Brain Research 882 2000 36–44 www.elsevier.com locate bres
Research report
Role of spinal a -adrenergic mechanisms in the control of lower
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urinary tract in the rat
a,b,c , a,d
a
Mitsuharu Yoshiyama , Takao Yamamoto
, William C. de Groat
a
Department of Pharmacology , University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
b
Department of Neurology , Chiba-Higashi National Hospital, 673 Nitona-cho, Chuo-ku, Chiba 260-8712, Japan
c
Department of Neurology , Chiba University School of Medicine, Chiba 260-8670, Japan
d
Medicinal Biology Research Laboratories , Fujisawa Pharmaceutical Co., Ltd., Osaka 532-8514, Japan
Accepted 5 July 2000
Abstract
The role of spinal a -adrenergic mechanisms in the control of urinary bladder function was examined in urethane 1.2 g kg s.c.
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anesthetized and decerebrate unanesthetized female Sprague–Dawley rats 250–320 g. Bladder activity was recorded via a transurethral catheter during continuous infusion 0.21 ml min cystometrograms or under isovolumetric conditions. All drugs were administered
intrathecally at the L -S segmental level of spinal cord. During cystometrograms, 3 or 30 nmol of phenylephrine a -adrenergic agonist
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did not alter bladder activity; whereas 300 nmol increased the intercontraction interval by 98 and pressure threshold for inducing micturition by 115, but did not change bladder contraction amplitude. A large dose of phenylephrine 3000 nmol completely blocked
reflex voiding and induced overflow incontinence at a high baseline pressure mean: 33 cmH O; range: 28–42 cmH O. Under
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isovolumetric conditions, 3–30 nmol of phenylephrine abolished bladder activity for 22–45 min; whereas smaller doses 0.003–0.3 nmol were inactive. Doxazosin 50 nmol, an a -adrenergic antagonist, decreased intercontraction intervals but did not change bladder
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contraction amplitude during cystometrograms. Under isovolumetric conditions this dose of doxazosin increased bladder contraction frequency and decreased bladder contraction amplitude. Smaller doses 5 or 25 nmol of doxazosin did not alter bladder activity. These
studies suggest that two types of spinal a -adrenergic mechanisms are involved in reflex bladder activity: 1 inhibitory control of the
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frequency of voiding reflexes presumably by regulating afferent processing in the spinal cord and 2 facilitatory modulation of the descending limb of the micturition reflex pathway.
2000 Elsevier Science B.V. All rights reserved.
Theme : Endocrine and autonomic regulation
Topic : Urogenital regulation
Keywords : a -Adrenoceptor; Afferent pathway; Efferent pathway; Locus coeruleus; Spinal cord; Urinary bladder
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1. Introduction bulbospinal noradrenergic pathways with 6-hydroxy-dopa-
mine did not depress voiding [14,20,21]; however, studies Interest in the role of central noradrenergic pathways in
in anesthetized cats, revealed that electrical stimulation of the control of micturition was stimulated by the report of
the LC induced bladder contractions that were blocked by ¨
Dahlstrom and Fuxe [1] that sympathetic and parasympa- the intrathecal i.t. injection of prazosin, an a -adrenergic
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thetic nuclei in the lumbosacral cord receive inputs from antagonist [26,27]. In addition, destruction of noradrener-
noradrenergic neurons in the brainstem. A significant gic cells in the LC by microinjection of 6-hydroxy-dopa-
proportion of these inputs arise in the locus coeruleus LC mine produced a hypoactive bladder, and this effect was
[1,14,20,21,23], which has been implicated in the supraspi- partially reversed by the i.t. injection of phenylephrine an
nal control of micturition [3,26,27]. In rats, destruction of a
-adrenergic agonist suggesting that bulbospinal norad-
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renergic pathways are involved in the micturition reflex. It is noteworthy, however, that iontophoretic application of
Corresponding author. Tel.: 181-43-261-5171; fax: 181-43-268-
norepinephrine to bladder preganglionic neurons PGNs
2613. E-mail address
: pxn15164nifty.ne.jp M. Yoshiyama.
did not excite but rather inhibited synaptic and amino acid
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 6 8 8 - 3
M . Yoshiyama et al. Brain Research 882 2000 36 –44
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evoked firing [18]. This finding is consistent with the i.t. catheter was inserted according to the technique of
electrophysiological data indicating that the descending Yaksh and Rudy [24]. The occipital crest of the skull was
noradrenergic excitatory pathway from the LC terminates exposed and the atlanto-occipital membrane was incised at
on interneurons in the region of the sacral parasympathetic the midline using the tip of a 16-Gauge needle as a cutting
nucleus rather than PGNs and that the interneurons make edge. A catheter PE-10 was inserted through the slit and
excitatory synaptic contacts with the PGNs to complete the passed caudally to the L -level of the spinal cord. Artificial
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descending pathway [28]. Iontophoretic application of cerebrospinal fluid CSF 7.5 ml was injected as a flush
prazosin blocked the excitatory effect of LC stimulation on following each drug administration volumes ranging from
interneurons but did not block the excitation of PGNs. In 1 to 5 ml. At the end of the experiment a laminectomy
contrast to these results in anesthetized cats, experiments was performed to verify the location of the catheter tip.
in conscious cats did not reveal an inhibitory effect of i.t. Decerebrations were performed according to published
prazosin on voiding [6]. However, 6-hydroxy-dopamine methods [19] which included ligating both carotid arteries
treatment did increase bladder capacity. followed by a precollicular decerebration using a blunt
Pharmacological studies in rats have also used adren- spatula under halothane anesthesia. Cotton and Avitene
ergic drugs to determine the function of bulbospinal MedChem Products Inc., Woburn, MA, USA were placed
noradrenergic pathways in the regulation of micturition in the intracranial cavity and covered with agar. Experi-
[4,25]. Kontani et al. [12] reported that in anesthetized rats, ments were started 2–4 h after the decerebration.
i.t. administration of phenylephrine abolished bladder A transurethral bladder catheter connected to a pressure
activity; whereas prazosin did not alter bladder contrac- transducer was used to record the bladder pressure iso-
tions during
continuous infusion
cystometrograms volumetrically with the urethral outlet ligated or to record
CMGs. On the other hand, Ishizuka et al. [10] noted that pressure during a CMG when the bladder was filled with a
i.t. administration of doxazosin, an a -adrenergic antago- constant infusion of physiological saline and allowed to
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nist, blocked micturition in unanesthetized rats. Thus, there empty around the catheter. Continuous CMGs were per-
is evidence for both excitatory and inhibitory adrenergic formed by a constant infusion 0.21 ml min of saline into
mechanisms in the control of micturition, as well as a the bladder to elicit repetitive voidings, which allowed
considerable variation between different studies in the rapid collection of data for a large number of voiding
effects of adrenergic agonists and antagonists on reflex cycles [15]. PE-90 and PE-50 cannulae were used for
bladder activity. Some of this variation might be due to the isovolumetric recording and constant infusion CMGs,
differences between the species, anesthesia and methods. respectively. For isovolumetric recording, the ureters were
In the present studies, the involvement of spinal a - tied distally, cut and the proximal ends cannulated PE-10
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adrenergic pathways in the regulation of micturition was and drained externally. This procedure prevented the
examined in anesthetized and decerebrate unanesthetized bladder from filling with urine during the experiment. The
rats by studying the effects of drugs administered in- effects of drugs obtained during continuous infusion
trathecally on reflex bladder contractions recorded under CMGs could reflect changes in the activity of the urethral
isovolumetric conditions or during continuous infusion sphincter i.e. both internal and external as well as the
CMGs. Our results revealed two types of spinal a -adren- bladder. For example, a decrease in amplitude of bladder
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ergic mechanisms involved in reflex bladder activity: 1 contractions during voiding could be produced by a
inhibitory control of the frequency of reflex bladder reduction of detrusor muscle contraction and or a decrease
contractions, presumably due to modulation of afferent in urethral outlet resistance. Similarly, an increase in the
processing in the spinal cord and 2 excitatory modulation intercontraction interval ICI, interval between two voiding
of the amplitude of bladder contractions, presumably due cycles [15] might be due to an increase in bladder
to regulation of the descending limb of the spinobulbospi- capacity and or improvement of voiding efficiency. Thus,
nal bladder reflex pathway. the continuous CMG method is useful for examining drug
A preliminary account of this work has been presented effects on voiding, but it can not always distinguish
in abstract form [5,30]. between effects on bladder and urethral outlet. On the
other hand, any changes in bladder activity recorded under isovolumetric conditions must be attributed to direct
2. Materials and methods effects on the bladder or changes in neural pathways
