Biomedical subjects

J W Downie

Publications and source records attributed to J W Downie.

At least 19 recordsLinked to original sources

PubMed2006

Parabrachial nucleus influences the control of normal urinary bladder function and the response to bladder irritation in rats.

The contribution of the parabrachial nucleus to the mediation of bladder contraction was examined in the rat. Constant infusion (0.1 ml/min) of saline or 0.2% acetic acid evoked normal or abnormal bladder contractions, respectively. Single unit activity was recorded in the parabrachial nucleus with tungsten microelectrodes. Seven units with activity that was correlated with bladder contraction during saline infusion were located in the lateral subnuclei and three units were located in the medial subnuclei of the parabrachial nucleus. Twelve units with activity that was correlated with abnormal bladder contractions were found widely distributed in the parabrachial nucleus. An inverse correlation of activity to normal or abnormal bladder contractions was identified in 11 units in the parabrachial nucleus. Pressure injection of 5 mM CoCl(2) into the parabrachial nucleus was used to block synaptic transmission unilaterally. Normal bladder contractions evoked by saline infusion were disrupted by 5 of 10 injections, 4 of them in the medial subnuclei of the parabrachial nucleus and one in the lateral subnuclei. Abnormal bladder contractions were converted to a normal pattern in nine experiments where CoCl(2) injections lay in the lateral subnuclei of the parabrachial nucleus. In five experiments, CoCl(2) disrupted abnormal bladder contractions; four effective sites were located in the lateral subnucleus and one lay in the medial subnucleus of the parabrachial nucleus. These data demonstrated that single units responding to both normal and abnormal contractions were located throughout the parabrachial nuclei whereas the lateral subnuclei play a predominant role in mediation of abnormal bladder contractions and the medial subnuclei play a predominant role in the mediation of normal bladder contractions.

Action Potentials↗

PubMed2000

Effect of anesthetics on reflex micturition in the chronic cannula-implanted rat.

It is well known that urethane is a suitable anesthetic for acute studies and has been extensively recommended for investigations related to micturition physiology. This is mainly because of the capability of urethane anesthesia to spare reflex micturition as well as its easily established long-lasting and stable anesthetic level. However, urethane anesthesia is usually restricted to acute experiments due to its potential toxicity. This study searched for an alternative to urethane that would be suitable for studies in which recovery from anesthesia was needed. The list of administered drugs was as follows: pentobarbital, thiobutabarbital, ketamine-acepromazine, ketamine-diazepam, tiletamine-zolazepam, fentanyl-droperidol, alphaxalone-alphadolone, propofol, isoflurane, methoxyflurane, azaperone, tribromoethanol, and buprenorphine. Among these drugs, only tiletamine-zolazepam spared the reflex micturition contractions. However, the duration of this anesthesia was too short (approximately 30 minutes) to complete the necessary testing and additional dosing of the anesthetic generally obliterated the micturition reflex. On the other hand, rats given i.v. urethane infusion (10% solution in 0.9% saline, 3.2-4.0 mg/kg/min, total dose 0.56-1.03 g/kg) maintained a stable anesthesia that permitted both reflex micturition and stereotaxic procedures. Rats moved spontaneously 3-16 hours after cessation of i.v. urethane anesthesia and completely recovered in 2 days without significant after-effects. Bladder function was normal. No pathological changes were seen 1 week later. The present results suggest that urethane is the most suitable anesthetic for acute and chronic physiological experiments that require demonstration of reflex micturition. Neurourol. Urodynam. 19:87-99, 2000.

Anesthesia↗

PubMed2000

Micturition evoked by glutamate microinjection in the ventrolateral periaqueductal gray is mediated through Barrington's nucleus in the rat.

Neural tracing experiments have demonstrated a direct spinal projection to Barrington's nucleus and a possible indirect pathway to Barrington's nucleus via the periaqueductal gray. We sought to identify the role of the periaqueductal gray matter in micturition in urethane-anesthetized rats. Blockade of micturition by focal injection of cobalt chloride was used to identify sites critical to micturition. These sites were located near the ventral margin of the caudal ventrolateral periaqueductal gray and in Barrington's nucleus. L-Glutamate injections into caudal regions of the periaqueductal gray evoked bladder contraction with coordinated sphincter activation. Additional L-glutamate sites with a similar pattern of response and sites where sphincter activation was produced without bladder contraction were found more rostrally and dorsally in the periaqueductal gray. Activation of bladder contractions by L-glutamate injection in the ventrolateral periaqueductal gray was blocked by prior injection of cobalt chloride into Barrington's nucleus. From these data we propose that ventrolateral periaqueductal gray is functionally important to micturition in the urethane-anesthetized rat. Further, we have shown that a periaqueductal gray to Barrington's nucleus pathway is functionally relevant to central mediation of bladder contraction.

Animals↗

PubMed2000

Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene.

PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogenesis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells. PEA3(-/-) mice arose from heterozygous crosses with the expected Mendelian frequency, revealing that PEA3 is dispensable for embryogenesis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce. PEA3 is expressed in several male sexual organs, but gross and histological analyses of the organs from PEA3(-/-) mice revealed no abnormalities. Spermatogenesis and spermiogenesis also appeared normal in mice homozygous for the PEA3 mutation, and their sperm were capable of fertilizing eggs in vitro. PEA3(-/-) males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine. Therefore, the infertility of PEA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction. However, PEA3 mutant mice are phenotypically distinguishable from other knockout mice with such deficits and thus provide a unique model for further investigation of male sexual dysfunction.

Acetylcholine↗

PubMed1999

Transmission of afferent information from urinary bladder, urethra and perineum to periaqueductal gray of cat.

The micturition reflex pathway is a supraspinal pathway. Anatomical tracing evidence is compatible with an involvement of the periaqueductal gray (PAG) in the ascending limb of this reflex. We tested the involvement of the PAG in receiving urinary tract- or perineum-related information and attempted to characterize this ascending path in terms of what type of information is being conveyed. Electrical stimulation of the pelvic nerves, which carry afferent information from the urinary bladder, evoked maximum field potentials in the caudal third of the PAG, primarily in the dorsal part of the lateral PAG and in the ventrolateral PAG. Since the regions activated by pelvic nerve stimulation differed from those activated by stimulation of the sensory pudendal or superficial perineal nerves, it is possible that specific pathways for different nerve inputs to the PAG exist. Sacral spinal cord neurons ascending to the PAG were identified by antidromic activation and then tested for inputs from pelvic, sensory pudendal or superficial perineal nerves. Of 18 units identified, only five received inputs from any of the peripheral nerves tested and only two projecting neurons received a pelvic nerve input. Thus the PAG may receive inputs from bladder and perineum, but the small proportion of cells with direct projections to the PAG receiving inputs from our test nerves implies that the major part of this pathway is not directly related to lower urinary tract function.

Afferent Pathways↗

PubMed1999

Sacral spinal cord neurons responsive to bladder pelvic and perineal inputs in cats.

In chloralose-anesthetized or decerebrate male cats, 70% of 73 sacral spinal cord neurons activated from the bladder branch of the pelvic nerve also received excitatory inputs from urethra and/or perineal cutaneous nerves (sensory pudendal in 55% and superficial perineal in 84% of neurons). Only 29% of these neurons were excited by the hindlimb skin and muscle nerves tested. The pelvic nerve-responsive neurons received monosynaptic urethral/perineal input in 25% of cases and required temporal summation of this input in 47% of cases. Of 211 neurons responding to superficial perineal nerve stimulation, 101 were not excited by the other nerves tested. Neurons activated by superficial perineal nerve stimulation were found predominantly in S2. It is likely that the superficial perineal nerve represents an important pathway whereby perineal stimulation influences bladder function.

Animals↗

PubMed1998

Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats.

Serotonin (5-HT) may be inhibitory to micturition at a spinal level. A potential mechanism of action for serotonergic inhibition of bladder function is a depression of the ascending limb of the supraspinal reflex mediating micturition. Ascending activity evoked by pelvic nerve stimulation was recorded in the thoracic spinal cord of anesthetized cats. For comparison, spinal reflex activity evoked by pelvic nerve stimulation was recorded on the pudendal nerve. The effects of intrathecal administration of serotonergic agents were examined to determine whether spinal and supraspinal responses to bladder afferent activation were modulated by 5-HT. Methysergide (60 nmol), a non-selective serotonergic antagonist, increased ascending activity by 61+/-7% and depressed spinal reflex activity by 38+/-6%. Zatosetron (10 nmol), a 5-HT3 antagonist had a similar effect on both activities (increased by 93+/-24% and decreased by 77+/-7%, respectively). The effect on ascending activity of blocking 5-HT3 receptors was also confirmed with ICS 205930 and MDL 72222. 2-Methyl-5-HT (800 nmol), a 5-HT3 agonist, depressed ascending activity to 46+/-9% of control, but enhanced spinal reflex activity by 73+/-92%. These results demonstrate that stimulation of 5-HT3 and methysergide-sensitive 5-HT receptors can inhibit ascending activity and facilitate spinal reflex activity elicited by activation of bladder afferents. It is suggested that descending serotonergic pathways may participate in the spinal coordination of urinary continence.

Afferent Pathways↗

PubMed1998

Volume-evoked micturition reflex is mediated by the ventrolateral periaqueductal gray in anesthetized rats.

The central pathway of the micturition reflex in the rat was investigated functionally by acute blockade of synaptic neurotransmission using microinjection of cobalt chloride into the periaqueductal gray or pontine tegmental region. In 27 urethan-anesthetized (1.2 g/kg ip) rats, the bladder pressure response to continuous infusion of the bladder with saline (0.1-0.25 ml/min) was assessed. Electromyographic activity of external urethral sphincter and arterial blood pressure were also monitored. Bladder contractions and external urethral sphincter activity were reversibly attenuated after unilateral or bilateral stereotaxic injections of 10 mM cobalt chloride into the caudal (bregma -7.80 to -8.80) ventrolateral periaqueductal gray as well as into Barrington's nucleus. Blood pressure was not affected by injection into either area. The results demonstrate that the caudal ventrolateral periaqueductal gray, in addition to Barrington's nucleus, is a critical part of the long-routed micturition reflex circuitry in the anesthetized rat.

Animals↗

PubMed1995

Serotonergic modulation of cat bladder function before and after spinal transection.

Micturition was evoked in conscious cats by infusing saline into the bladder at a physiological rate. Drugs were administered intrathecally. Micturition volume threshold was increased by 5-hydroxytryptamine (5-HT, serotonin) and decreased by zatosetron, a 5-HT3 receptor antagonist, in spinally intact cats. Thus 5-HT3 receptors inhibit micturition. After complete spinal transection, serotonin reduced volume threshold in 3 of 4 cats, indicating an alteration in serotonergic control. However, 2-methyl-5-HT, a 5-HT3 receptor agonist, increased volume threshold. Thus 5-HT3 receptor-mediated inhibition of bladder function remains after spinal transection. We conclude that some, but not all, serotonergic modulation of bladder function is altered after spinal transection.

Animals↗

PubMed1994

Statistical evaluation of the function of the 1992 International Continence Society Scientific Committee.

Papers submitted to the International Continence Society are read by the six members of the scientific committee, who assign three scores to each paper, one for its originality, one for its scientific value, and one for its academic or clinical interest. Following discussion at the scientific committee meeting, a program is made from the abstracts with the highest scores. In this study statistical properties of the assigned score values for the 1992 ICS meeting are discussed. It is concluded that the three scores do not measure independent properties of the abstracts, that different abstract types (for instance "clinical" and "basic" papers) are scored differently by the different committee members, that there is a significant consensus among the committee members, that the scientific committee meeting has a relatively small effect on the scores, and that different abstract types are not equally represented in the final program.

Congresses as Topic↗

PubMed1994

Reduction of perineal evoked excitatory postsynaptic potentials in cat lumbar and sacral motoneurons during micturition.

These experiments were undertaken to examine whether both premotoneuronal mechanisms and direct actions on motoneurons could contribute to suppression of excitatory perineal reflex pathways during micturition. Intracellular recordings were obtained from motoneurons innervating the external urethral sphincter (EUS), external anal sphincter (EAS), and selected hindlimb muscles in decerebrate male cats. The peak amplitudes of EPSPs evoked by electrical stimulation of peripheral cutaneous afferents were measured during micturition. In the EUS, EAS, and hindlimb motoneurons examined, EPSPs produced by stimulation of perineal afferents (superficial perineal or sensory pudendal nerves) were reduced in amplitude during micturition. The sample of PSPs evoked by stimulation of hindlimb cutaneous nerves recorded in hindlimb motoneurons revealed that these PSPs could also be reduced. In contrast, no changes were seen in monosynaptic EPSPs evoked by muscle afferent stimulation. The present study demonstrates that during micturition there is a strong suppression of perineal reflexes to both sphincter and hindlimb motoneurons. Since reduced EUS activity is required for efficient micturition, suppression of the strong excitatory perineal input to EUS motoneurons likely contributes to decreased EUS activity during the bladder contraction. It appears that the micturition circuitry utilizes both premotoneuronal mechanisms and direct motoneuronal inhibition to achieve this reflex suppression. The function of the micturition-related reduction of perineal reflexes to hindlimb or EAS motoneurons is not known at this time and further investigations are required to elucidate the interaction between micturition circuitry and hindlimb cutaneous pathways.

Afferent Pathways↗

PubMed1993

ATP release from dorsal spinal cord synaptosomes: characterization and neuronal origin.

The present study determined the Ca(2+)-dependence of the release of adenosine 5'-triphosphate (ATP) from dorsal spinal cord synaptosomes evoked by depolarization with K+ and capsaicin, and the effect of intrathecal capsaicin pretreatment, dorsal rhizotomy and intrathecal pretreatment with 6-hydroxydopamine on such release. Release of ATP evoked by K+ was Ca(2+)-dependent, while that evoked by capsaicin was Ca(2+)-independent. Capsaicin pretreatment (60 micrograms, 7 days), which lesions small diameter afferents, did not alter release of ATP evoked by either K+ or capsaicin. Dorsal rhizotomy, which lesions all afferents, produced a significant reduction in the amount of ATP released from the rhizotomized side compared to the intact side. Pretreatment with 6-hydroxydopamine (100 micrograms, 7 days) to destroy adrenergic nerve terminals, markedly reduced spinal cord noradrenaline levels, but did not alter the K(+)-evoked release of ATP. These results suggest that some K(+)-evoked release of ATP could originate from large but not small diameter afferent nerve terminals in the spinal cord. ATP does not appear to originate from small diameter afferents as, although ATP is released by in vitro exposure to capsaicin, such release occurs only at high concentrations, release is Ca(2+)-independent and it is unaltered by pretreatment with capsaicin. The bulk of the ATP released from the spinal cord does not originate from descending noradrenergic nerve terminals.

Adenosine Triphosphate↗

PubMed1993

The pathophysiology of contractile activity in the chronic decentralized feline bladder.

Autonomous wave activity occurs in the decentralized bladder and may contribute to upper tract damage and incontinence. In order to clarify the poorly understood pathophysiology and neuropharmacology of autonomous waves, cats were prepared with L7-S3 ventrodorsal rhizotomy alone or with L7-S3 ventral rhizotomy with and without total sympathectomy. The incidence of autonomous waves was < 15% 12 weeks after ventral or ventrodorsal rhizotomy, but acute sympathectomy at 13 weeks increased the incidence to 58% in these groups. With chronic sympathectomy the incidence was 100%. This suggests that the waves arise locally via a mechanism which is independent of L7-S3 dorsal roots, due to lack of a suppressive sympathetic pathway. Autonomous waves were inhibited by atropine after acute sympathectomy and by prazosin after chronic sympathectomy, but increased inhibition occurred after both drugs in either case. Adrenergic neuron depletion with 6-hydroxydopamine enhanced wave activity, which was incompletely inhibited by subsequent atropine. This implies that the peripheral reflex pathway has facilitatory alpha 1-adrenergic, muscarinic and also noncholinergic nonadrenergic elements. Clinically, sensory or sympathetic damage caused incontinence, but sympathectomy also caused high pressure waves, which may cause upper tract damage and treatment resistant incontinence in patients.

Adrenergic Fibers↗

PubMed1993

Control of detrusor stiffness in the chronic decentralized feline bladder.

The neuropharmacology of increased bladder stiffness, which may contribute to upper tract damage and incontinence, was investigated in 76 cats. beta-blockade increased but combined alpha 1-adrenergic with muscarinic blockade decreased filling phase stiffness in normal cats. Bladder wall stiffness during the early filling phase was unaffected by chronic S2 ventrodorsal rhizotomy or L7-S3 ventral rhizotomy, but was decreased when L7-S3 dorsal rhizotomy or total sympathectomy was combined with the ventral root lesion, implying that sacral dorsal roots and sympathetic efferents maintain normal detrusor stiffness. Acute sympathectomy increased stiffness in all the former 3 chronic groups, implying that a tonic or reflex sympathetic inhibition operates independently of the L7-S3 dorsal roots. Stiffness during early filling phase decreased with acute ventral rhizotomy. This change persisted with chronic sympathectomy but returned to normal if sympathetic nerves were left intact. These results suggest that bladder stiffness is modulated by tonic or reflexic sympathetic activity, which is influenced by L7-S3 afferents. Detrusor stiffness during the later stages of filling, which was decreased by acute sympathectomy in chronic groups but increased by chronic sympathectomy, was reduced by interference with adrenergic or muscarinic mechanisms after either lesion. Therefore, a peripheral pathway with facilitatory alpha 1-adrenergic and muscarinic receptors is involved in the production of increased late stage stiffness after chronic sympathetic damage. We propose that the increased bladder stiffness seen in congenital sacral lesions may be analogous to the stiffness during late stages of filling reported here. Our results also imply that the presence of this increased stiffness is closely associated with chronic sympathetic damage. Whether the increased stiffness in congenital and traumatic neural lesions in humans arises from sympathetic damage remains to be determined.

Animals↗

PubMed1992

Effect of 5-HT receptor and adrenoceptor antagonists on micturition in conscious cats.

Micturition was induced in awake cats by infusing saline into the bladder at a physiological filling rate. Methysergide, a serotonergic antagonist given intrathecally, decreased the volume at which micturition occurred. Phentolamine, a non-specific alpha-adrenoceptor antagonist, also decreased volume threshold. Prazosin, an alpha 1-adrenoceptor antagonist, was without effect on micturition. These results imply that 5-HT receptors and alpha 2-adrenoceptors may be inhibitory to micturition at a spinal level.

Adrenergic alpha-Antagonists↗

PubMed1992

Spinal distribution of extracellular field potentials generated by electrical stimulation of pudendal and perineal afferents in the cat.

Electrical stimulation of sensory pudendal and superficial perineal nerves evokes focal synaptic potentials produced by activation of spinal neurons in the lumbosacral gray matter in chloralose anesthetized or decerebrate cats. The field potentials evoked by sensory pudendal nerve stimulation were located in medial parts of laminae V and VI, and lamina X in the S1 to S3 spinal segments. The superficial perineal cutaneous field potentials partially overlapped with those produced by the pudendal nerve, but in general were localized more laterally in laminae V and VI. The central latencies of the earliest portion of the field potentials evoked by either sensory pudendal or superficial perineal nerves were less than 0.9 ms suggesting that monosynaptic activation of neurons contributed to the potentials.

Afferent Pathways↗

PubMed1992

Mechanoreceptor afferent activity compared with receptor field dimensions and pressure changes in feline urinary bladder.

The relationship between vesical mechanoreceptor field dimensions and afferent nerve activity recorded in pelvic plexus nerve filaments was examined in chloralose-anesthetized cats. Orthogonal receptor field dimensions were monitored with piezoelectric ultrasonic crystals. Reflexly generated bladder contractile activity made measurements difficult, therefore data were collected from cats subjected to actual sacral rhizotomy. Afferent activity was episodic and was initiated at different pressure and receptor field dimension thresholds. Maximum afferent activity did not correlate with maximum volume or pressure. Furthermore, activity was not linearly related to intravesical pressure, receptor field dimensions, or calculated wall tension. Pressure-length hysteresis of the receptor fields occurred. The responses of identified afferent units and their associated receptor field dimensions to brief contractions elicited by the ganglion stimulant 1,1-dimethyl-4-phenylpiperazinium iodide (2.5-20 micrograms i.a.), studied under constant volume or constant pressure conditions, are compatible with bladder mechanoreceptors behaving as tension receptors. Because activity generated by bladder mechanoreceptors did not correlate in a simple fashion with intravesical pressure or receptor field dimensions, it is concluded that such receptors are influenced by the viscoelastic properties of the bladder wall. Furthermore, as a result of the heterogeneity of the bladder wall, receptor field tension appears to offer a more precise relationship with the activity of bladder wall mechanoreceptors than does intravesical pressure.

Animals↗

PubMed1991

Alpha 2-adrenoceptors not imidazole receptors mediate depression of a sacral spinal reflex in the cat.

In chloralose-anaesthesized cats, clonidine, an alpha 2-adrenoceptor agonist with an imidazole ring, depressed pudendal nerve reflex activity. Clonidine's inhibitory action on this compound action potential response was mimicked by guanabenz, a non-imidazole alpha 2-adrenoceptor agonist, and was reversed by SK & F 86466, a non-imidazole alpha 2-adrenoceptor antagonist. These results imply that clonidine's action on this reflex related to urinary sphincter function is mediated by alpha 2-adrenoceptors and is not dependent on an imidazole structure.

Action Potentials↗