing mechanical effects impeding the movement of a ureteral stone down the ureter.     

Function and distribution of autonomic receptors in canine ureteral smooth muscle

There have been only a few reports of the measurement of autonomic receptors in ureteral smooth muscle. Furthermore, it is so difficult to maintain stable spontaneous contractions in the ureter, that either electrical field stimulation or KCl at high concentrations are utilized to induce ureteral contractions in many in vitro ureteral pharmacologic examinations. We used the spiral ureteral strips which generate spontaneous contractions in the ureter in present experiments. Norepinephrine, phenylephrine, clonidine, carbachol, and prostaglandin F_2α enhanced the spontaneous contractile force and/or increased the contractile frequency of spontaneous rhythmic contractions in spirally-incised muscle strips from isolated canine ureters. In contrast, isoproterenol, terbutaline, a β₂-adrenergic agonist, and prostaglandin E₂ reduced the spontaneous contractile force and/or decreased the contractile frequency of spontaneous rhythmic contractions. Dobutamine, a β₁-adrenergic agonist, did not affect significantly the spontaneous rhythmic contractions. The effects of the proslaglandins were not influenced by autonomic antagonists or tetrodotoxin. The existence of α₁ -, α₂ -, and β-adrenoceptors and muscarinic cholinergic receptors were demonstrated in the canine ureter using radioligand techniques. The density of α₁ -receptors binding sites was significantly greater than that of the other receptors examined. Our data show that the sympathetic nervous system is more involved than the para-sympathetic nervous system in canine ureteral contractile activities, and that α – and β -receptors contained in canine ureteral smooth muscle are comprised mainly of the α₁ – and β -subtypes. It is also suggested that prostaglandins directly affect canine ureteral contraction. © 1994 Wiley-Liss, Inc.     

Modification of ureteral motility and promotion of urine flow around an intraureteral obstruction by CL-316243, phenylephrine, and furosemide in dogs

The aim of this study was to evaluate the effects of a beta3-adrenoceptor (AR) agonist (CL-316243), an alpha1-AR agonist (phenylephrine), and a loop diuretic (furosemide) on the spontaneous rhythmic contractions of the isolated canine ureter and on an acute ureteral obstruction produced by inflation of a balloon catheter in anesthetized dogs. In the isolated ureter, CL-316243 concentration dependently reduced both the amplitude and frequency of the rhythmic contractions (pD(2): 7.19 +/- 0.33), whereas phenylephrine significantly enhanced both variables (pD(2): 5.26 +/- 0.09) and furosemide reduced them only slightly. In the acute ureteral obstruction model, the intraureteral pressure (IUP) gradually rose to reach a plateau of 58.9 mm Hg after inflation of a balloon catheter within the lower ureter. Intravenous administration of CL-316243 (0.3 microg/kg) significantly reduced the elevated IUP and the resumed urine flow (UF), leading to a sustained reduction in the IUP. In contrast, the IUP continued to increase above the plateau level for 10 minutes after phenylephrine administration (10 microg/kg) and for 30 minutes after furosemide administration (1,000 microg/kg). In the phenylephrine group, the UF resumed when the IUP reached 75.8 mm Hg, and thereafter the IUP gradually decreased in parallel with the increase in the UF. From these results, we conclude that in dogs, CL-316243 reduces the IUP by allowing the UF to resume as a result of a relaxation of ureter at the obstruction site, whereas with phenylephrine, the reduction in the IUP is secondary to a resumption in the UF resulting from an induced contraction of ureter that causes an increase in hydrostatic pressure above the obstruction site.     

Gigantic ureteral diverticulum or pelvic cyst?

Ureteral diverticulum is a rare anomaly, and very few reported cases concerning it can be found in literature. We report a 3.5-year-old boy who presented with urinary tract infection, rare voiding, and straining during voiding. Ultrasonography and magnetic resonance imaging showed a cystic pelvic mass. At surgical intervention, however, a massive ureteral cystic structure communicating both with the ureteropelvic and ureterovesical portion of the ureter was observed. Finding the presence of a smooth muscle layer, the pathologist confirmed this to be a true diverticulum. The fact that fenoterol (which was used for the prevention of preterm labor in the boy's mother) significantly decreases frequency and amplitude of upper urinary tract contractions suggests that fenoterol treatment might have influenced the occurrence of this abnormality.     

Pharmacological modulation of ureteral peristalsis in a chronically instrumented conscious pig model. I: Effect of cholinergic stimulation and inhibition

PURPOSE: We evaluated in vivo the role of muscarinic receptors on ureteral peristaltic frequency and contraction force in a large animal model using pharmacological manipulation. MATERIALS AND METHODS: A total of 12 female pigs weighing a mean +/- SEM of 72 +/- 4 kg were chronically instrumented using an electronic pressure monitoring catheter in the right ureter. Furthermore, nephrostomy, arterial, venous and cystostomy catheters were placed. Ureteral peristalsis was repeatedly recorded before and after the administration of atropine and carbachol. RESULTS: Systemic and local effects of the 2 agents were observed. Compared with controls we recorded an increase in mean ureteral peristaltic frequency (2.0 +/- 0.3 versus 1.6 +/- 0.6 minutes-1, p <0.05) and mean contraction force (50.1 +/- 1.4 versus 45.3 +/- 1.7 cm H(2)O, p <0.05) during renal pelvis perfusion with 0.25 ml per minute saline. Administration of atropine or carbachol modulated neither the force of contraction nor the frequency of ureteral peristalsis in vivo (p >0.05). CONCLUSIONS: Smooth muscle motor activity at the mid and distal ureter is not modulated by muscarinic receptors. Peristaltic frequency is directly related to the pyelocaliceal load during a rate of diuresis not exceeding animal normal diuresis plus 0.25 ml per minute. Ureteral contraction force increases only in the mid ureter with increased diuresis.     

The effect of ureteral distension on peristalsis

Summary Isolated sheep and human ureteral preparations (from patients with bilharzia) were subjected invitro to graded elongation and the effect on tension and spontaneous peristaltic frequency was assessed. Sheep specimens were obtained from three locations: the intra- and extrarenal portion of the pelvis and distal ureter. Elongation (stretch) induced an increase in spontaneous frequency only in pelvic ureteric specimens, but not in the distal ureter. Basal tension increased exponentially with stretch and most markedly in the distal sheep ureter and also in human preparations. Active tension (amplitude of phasic contractions) increased with stretch in specimens from all locations and reached a maximum at 110–115% elongation. These data suggest that acute distension of the ureter incrases frequency of peristalsic waves only in the intrarenal parts of the ureter. Acute obstruction in renal colic can induce hypermotility in terms of increased frequency and force of contraction.Supported by Grant MR 019, Kuwait University     

Physiology and pharmacology of the human ureter: basis for current and future treatments

INTRODUCTION: This article sets out to be a review regarding agents that affect contraction and relaxation of the ureter in order to establish a basis for current and future treatments for upper urinary tract obstruction. MATERIAL AND METHODS: A complete review of the English literature using MEDLINE was performed between 1960 and 2007 on ureter physiology and pharmacology with special emphasis on signal transduction mechanisms involved in the contractile regulation of the human ureter. RESULTS: Activation of muscarinic and adrenergic receptors increases the amplitude of ureteral contractions. The sympathetic nerves modulate the contractions by alpha-adrenoceptors and relaxation by beta-adrenoceptors. The purinergic system is important in sensory/motor functions and ATP is an important non-adrenergic non-cholinergic (NANC) agent causing contraction. Nitric oxide (NO) is a major inhibitory NANC neurotransmitter causing relaxation. Serotonin causes contraction. Prostaglandin-F(2)alpha contracts whereas prostaglandin-E(1)/E(2) relaxes the ureter. Phosphodiesterases (PDE) and the Rho-kinase pathway have recently been identified in the human ureter. PDE-IV inhibitors, K(+) channel openers, calcium antagonists, alpha(1)-adrenoceptor antagonists and NO donors seem to be promising drugs in relieving obstruction and facilitating stone passage. CONCLUSIONS: Further understanding of the ureteral function and pharmacology may lead to the discovery of promising new drugs that could be useful in relieving ureteral colic, facilitating spontaneous stone passage, preparing the ureter for ureteroscopy as well as acting adjunctive to extracorporeal shock-wave lithotripsy.     

The effect of nitric oxide on the pressure of the acutely obstructed ureter

Acute ureteral obstruction leads to changes in pressure inside the ureter, interrupting ureter function. The aim of our study is to explore the relationship between nitric oxide (NO) concentration and pressure in the ureter and to observe the effects of nitric oxide on the revival of renal function. We created the animal models by embedding balloons in the lower ureters of anesthetized dogs and expanding them to simulate acute ureteral obstruction. First, the test animals were pre-treated intravenously with different doses of L-NAME (non-selective nitric oxide synthase inhibitor) to inhibit nitric oxide synthase (NOS), and 10 min later, each subject was administered an intravenous dose of isoproterenol (10 μg/kg). We measured ureter pressure (UP), total and peak concentrations of NO (using an NO monitor, model inNO-T) in ureteral urine, and the volume of the urine (UFV) leaking from the balloon edge. After a certain amount of time had elapsed, it became clear that the dose of L-NAME was inversely related to the total and peak concentrations of NO, the rate of change in UP, and the volume of urine produced. We conclude that L-NAME prevents the NOS from inhibiting the release of NO, then inhibits the effect of isoproterenol reducing the pressure of the acute obstructive ureter. Inversely, we think that NO can reduce the pressure of the acute obstructive ureter and make the obstructive ureter recanalization. And when more the concentration of nitric oxide, the more the pressure will be reduced, and more urine will be collected.     

Response of normal canine ureter to photodynamic therapy using a cylindrical fiber

Photodynamic therapy (PDT) was performed utilizing a cylindrical optical fiber to determine feasibility of distal ureteral treatment on 10 study and two control NIH foxhounds. The study animals were administered three mg./kg. dihematoporphyrin ether (Photofrin II) intravenously followed 48 hours later by open cystotomy. One ureter was irradiated with 42 joules of 630 nm. light delivered by a 660 micron diameter optical fiber modified for cylindrical light distribution. Intravenous urography was performed both at three days and six weeks post PDT. Hydroureteronephrosis was revealed in one treated ureter and one untreated ureter. Mild dilatation of the ureter was noted by urography in another treated ureter and in one ureter that did not undergo light irradiation; no distal obstruction was revealed in either case by proximal infusion of saline or by histopathology. Nine of the 10 treated ureters were found to have either no abnormal pathology or only minimal lymphocytic infiltration. In this study, the normal ureter was shown to tolerate photodynamic therapy at energy densities equivalent to those used to effect tumor regression and the feasibility of using a cylindrical optical fiber for treatment of ureteral malignancies was confirmed.     

Physiologic effect of nifedipine and tamsulosin on contractility of distal ureter

BACKGROUND AND PURPOSE: Renal colic not only leads to significant morbidity but imposes a financial burden on society in lost productivity and healthcare dollars spent. Both tamsulosin and nifedipine can facilitate spontaneous stone passage in the distal ureter and reduce the associated colic. We evaluated the physiologic effect of these agents on the distal pig ureter. MATERIALS AND METHODS: Bilateral ureters were removed en bloc with the bladder trigone from three pigs. Five-millimeter rings were taken from the intramural and distal ureter. Isometric tension recording was performed during both spontaneous and electrically stimulated contraction. Measurements of contractile interval and amplitude were taken in baseline buffer solution, nifedipine at 10(-6) g/L, and tamsulosin at 10(-6) g/L. Spontaneous contractile activity was also measured with phenylephrine at 10(-4) g/L followed by tamsulosin at 10(-6) g/L. RESULTS: Under conditions of spontaneous contractility, phenylephrine decreased the contraction interval by 46%, an effect which was reversed by tamsulosin. Tamsulosin increased the baseline interval by 27% (P < 0.025) and decreased the amplitude by 7% (P > 0.1). Nifedipine blocked all contractile activity. Under stimulated contractility, tamsulosin had no effect on the interval and decreased the amplitude by 7% (P > 0.1). Nifedipine blocked all contractile activity. CONCLUSIONS: We believe that both tamsulosin and nifedipine prevent the disorganized antiperistalsis associated with ureteral spasm while allowing some degree of antegrade fluid-bolus (stone) propagation. It is this mechanism of action that facilitates spontaneous passage and reduces associated renal colic when tamsulosin and nifedipine are used for the management of ureteral stone disease.     

The function of autonomic receptors in canine ureteral smooth muscle]

I have investigated the effects of autonomic drugs and prostaglandins on in vitro smooth muscle spontaneous contractions and made the quantitative analysis of autonomic receptors in the canine ureter. Ureteral muscle strip cut helically usually generated spontaneous contractions whereas those cut circularly or longitudinally did not generate spontaneous contractions. These results suggest the importance of knowing which direction to cut the ureteral smooth muscle in order to generate spontaneous contractions. Norepinephrine (alpha), phenylephrine (alpha 1), carbachol (muscarinic) and PGF2 alpha caused significant increase in contractile force. Terbutaline (beta 2) and PGE2 caused significant decreases in contractile force, while dobutamine (beta 1) and clonidine (alpha) caused no effect. Autonomic receptor densities were determined using radiology and binding techniques. The number of maximum binding sites (Bmax) of 3H-prazosin (PZ), 3H-yohimbine (YOH), 3H-dihydroaloprenolol (DHA) and 3H-quinuclidinylbenzilate (QNB) were 53.8, 16.9, 11.2 and 5.28 fmol/ml protein, respectively. These data suggest that the contractile responses to adrenergic and cholinergic agonists in the canine ureter are mediated through functional adrenergic (alpha 1, beta 2) and muscarinic cholinergic receptors and that the prostaglandins have a role in the contraction of the canine ureter.     

Basic physiological studies of the effects of autonomic drugs on the pacemaker of renal pelvic peristalsis

An electromyographic study of the effects of noradrenaline, isoproterenol, and acetylcholine on the calyceopelviureteral system was performed in isolated canine pyeloureteral preparations with continuous infusion of oxygenated Krebs-Ringer solution into the renal pelvis to provide a condition of constant urine volume. The calyceal pacemaker was slightly stimulated by noradrenaline and acetylcholine and was also quickened in pace by isoproterenol. Noradrenaline caused a marked elevation of renal pelvic pressure and enhancement of propagation of peristalsis generated at the pacemaker region with an increase in frequency of ureteral peristalsis. In contrast, isoproterenol lowered the renal pelvic pressure to an extent of pressure wave disappearance and concomitant blockade of peristaltic movement propagation to the ureter, with consequent suppression of ureteral peristalsis. Acetylcholine slightly reduced the renal pelvic pressure but at the same time exerted a marked effect on the ureter, causing a transient increase in frequency of ureteral peristalsis.     

Effects of autonomic drugs on in vivo recording of electromyograms of canine renal pelvis and ureter

The effects of the autonomic drugs (noradrenaline, isoproterenol and acetylcholine) and the urine volume change on the pacemaker of ureteral peristalsis were studied by our new method of the in vivo recording of electromyograms (EMGs) of canine renal pelvis. The EMGs of the pelvicalyceal region showed a two phasic slow-rising potential of amplitude of 20 microV and discharge interval of 5 s and was different from propagated waves and therefore considered to be the pacemaker potentials. In the diuretic state the pacemaker potentials kept a constant discharge interval. On the contrary, the discharge interval of the ureter EMG became shorter and finally corresponded to the pacemaker EMG one to one. These results suggest that the urine transport in the diuretic state is controlled by the change of efficiency of the peristaltic propagation and not by the changes of the discharge of the pacemaker itself. Noradrenaline promoted the ureteral peristalsis and isoproterenol inhibited the ureteral peristalsis. These two drugs had no effects on the pacemaker potentials. Acetylcholine had a great variety of the effects on the ureter EMG and the pacemaker EMG separately. These results suggest that the pacemaker of the ureteral peristalsis is controlled under the influence of the parasympathetic system and the ureter is controlled under the influence of both the sympathetic and parasympathetic system.     

体外冲击波对兔输尿管功能影响的研究

目的：观察和测定冲击波对输尿管功能的影响。方法：将30只成年兔随机分为6组，每组5只。第1组为正常对照组；第2－4组接近2000次冲击，分别在冲击后当天，第1天和第5天取出输尿管，第5，6组分别冲击2组，4期，在最后一期冲击后2周取材。采取高浓度的KCl溶液诱导并记录离体输尿管段的收缩反应。结果：94mmol/L的KCl溶液可诱发正常及冲击组输尿管段的双相收缩反应。第2，3组平滑肌收缩幅度明显低于正常组（P＜0．05），但收缩频率反而有所上升。其余各组收缩幅度和频率与正常相比无明显区别。结论：输尿管平滑肌收缩力量在冲击后当天及第1天明显降低，至第5天已基本恢复正常。     

Chronic ureteric obstruction and its impact on the coordinating mechanisms of peristalsis (Pyeloureteric Pacemaker System)

Summary We present the results of a study designed to characterise urine transport in the healthy and chronically obstructed upper urinary tract. Fifteen healthy and 11 hydronephrotic pigs were used; experimental hydronephrosis was produced by partially obstructing the ureter. Data consisting of the peristaltic rate, bolus volume, and the urine flow rate were collected and related to varying increments of diuresis. The transmission characteristics of renal pelvic to ureteric contractions were studied by extracellular electrodes. Similarly, in hydronephrotic preparations we studied the transmission between the proximal and middle pelvis to the ureter. In healthy preparations, the contraction frequency of the renal pelvis and the ureter is identical, while in obstructive cases, the contraction frequency of the upper pelvis is not coordinated with the lower pelvis or ureter. While diuresis increased bolus volume to a maximum of 1,200% in the healthy and 660% in the hydronephrotic kidney, the peristaltic rate changed by only 45% and 50% respectively. The results of this study show that chronic ureteric obstruction alters the coordination of ureteric peristalsis and thereby disrupts the pacemaker mechanisms of the renal pelvis.     

Effects of noradrenaline, isoproterenol and acetylcholine on ureteral resistance

Resistance to fluid flow in the canine ureter can be divided into two categories. The higher resistance is recorded at flow rates less than or equal to 2.16 ml./min. At these rates the ureter is able to completely coapt its walls so that urine is transported in individual boluses. The lower resistance is recorded at flow rates greater than or equal to 5.40 ml./min. At these rates the ureteral walls remained open and urine is transported as a column of fluid. Noradrenaline causes a marked increase in ureteral resistance at low flow rates and a small but statistically significant increase in ureteral resistance at high flow rates. Acetylcholine increases resistance only at the low flow rates. Isoproterenol significantly decreases resistance at both low and high flow rates. These findings are consistent with ureteral resistance to fluid flow being composed of two components. One is the ureteral peristaltic contraction which plays a principal role in urinary bolus transport at low flows; the other is ureteral wall tonus, which plays an important role in the transport of columns of urine by the ureter, which does not coapt its walls, at the higher flow rates.     

URETHRAL AFFERENT NERVE ACTIVITY AFFECTS THE MICTURITION REFLEX; IMPLICATION FOR THE RELATIONSHIP BETWEEN STRESS INCONTINENCE AND DETRUSOR INSTABILITY

PURPOSE: A causative relationship between stress urinary incontinence (SUI) and detrusor instability has been suspected but never proven. Many women with mixed incontinence have resolution of detrusor instability after surgical correction of SUI. We sought experimental support that stimulation of urethral afferent nerves can induce or change reflex detrusor contractions. MATERIALS AND METHODS: Urethral perfusion pressure and isovolumetric bladder pressure were measured with catheters inserted through the bladder dome in urethane anesthetized female S.D. rats (250 to 300 grams; n = 12). The catheter assembly was seated securely in the bladder neck to block passage of fluid between the bladder and urethra without affecting the nerve supply to the organs. The external urethra was not catheterized. Responses were examined in the control state at a urethral saline perfusion speed of 0.075 ml. per minute. Intraurethral drugs were administered following blockade of striated sphincter activity with intravenous alpha-bungarotoxin (0.1 mg./kg.). RESULTS: Stopping the urethral saline infusion caused a significant decrease in micturition frequency in approximately 50% of the animals studied (n = 12). Intraurethral lidocaine (1%) infused at 0.075 ml. per minute caused a slight decrease in urethral perfusion pressure but no change in detrusor contraction amplitude. However, intraurethral lidocaine caused a significant (45%) decrease in the bladder contraction frequency (n = 5). The micturition frequency returned to baseline 30 minutes after stopping lidocaine infusion. Intraurethral infusion of nitric oxide (NO) donors (S-nitroso-N-acetylpenicillamine [SNAP] (2 mM) or nitroprusside (1 mM) immediately decreased urethral perfusion pressure by 30 to 37% (n = 5). A 45 to 75% decrease (n = 5) in bladder contraction frequency was also seen, which was similar to that observed following lidocaine. Neither NO donor changed the amplitude of bladder contractions. CONCLUSIONS: These results indicate that in the anesthetized rat activation of urethral afferents by urethral perfusion can modulate the micturition reflex. Thus in patients with stress urinary incontinence, leakage of urine into the proximal urethra may stimulate urethral afferents and facilitate voiding reflexes. This implies that stress incontinence can induce and/or increase detrusor instability. These findings have significant implications for the treatment of patients with mixed urge and stress incontinence. Correction of stress incontinence by surgery or pelvic floor exercise in patients with mixed incontinence may resolve the detrusor instability.     

Clinical, Hormonal and Pathological Findings in a Comparative Study of Adrenocortical Neoplasms in Childhood and Adulthood

The present study investigated the role of nitric oxide (NO) in the reflex changes in urethral outlet activity during micturition. Isovolumetric bladder contractions, urethral pressure and external urethral sphincter electromyogram (EUS EMG) activity were recorded independently in urethane-anesthetized rats. During reflex bladder contractions, the urethra exhibited reflex responses characterized by an initial decrease in urethral pressure in conjunction with a rise in bladder pressure. This was followed by a period of high frequency oscillations (HFOs) associated with maximal urethral relaxation and burst type EUS EMG activity. Administration of N-nitro-L-arginine (L-NOARG) 10 mg./kg. intravenously, a nitric oxide synthase inhibitor, reversibly decreased the magnitude (62 percent, p less than 0.05) and duration (40 percent, p less than 0.05) of reflex urethral relaxation (N = 7). In 4 additional experiments, L-NOARG (10 to 15 mg./kg. intravenously) completely eliminated reflex urethral relaxation during micturition, and this effect was reversed in all animals by the administration of L-arginine (100 to 150 mg./kg. intravenously). Administration of N-nitro-D-arginine (D-NOARG) (10 to 30 mg./kg. intravenously) had no effect on reflex urethral relaxation. Neuromuscular blockade (vecuronium bromide 5 mg./kg. intravenously) reversibly decreased resting urethral pressure and eliminated the HFOs. The urethral smooth muscle relaxation that remained after neuromuscular blockade was eliminated following administration of L-NOARG (10 mg./kg. intravenously) in 2 of 3 animals. These results suggest that reflex urethral responses during micturition involve changes in both smooth and striated muscle activity, and that the predominant neurotransmitter mechanisms that mediate reflex urethral smooth muscle relaxation involve NO.