Research Article
Spike generation from dorsal roots and cutaneous afferents by hypoxia or hypercapnia in the rat in vivo
- Gábor Pethô, Róbert Pórszász, Barna Peitl, János Szolcsányi
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- 03 January 2001, pp. 1-15
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The present study aimed at investigating the responsiveness of different parts of the primary afferent neurones to a brief hypoxia, hypercapnia or ischaemia under in vivo conditions. Action potentials were recorded in separate groups of anaesthetized rats from (i) the peripheral end of the central stump of the cut L3, L4 or L5 dorsal root (dorsal root preparation); (ii) the central end of the peripheral stump of the cut saphenous nerve (saphenous-receptor preparation); (iii) the distal end of a segment of the saphenous nerve cut at both ends (axon preparation). In paralysed animals interruption of artificial ventilation for 20-60 s elicited or increased the frequency of action potentials in both the dorsal root and saphenous-receptor preparations. Activation of these preparations was also achieved by inspiration of gas mixtures containing 10-0 % oxygen (mixed with nitrogen) or 20-50 % carbon dioxide (mixed with oxygen) which elicited in the blood a decrease in PO2 or an increase in PCO2 with a fall in pH. Occlusion of the femoral artery for 3 min also caused spike generation in the saphenous-receptor preparations with little alteration in blood pressure. All these stimuli failed to evoke action potentials in the axon preparations. Systemic (300 mg kg-1 S.C.) or perineural (2 %) capsaicin pretreatment failed to inhibit the effect of hypoxia, hypercapnia or ischaemia, indicating a significant contribution of capsaicin-insensitive neurones to the responses. It is concluded that central and peripheral terminals but not axons of primary afferent neurones are excited by a brief hypoxia or hypercapnia and the peripheral terminals by a short local ischaemia as well. Excitation of central terminals by hypoxia or hypercapnia revealed in this way an antidromic activation of dorsal roots in response to natural chemical stimuli.
Separate receptors mediate oxytocin and vasopressin stimulation of cAMP in rat inner medullary collecting duct cells
- E. T. Wargent, W. J. Burgess, J. F. Laycock, R. J. Balment
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- 03 January 2001, pp. 17-25
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The two neurohypophysial hormones arginine vasopressin (AVP) and oxytocin have actions in the inner medullary collecting duct (IMCD) where both peptides induce an increase in cAMP accumulation. The present study has employed a novel IMCD cell line to determine whether these two hormones induce cAMP accumulation via common or separate receptors, and to characterize the potential receptors responsible. Equal volumes of vehicle (150 mM NaCl) or hormone/antagonist solutions were added to aliquots of 104 IMCD cells in the presence of 10-3 M 3-isobutylmethylxanthine (IBMX) and incubated at 37°C for 4 min. cAMP levels were determined by radioimmunoassay and protein concentration by Bradford assay. Both AVP and oxytocin elicited dose-dependent increases in cAMP generation, though oxytocin was less potent than AVP (EC50 = 1Σ6 × 10-8 M vs. 7Σ4 × 10-10 M). AVP at 10-8 M and oxytocin at 10-6 M, concentrations sufficient to elicit near-maximal cAMP accumulation, resulted in cAMP levels of 73Σ4 ± 1Σ7 and 69Σ0 ± 3Σ3 pmol (mg protein)-1 (4 min)-1, respectively (n = 10), compared with the vehicle-treated basal value of 37Σ7 ± 2Σ2 pmol (mg protein)-1 (4 min)-1 (P < 0Σ001, n = 10). Combined AVP (10-8 M) and oxytocin (10-6 M) resulted in cAMP accumulation of 63Σ8 ± 3Σ1 pmol (mg protein)-1 (4 min)-1 (n = 10), which was not significantly different from the effect of oxytocin alone, but slightly less than that for AVP alone (P < 0Σ05). A submaximal concentration of AVP (10-10 M) induced cAMP accumulation of 48Σ6 ± 2Σ5 pmol (mg protein)-1 (4 min)-1 (P < 0Σ01 compared with basal level of 34Σ9 ± 2Σ4 pmol (mg protein)-1 (4 min)-1, n = 10), which was blocked in the presence of a vasopressin V2 receptor antagonist (10-7 M OPC-31260) but not by the oxytocin receptor antagonist (10-6 M [Pen1,pMePhe2,Thr4,Orn8]oxytocin) (36Σ3 ± 6Σ1 and 45Σ1 ± 1Σ3 pmol (mg protein)-1 (4 min)-1 respectively, P < 0Σ05, n = 10). A submaximal concentration of oxytocin (10-7 M) induced a cAMP accumulation of 45Σ8 ± 1Σ8 pmol (mg protein)-1 (4 min)-1 (n = 10), which was reduced by addition of 10-6 M oxytocin antagonist (36Σ3 ± 2Σ1 pmol (mg protein)-1 (4 min)-1, P < 0Σ05, n = 10), whereas co-incubation with 10-6 M of the V2 receptor antagonist had no effect (43Σ2 ± 1Σ3 pmol (mg protein)-1 (4 min)-1, n = 10). These results indicate that AVP and oxytocin induce cAMP accumulation from a common ATP pool in IMCD cells, and that separate vasopressin V2 and oxytocin receptor systems are involved, perhaps coupled to a common adenylate cyclase system.
Anion efflux from cytotrophoblast cells derived from normal term human placenta is stimulated by hyposmotic challenge and extracellular a23187 but not by membrane-soluble cAMP
- M. A. Turner, M. K. Sides, C. P. Sibley, S. L. Greenwood
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- 03 January 2001, pp. 27-40
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The regulation of placental anion transport influences fetal accretion and placental homeostasis. We investigated whether efflux of 125I- or 36Cl- from multinucleated cytotrophoblast cells derived from human term placenta is regulated by one of three stimuli: (a) the calcium ionophore A23187, (b) a 'cocktail' of agents designed to raise intracellular levels of cAMP, (c) a hyposmotic solution. After loading with the appropriate isotope for 2 h and thorough washing, cells were exposed to sequential aliquots of buffer applied and removed each minute. Following an equilibration period of 5 min one of the stimuli was applied at room temperature At the end of the experiment the cells were lysed to give a lysate count which was used to express the count obtained from each aliquot as percentage efflux of that possible for that minute. The cAMP 'cocktail' and A23187 were applied for 5 min; the hyposmotic solution was applied for 10 min. The results for 125I- at 7 min showed that the mean efflux in the presence of hyposmotic shock was greater than control (5Σ7 ± 1Σ0 % min-1versus 2Σ2 ± 0Σ1 % min-1, respectively; mean ± S.E.M., n = 4 placentas). Similarly mean efflux at 6 min in the presence of A23187 was also significantly greater than control (6Σ5 ± 1Σ9 % min-1versus 2Σ6 ± 1Σ0 % min-1, respectively, n = 3 placentas). The mean efflux in the presence of the cAMP cocktail was not different from control at any time point. The results were qualitatively the same if 36Cl- was used in the place of 125I- and when the experiment was performed with 36Cl- in a HCO3- buffer gassed with CO2. Mean 125I- efflux at 6 min in response to hyposmotic challenge was 33 % less (P < 0Σ01) in the presence of 1 mM 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (DIDS) and 37 % less (P < 0Σ005) in the presence of 10 µM tamoxifen but no different if the hyposmotic solution was nominally calcium free. We conclude that there are differential effects of second messengers on anion efflux from the differentiated cytotrophoblast cells.
Ryanodine receptors in human bladder smooth muscle
- Pauline Chambers, David E. Neal, James I. Gillespie
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- 03 January 2001, pp. 41-46
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The role of intracellular Ca2+ release in the activation of human bladder smooth muscle is controversial. We have measured the expression of mRNA encoding for the ryanodine receptor (RyR) isoforms (RyR1, RyR2 and RyR3) in isolated human detrusor smooth muscle. mRNA for RyR2 was detected in all samples but no mRNA for RyR1 or RyR3 could be found. Human bladder smooth muscle cells in culture are unresponsive to caffeine, suggesting the absence of a functional RyR system. However, mRNA encoding for RyR2 was detected in these cells. Using saponin-permeabilized cells, a Ruthenium Red-sensitive Ca2+-dependent 45Ca2+ release could be demonstrated from the sarcoplasmic reticulum (SR). These data confirm the functional presence of Ca2+-induced Ca2+ release (CICR) in cells and suggest that the properties of the RyR2 isoform in human detrusor may change when the cells are maintained in culture. The implications of these observations to detrusor smooth muscle function are discussed.
Hypoxia inhibits baroreflex vagal bradycardia via a central action in anaesthetized rats
- Mariko Kongo, Rie Yamamoto, Masayoshi Kobayashi, Shoichiro Nosaka
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- 03 January 2001, pp. 47-56
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It is known that arterial baroreflexes are suppressed in stressful conditions. The present study was designed to determine whether and how hypoxia affects arterial baroreflexes, especially the heart rate component, baroreflex vagal bradycardia. In chloralose-urethane-anaesthetized rats, baroreflex vagal bradycardia was evoked by electrical stimulation of the aortic depressor nerve, and the effect of 15 s inhalation of hypoxic gas (4 % O2) was studied. Inhalation of hypoxic gas was found to inhibit baroreflex vagal bradycardia. The inhibition persisted after bilateral transection of the carotid sinus nerve. Cervical vagus nerves were cut bilaterally and their peripheral cut ends were stimulated to provoke vagal bradycardia of peripheral origin so as to determine whether hypoxia could inhibit vagal bradycardia by acting on a peripheral site. In contrast to baroreflex vagal bradycardia, the vagus-induced bradycardia was not affected by hypoxic gas inhalation. It is concluded that baroreflex vagal bradycardia is inhibited by hypoxia and the inhibition is largely mediated by its direct central action.
The effects of acute and chronic systemic hypoxia on muscle oxygen supply and oxygen consumption in the rat
- Janice M. Marshall, William R. Davies
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- 03 January 2001, pp. 57-68
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The aims of the present study were to evaluate how acute systemic hypoxia affects O2 delivery to skeletal muscle and muscle O2 consumption (VO2) of the rat and to establish how these relationships are altered by chronic systemic hypoxia. Thus, the effects of breathing different concentrations of O2 (air, 12 % and 8 % O2) upon oxygen delivery and VO2 were studied in hindlimb muscles of control, normoxic (N) rats and of rats that had been made chronically hypoxic in a chamber at 12 % O2 for 3-4 weeks (CH) rats. Under anaesthesia, arterial blood pressure, femoral blood flow (FBF), arterial O2 content (Ca,O2) and venous O2 content in the efflux from hindlimb were measured. In N rats, changing the inspirate from air to 12 % and 8 % O2 for 5 min each, reduced Ca,O2 from 20 ± 0·3 ml (100 ml)-1 in air to 13 ± 1·0 ml (100 ml)-1 in 8 % O2. FBF did not change significantly (1·7 ± 0·1 ml min-1 in air) so that O2 delivery to hindlimb muscles fell from 0·28 ± 0·07 to 0Σ16 ± 0Σ02 ml min-1 in 8 % O2. Nevertheless, the VO2 of hindlimb muscles was well maintained: 0Σ06 ± 0Σ02 ml min-1 in air and 0Σ08 ± 0Σ02 ml min-1 in 8 % O2. In CH rats breathing 12 % O2, Ca,O2 (23 ± 1Σ0 ml (100 ml)-1) was comparable to that of N rats breathing air, due to an increase in haematocrit, as were FBF (1Σ6 ± 0Σ2 ml min-1) and O2 delivery (0Σ39 ± 0Σ05 ml min-1). However, VO2 was 2Σ5-fold greater in CH rats (0Σ16 ± 0Σ03 ml min-1). As in N rats, FBF was well maintained at 1Σ7 ± 0Σ2 and 1Σ6 ± 0Σ2 ml min-1 in 8 % O2 and air, respectively. Further, VO2 was also well maintained, at 0Σ17 ± 0Σ02 and 0Σ12 ± 0Σ02 ml min-1 in 8 % O2 and air, respectively. These results suggest that, contrary to previous reports, muscle VO2 of the rat is independent of O2 delivery over a wide range of O2 delivery values. They also suggest that muscle VO2 of CH rats is similarly independent of O2 delivery. The novel finding that muscle VO2 has a greater absolute value in CH rats can, we propose, be explained by an increase in VO2 of the vasculature rather than of the skeletal muscle fibres and reflects increased biosynthetic activity of the vessel walls and/or vascular remodelling.
Cardiac function and morphology studied by two-dimensional doppler echocardiography in unsedated newborn pigs
- Drude Fugelseth, Saulius Satas, Martin Runde, Per Hågå, Marianne Thoresen
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- 03 January 2001, pp. 69-78
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The newborn pig is currently the most used species in animal neonatal research. Valid non-invasive monitoring is important in particular for long-term survival of unsedated animals. In the unsedated newborn pig (n = 35, median age 24 h, range 7-48 h) we standardized two-dimensional Doppler echocardiography and determined the normal ranges for cardiac function. Probe positioning had to be adjusted to the V-shaped thorax and the mid-line position of the heart. Six out of the sixteen animals < 20 h had a patent ductus arteriosus compared with one of the twenty animals > 20 h old. One atrial septal defect (5 mm) and one small ventricular septal defect were diagnosed. The average heart size was 0Σ7-0Σ9 % of body weight which is similar to human infants of the same size. The mean aortic diameter was 6Σ0 ± 0Σ5 mm (mean ± S.D.) and cardiac output was 0Σ38 ± 0Σ08 l min-1; both correlate with body weight (r = 0Σ80 and 0Σ73, respectively). Tricuspid regurgitation velocity was 3Σ0 ± 0Σ4 m s-1 (mean ± S.D.), giving an estimated pressure gradient across the tricuspid valve of 37 ± 9Σ7 mmHg. The aortic diameter and the heart weight per kg body weight are comparable to those reported for preterm neonates. The cardiac output and velocities across the four valves are more comparable with term neonates.
Exercise gas transport determinants in elderly normotensive and hypertensive humans
- R. J. Petrella, D. A. Cunningham, D. H. Paterson
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- 03 January 2001, pp. 79-91
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This study examined the effect of the phenylalkylamine calcium channel blocker verapamil, on resting left ventricular (LV) function and O2 uptake rate (VO2) during exercise at maximal and submaximal work rates. Nine older hypertensive (71 years; OH), 10 older sedentary normotensive (69 years; OS), 10 older active (71 years; OA) and 10 young (24 years; Y) individuals volunteered. Studies were completed in the control condition and 4-6 h following 240 mg verapamil SR per os. Resting LV systolic (fractional shortening; FS) and diastolic (early : late (E/A) flow velocity ratio and isovolumic relaxation time (IVRT)) were measured by Doppler echocardiography. Maximal oxygen uptake (VO2,max) and, on subsequent test days, four transitions to and from a 6 min square wave exercise perturbation at a sub-anaerobic threshold intensity of 40 W (OH, OS, OA) or 100 W (Y) for determination of VO2 kinetics were performed on a cycle ergometer. Breath-by-breath VO2 transients were fitted with a monoexponential equation, starting at phase 2 of the response, while heart rate (HR) was fitted from phase 1, for the determination of the time constant of VO2 ([tau]VO2) and HR ([tau]HR). Baseline left ventricular FS was significantly greater in the OS (32 %), OA (34 %) and Y (34 %) than in the OH (23 %) groups, while E/A was significantly greater in the OA (1Σ16) and Y (2Σ34) than in the OH (0Σ9) and OS (0Σ82) groups (P < 0Σ05). Baseline VO2,max was higher and [tau]VO2 faster in the young (41Σ4 ml kg-1 min-1; 25Σ2 s) than in the older groups and in the OA (28Σ8 ml kg-1 min-1; 44Σ3 s) than in both OH (20Σ8 ml kg-1 min-1; 71Σ3 s) and OS (22Σ0 ml kg-1 min-1; 59Σ5 s) groups (P < 0Σ05). Heart rate kinetics showed similar differences to VO2 kinetics among the groups. After verapamil, no significant changes in FS, E/A or IVRT were observed in the OA and Y groups. In the OH group, FS (32 %) and E/A (1Σ15) increased while IVRT decreased significantly (from 0Σ103 to 0Σ07; P < 0Σ05). In the OS group, only E/A increased significantly (0Σ82 to 1Σ0; P < 0Σ05). None of the exercise variables (VO2,max, [tau]VO2 or [tau]HR) were altered for the OA or Y groups. VO2,max increased (from 20Σ8 to 22Σ8 ml kg-1 min-1) in the OH and (from 22Σ0 to 24Σ1 ml kg-1 min-1) in the OS (P < 0Σ05). [tau]VO2 was accelerated from 71Σ3 to 49Σ2 s in the OH group and from 59Σ5 to 48Σ2 s in the OS group (P < 0Σ05). These results suggest that VO2 responses at maximal and submaximal work rates may be dependent upon the initial cardiac pump function of the study population.
Evolution of contractile and elastic properties of rat soleus muscle fibres under unloading conditions
- T. Toursel, L. Stevens, Y. Mounier
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- 03 January 2001, pp. 93-107
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Rats were submitted to 14 days of hindlimb suspension in order to examine the contractile and elastic properties of the soleus muscles under disuse conditions. The calcium/strontium activation properties, the maximal shortening velocity (V0), as well as the time behaviour of force transients following quick releases and the T1 curves characterizing the active part of the series elastic elements, were determined on single chemically skinned fibres. After the functional measurements, the fibres were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis in order to analyse both the myosin heavy (MHC) and light (MLC) chain isoforms. According to the MHC and MLC composition, two groups of fibres were defined after hindlimb suspension: a group of slow fibres expressing the slow set of both MHC and MLC isoforms, and a group of fast fibres co-expressing the slow and fast MHC and MLC isoforms with a predominant expression of the fast ones. For the first group, the contractile as well as the elastic properties were found to be close to those of control slow soleus fibres. For the second group, both contractile and elastic properties were modified insofar as they became close to those found in a fast muscle such as the extensor digitorum longus. We suggested that between the two populations found in the soleus muscle after hindlimb suspension the modifications in the contractile properties, as well as the alterations in the elastic characteristics, were concomitant to the changes in both MHC and MLC compositions.
Breathing patterns during slow and fast ramp exercise in man
- Barry W. Scheuermann, John M. Kowalchuk
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- 03 January 2001, pp. 109-120
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Breathing frequency (fb), tidal volume (VT), and respiratory timing during slow (SR, 8 W min-1) and fast (FR, 65 W min-1) ramp exercise to exhaustion on a cycle ergometer was examined in seven healthy male subjects. Expiratory ventilation (VE), pulmonary gas exchange (VO2 and VCO2) and end-tidal gas tensions (PET,O2 and PET,CO2) were determined using breath-by-breath techniques. Arterialized venous blood was sampled from a dorsal hand vein at 2 min intervals during SR and 30 s intervals during FR and analysed for arterial plasma PCO2 (Pa,CO2). PET,CO2 increased with increasing work rates (WRs) below the ventilatory threshold (VT); at WRs >= 90 % VO2,max, PET,CO2 was reduced (P < 0Σ05) below 0 W values in SR but not in FR. fb and VT were similar for SR and FR at all submaximal WRs, resulting in a similar VE. At exhaustion VE was similar but fb was higher (P < 0Σ05) and VT was lower (P < 0Σ05) in SR ( fb, 51 ± 10 breaths min-1; VT, 2590 ± 590 ml) than in FR ( fb, 42 ± 8 breaths min-1; VT, 3050 ± 470 ml). The time of expiration (TE) decreased with increasing WR, but there was no difference between SR and FR. The time of inspiration (TI) decreased at exercise intensities >= VT; at exhaustion, TI was shorter (P < 0Σ05) during SR (0Σ512 ± 0Σ097 s) than during FR (0Σ753 ± 0Σ100 s). The TI to total breath duration (TI/TTot) and the inspiratory flow (VT/TI) were similar during SR and FR at all submaximal exercise intensities; at VO2,max, TI/TTot was lower (P < 0Σ05) and VT/TI was higher (P < 0Σ05) during SR (TI/TTot, 0Σ473 ± 0Σ030; VT/TI, 5Σ092 ± 0Σ377 l s-1) than during FR (TI/TTot, 0Σ567 ± 0Σ050; VT/TI, 4Σ117 ± 0Σ635 l s-1). These results suggest that during progressive exercise, breathing pattern and respiratory timing may be determined, at least at submaximal work rates, independently of alveolar and arterial PCO2.
Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects
- B. L. Mtinangi, R. Hainsworth
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- 03 January 2001, pp. 121-130
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The effect of physical training on an individual's ability to withstand an orthostatic stress is unclear. This study was undertaken to determine the effects on orthostatic tolerance in healthy volunteers of training at a level appropriate for unfit subjects and cardiorespiratory patients. In 11 asymptomatic, untrained subjects the following assessments were made: plasma volume by Evans Blue dye dilution and blood volume derived from haematocrit; carotid baroreceptor sensitivity from the slope of the regression of change in cardiac interval against pressure applied to a neck chamber; orthostatic tolerance as time to presyncope in a test of head-up tilting combined with lower body suction; exercise test relating heart rate to oxygen consumption. Subjects were then given a training schedule (5BX/XBX, Royal Canadian Air Force) involving 11-12 min of mixed exercises per day until an age/sex related 'target' was reached. Following training all subjects showed evidence of improved fitness, seen as decreases in heart rate at an oxygen uptake (VO2) of 1Σ5 l min-1 and in the elevation of the regression line between heart rate and VO2. All also had increases in plasma and blood volumes and decreases in baroreceptor sensitivity. Seven of the subjects showed increases in orthostatic tolerance. Improvement in orthostatic tolerance was related to a low initial tolerance, and was associated with increases in plasma volume and decreases in baroreceptor sensitivity. These results show that moderate exercise training increases orthostatic tolerance in subjects who do not already have a high initial tolerance and suggest that training may be of value in the management of untrained patients with attacks of syncope due to orthostatic intolerance.
Physiological Society Symposium: The physiology and pathophysiology of the lower urinary tract
The activation of bladder wall afferent nerves
- John Morrison
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- 03 January 2001, pp. 131-136
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The functional state of the lower urinary tract is monitored more or less continuously by afferent nerves, which provide a sensory input in the control of the bladder and the external urinary sphincter. The functional state of the former is regulated by the autonomic nerves to the bladder, principally the parasympathetic (pelvic) nerves, which cause the detrusor muscle to contract, and possibly also by the sympathetic (mainly hypogastric nerve) innervation, which may reduce the resting tone of the smooth muscle. Continence is normally maintained by the resistance of the urethral sphincters; the tone generated by the skeletal muscle external sphincter is under the control of the somatic [alpha]-motoneurones running in the pudendal nerve, and possibly some somatic efferents in the pelvic nerve of some species.
The spontaneously hypertensive rat: insight into the pathogenesis of irritative symptoms in benign prostatic hyperplasia and young anxious males
- William D. Steers, David B. Clemow, Katarina Persson, Todd B. Sherer, Karl-Erik Andersson, Jeremy B. Tuttle
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- 03 January 2001, pp. 137-148
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Recent epidemiological studies have shown that hypertensive men are more likely to undergo surgical intervention for irritative voiding symptoms from BPH than age-matched controls. Indeed, noradrenergic nerves which regulate vascular tone also participate in the functional component of bladder outlet obstruction due to BPH. Newer, less invasive therapies for BPH such as thermal therapy can relieve symptoms yet do not eliminate obstruction based on urodynamic studies. Coincidentally, drugs such as [alpha]-adrenoceptor antagonists, which have been thought to relieve obstruction due to a peripheral effect, can be given intrathecally in animals to relieve urinary frequency due to obstruction. Taken together these observations implicate both peripheral and central sympathetic pathways in the motor control of the urinary bladder especially with disease states.We have used the hypertensive and behaviourally hyperactive spontaneously hypertensive rat (SHR), to investigate the roles sympathetic pathways or micturition. Elevated nerve growth factor (NGF) derived from vascular and bladder smooth muscle cells of the SHR appears to direct morphological, biochemical, and functional changes. The increase in NGF can apparently be explained by stabilization of its mRNA leading to increased synthesis of NGF. Bladders from SHRs develop a profuse noradrenergic hyperinnervation compared with the control WKY strain. Since afferents supplying the SHR bladder are hypertrophied, changes in afferent pathways are also likely.These differences in innervation and NGF in the SHR may explain changes in function. SHRs void 3 times as frequently as their genetic controls. Urinary frequency can be reduced by [alpha]-adrenoceptor antagonists. Cystometrograms performed in SHRs reveal lower bladder capacities and micturition volumes and the presence of unstable contractions compared with the WKY rat. Intrathecal, rather than intra-arterial administration of the [alpha]-adrenoceptor antagonist doxazosin reduces unstable contractions in the SHR. In vitro muscle bath studies have shown enhanced responses of SHR bladder smooth muscle to [alpha]-adrenoceptor agonists.It is likely that upregulation of NGF production causes sensory and possibly noradrenergic pathways to elicit hyperactive voiding. Increase in NGF in the adult bladder due to pathological conditions yields similar, yet distinct, consequences for voiding behaviour and innervation. Likewise, increased NGF in adult bladders following obstruction or inflammation triggers neuronal hypertrophy, enhanced reflex activity and urinary frequency. In contrast to the SHR, hyper-innervation is not observed. Moreover, peripheral or spinal [alpha]-adrenoceptor blockade eliminates urinary frequency following obstruction. These observations support the role for sympathetic pathways in the motor function of the bladder, especially in congenital or adult disease states. A similar process may underlie the neuroplasticity involved in alterations after obstruction or inflammation of the lower urinary tract in humans. The SHR strain raises the possibility that a common genetic defect exists capable of predisposing to both hypertension and overactivity of the urinary bladder. Whether a genetic predisposition to sustained bladder overactivity in response to inflammatory stimuli in obstruction exists in humans is an intriguing prospect.
Neuromodulation of the lower urinary tract
- Michael Craggs, Jonathon McFarlane
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- 03 January 2001, pp. 149-160
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The urinary bladder has only two functions, to store urine and to eliminate it from the body at socially convenient times. These functions depend on total integrity of the nervous system from brain to bladder. Many different neurotransmitter pathways are involved, modulating proper voluntary control over the reciprocal relationship between the storage function of the bladder and the outlet sphincters of the urethra. When voluntary control is lost or disrupted through neurological disease or damage then aberrant reflexes can take over resulting in incontinence. Such reflexes often involve the loss of those inhibitory mechanisms which normally suppress bladder contractions during the filling phase or sphincter contractions during the emptying phase. Treatment of incontinence by applied neuromodulation probably utilizes residual reflex pathways by which electrical stimulation can inhibit unwanted detrusor contractions or suppress the overactive urethral sphincter. With improvements in our understanding of the pathophysiology of voiding dysfunction, better diagnosis and the latest technical advances, for example, combining neuromodulation for detrusor hyper-reflexia with sacral anterior root stimulation for emptying the paralysed bladder (Brindley, 1988), we might hope to develop a new generation of implantable devices for treating people with incontinence (Craggs, 1997).There are still many gaps in our knowledge of neuromodulation of the lower urinary tract, for example we know little about the cerebral control of micturition in man. Such knowledge may be important for a better understanding of the many conditions we currently label 'idiopathic'. Future opportunities offered by functional magnetic resonance imaging and spectroscopy may help us to identify pathways and neurotransmitters in the brain of humans to complement the latest animal studies using transneuronal virus tracing to identify central micturition pathways.
Bladder instability and detrusor smooth muscle function
- C. H. Fry, C. Wu, A. R. Mundy
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- 03 January 2001, pp. 161-169
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Bladder, or detrusor, instability is a symptomatic condition which is characterized by uncontrollable rises in pressure within the bladder lumen leading to a feeling of urgency of micturition and, if severe enough, urinary incontinence. The rises in pressure are brought about by contraction of the detrusor smooth muscle which forms the major tissue component of the urinary bladder wall. This abnormality can be associated with a number of clinical conditions and when there is evidence of associated neurological deficits it is termed detrusor hyper-reflexia. An increase in bladder outflow resistance is also associated with detrusor instability and this is especially prevalent in men due to the age-related hypertrophy of the prostate gland which surrounds the urethra. However, in the majority of cases the cause is idiopathic and probably multifactorial. No matter what the cause, detrusor instability is one the largest causes of morbidity in the community; in the UK its prevalence increases from about 2 % in men and 9 % in women aged 15-64 years to 7 % and 12 %, respectively, in the over 65 years age group (Thomas et al. 1980; Brocklehurst, 1993).
Metabolic factors influencing lower urinary tract function
- Robert M. Levin, Niels Haugaard, Joseph A. Hypolite, Alan J. Wein, Ralph Buttyan
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- 03 January 2001, pp. 171-194
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The urinary bladder is a smooth muscle organ the function of which is to collect and store urine at low intravesical pressures, and then periodically to expel urine via a highly co-ordinated sustained contraction (Levin et al. 1990a; Anderson, 1993; Steers, 1994; Zderic et al. 1996a). The urethra functions to maintain continence during bladder filling, and then to provide a low-resistance pathway during micturition. The control of lower urinary tract function is through the autonomic nervous system. During bladder filling, the sympathetic nervous system is active and this produces an increase in tension of the bladder base and urethra via activation of a-adrenergic receptors, and relaxation of the bladder body via activation of ß-adrenergic receptors. In addition, sympathetic activity inhibits parasympathetic ganglionic transmission via postsynaptic sympathetic fibres which act upon a2-type receptors located in the ganglia. Micturition is mediated via the co-ordinated parasympathetic activation of cholinergic muscarinic receptors of the bladder body with the simultaneous inhibition of [alpha]-adrenergic tone of the bladder neck and urethra (Steers, 1994; Zderic et al. 1996a). Active urethral relaxation mediated by nitric oxide may also play a role during micturition (Anderson, 1993; Steers, 1994; Zderic et al. 1996a).
Advances in the pharmacological control of the bladder
- Karl-Erik Andersson
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- 03 January 2001, pp. 195-213
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To effectively control bladder activity, and to treat urinary incontinence caused by bladder overactivity, identification of suitable targets for pharmacological intervention is necessary. Such targets may be found in the central nervous system (CNS) or peripherally. The causes of bladder overactivity are not known, but theoretically increased afferent activity, decreased inhibitory control in the CNS and/or peripheral ganglia, and increased sensitivity of the detrusor to efferent stimulation may be involved. Several CNS transmitters may modulate voiding, but few drugs with a defined CNS site of action have been developed for treatment of voiding disorders. Potentially, drugs affecting GABA, opioid, 5-HT, noradrenaline, dopamine, or glutamatergic receptors and mechanisms can be developed, but a selective action on the lower urinary tract may be difficult to obtain. Traditionally, drugs used for treatment of bladder overactivity have had a peripheral site of action, mainly the efferent neurotransmission or the detrusor muscle itself. Antimuscarinic drugs, β-adrenoceptor agonists, α-adrenoceptor antagonists, drugs affecting membrane channels, prostaglandin synthetase inhibitors and several other agents have been used. However, none of them has been developed specifically for treatment of bladder disorders, and their efficacy, as judged from controlled clinical trials (where performed), is often limited. Recent information on the α-adrenoceptor, β-adrenoceptor (β3), and muscarinic receptor subtypes of the human detrusor and outflow region can be the basis for the development of compounds with effect on bladder overactivity and with improved tolerance. New ways of decreasing acetylcholine release may represent a promising way of controlling bladder contraction. Potassium channel (KATP) openers are theoretically attractive, but the drugs available so far have targeted vascular rather than bladder smooth muscle, which has limited their clinical use. However, new drugs belonging to these groups with an interesting profile of action have been developed. Drugs decreasing afferent activity represent an attractive therapeutic approach and transmitters of afferent nerves and their receptors are possible targets for pharmacological interventions. Tachykinins, such as substance P, neurokinins A and B, and other neuropeptides have been demonstrated in nerves of the lower urinary tract and have been shown to influence bladder function. Agents affecting these nerves by causing release of tachykinins, such as capsaicin and resiniferatoxin, given intravesically can be effective in some cases of bladder overactivity, and agents antagonizing tachykinin receptors may also be of therapeutic interest.New drugs specifically directed for control of bladder activity are under development and will hopefully lead to improved treatment of urinary incontinence.This study was supported by the Swedish Medical Research Council (grant no. 6837).
The physiology of the mammalian urinary outflow tract
- Alison F. Brading
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- Published online by Cambridge University Press:
- 03 January 2001, pp. 215-221
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Urinary outflow from the mammalian bladder occurs through the urethra. This outflow tract is a complicated structure composed of striated and smooth muscle and vascular urothelium. It is controlled by somatic and autonomic nerves and has several functions: it generates sustained tone to prevent urinary leakage during bladder filling; it generates transient reflex increases in pressure to prevent opening of the lumen when abdominal pressure rises; it undergoes relaxation preceding micturition and can generate urethral opening and shortening during micturition. A urethral pressure profile shows a peak pressure of [greater than or equal to] 100 cmH2O. The outermost coat is striated muscle, the striated or external sphincter. The fibres are predominantly circularly oriented. The extent varies in different species and between sexes. In the human female it extends the length of the urethra, and is composed mainly of slow twitch fibres. In the male, the sphincter extends from the membranous urethra over the base of the prostate and has nearly equal numbers of slow and fast twitch fibres. In both sexes, the posterior border may be deficient in striated muscle, and filled by circularly oriented smooth muscle. Activity in the slow twitch fibres through somatic nerves may be continuous during bladder filling. Outer circular and inner longitudinal smooth muscle is present Strips from either layer will generate sustained tone particularly if dissected from the high pressure zone. This tone is myogenic, and may be achieved in the absence of action potentials, but relies on influx of calcium through L-type calcium channels. Both layers receive sympathetic and parasympathetic excitatory innervation and nitrergic inhibitory innervation. Normal urethral pressure requires blood flow to the urothelium (lamina propria). Striated and smooth muscles are both thought to contribute to the resting urethral pressure in the human. The precise role of the smooth muscles during micturition is as yet unresolved.
Rapid Communication
Volumetric change of the lateral ventricles in the human brain following glucose loading
- B. K. Puri, H. J. Lewis, N. Saeed, N. J. Davey
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- Published online by Cambridge University Press:
- 03 January 2001, pp. 223-226
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Lateral ventricular volumes were monitored and quantified using accurately registered magnetic resonance images (MRIs) in six healthy individuals 30 min before and up to 4 h after ingestion of a glucose drink. The volume of the lateral ventricles increased by an average (± S.E.M.) of 2Σ4 ± 0Σ4 % as blood glucose levels rose from 4Σ8 ± 0Σ2 mmol l-1 to 8Σ4 ± 0Σ4 mmol l-1. This was followed by a peak decrease of 5Σ99 ± 3Σ3 % below initial fasting volumes as blood glucose levels fell to 5Σ0 ± 0Σ3 mmol l-1. We suggest that the secondary volume decrease demonstrates a homeostatic process of brain volume regulation for which the mechanism remains uncertain.
Book Review
Glandular Mechanisms of Salivary Secretion
- Maynard Case
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- 03 January 2001, pp. 227-228
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Glandular Mechanisms of Salivary Secretion. Edited by J. R. Garrett, J. Ekström and L. C. Anderson. Pp. 226. Karger, Basle, 1998. $167.00 hardback. ISBN 3 8055 6630 1.