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Am J Physiol Regul Integr Comp Physiol 280: R1414-R1419, 2001;
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Vol. 280, Issue 5, R1414-R1419, May 2001

Role of spinal alpha 1-adrenoceptor subtypes in the bladder reflex in anesthetized rats

Mitsuharu Yoshiyama1,2,3 and William C. De Groat1

1 Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261; 2 Department of Neurology, Chiba University Graduate School of Medicine, Chiba, 260 - 8670; and 3 Department of Neurology, Chiba-Higashi National Hospital, Chiba, 260 - 8712, Japan


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The contribution of different subtypes of alpha 1-adrenoceptors in the lumbosacral spinal cord to the control of the urinary bladder was examined in urethane-anesthetized rats. Bladder pressure was recorded via a transurethral catheter under isovolumetric conditions. Drugs were administered intrathecally at the L6-S1 segmental level of spinal cord. RS-100329 (an alpha 1A-antagonist) in doses of 25, 50, and 100 nmol significantly decreased bladder-contraction amplitude by 38%, 52%, and 95%, respectively, whereas (+)-cyclazosin (an alpha 1B-antagonist) significantly decreased bladder-contraction amplitude (48% reduction) only in a 50-nmol but not a 100-nmol dose. Fifty nanomoles of RS-100329 and (+)-cyclazosin increased bladder-contraction frequency by 54% and 44%, respectively. BMY7378 (an alpha 1D-antagonist), in doses of 25, 50, and 100 nmol, did not change bladder activity. These studies suggest that reflex-bladder activity is modulated by two types of spinal alpha 1-adrenergic mechanisms: 1) alpha 1A- or alpha 1B-inhibitory control of the frequency of voiding reflexes presumably mediated by an alteration in the processing of bladder afferent input and 2) alpha 1A-facilitatory modulation of the descending efferent limb of the micturition-reflex pathway. Spinal alpha 1D-adrenoceptors do not appear to have a significant role at either site.

afferents; descending efferents; locus ceruleus


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

MODULATION OF MICTURITION by central noradrenergic pathways has been a topic of interest because it was reported that sympathetic and parasympathetic nuclei in the lumbosacral cord receive inputs from noradrenergic neurons in the brain stem (2). A large part of this input arises from neurons in the locus ceruleus (LC) (2, 16, 18, 19, 25), which has been implicated in the supraspinal control of micturition (3, 29, 30). In anesthetized cats, electrical stimulation of the LC induced bladder contractions that were blocked by the intrathecal injection of prazosin, an alpha 1-adrenoceptor antagonist (29, 30). In addition, destruction of noradrenergic cells in the LC by microinjection of 6-hydroxydopamine, a toxin for catecholaminergic neurons, produced a hypoactive bladder, and this effect was partially reversed by the intrathecal injection of phenylephrine, an alpha 1-adrenoceptor agonist (30). On the basis of these studies, it was proposed that bulbospinal noradrenergic inputs to the sacral parasympathetic nucleus played an essential role in voiding function. Although these findings were not confirmed in conscious cats (5, 6), they indicated that under certain conditions, alpha 1-adrenergic mechanisms in the spinal cord could modulate voiding function. Studies in anesthetized (4, 35) and conscious (11) rats also support this conclusion.

Our previous studies in anesthetized rats revealed that reflex-bladder activity is modulated by two types of spinal alpha 1-adrenergic mechanisms: 1) inhibitory control of the frequency of reflex-bladder contractions presumably due to modulation of afferent processing in the spinal cord and 2) excitatory modulation of the amplitude of bladder contractions due to regulation of the descending glutamatergic limb of the spinobulbospinal bladder-reflex pathway (4, 35). These mechanisms could involve activation of three subtypes of alpha 1-adrenoceptors: alpha 1A, alpha 1B, and alpha 1D (10). This was examined in the present experiments by studying the effects on reflex-bladder activity of intrathecal administration of drugs that selectively block different subtypes of alpha 1-adrenoceptors.

A preliminary account of this work has been presented in an abstract (34).


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animal preparation. Experiments were performed on urethane-anesthetized (1.2 g/kg sc) female Sprague-Dawley rats weighing 250-300 g. The trachea was cannulated with a polyethylene tube (PE-240) to facilitate respiration, and an intrathecal catheter was inserted according to the technique of Yaksh and Rudy (28). The occipital crest of the skull was exposed and the atlanto-occipital membrane was incised at the midline using the tip of a 16-gauge needle as a cutting edge. A catheter (PE-10) filled with artificial cerebrospinal fluid (CSF) (7, 17) was inserted through the slit and passed caudally to the L6 level of the spinal cord. At the end of the experiment, a laminectomy was performed to verify the location of the catheter tip.

A transurethral bladder catheter (PE-90) connected to a pressure transducer was used to record the bladder pressure isovolumetrically with the urethral outlet ligated. The bladder was filled via the bladder catheter by incremental volumes of physiological saline until spontaneous bladder contractions occurred (total volume: 0.8-1.5 ml). For isovolumetric recording, the ureters were tied distally, cut, and the proximal ends cannulated (PE-10) and drained externally. This procedure prevented the bladder from filling with urine during the experiment.

The protocols in these studies were approved by the Animal Care and Use Committee of the University of Pittsburgh.

Drugs. Drugs used in these studies included urethane (ethyl carbamate, Sigma, St. Louis, MO), N-[(2-trifluoroethoxy)phenyl],N'-(3-thyminylpropyl)piperazine hydrochloride (RS-100329, Roche Bioscience, Palo Alto, CA) (12, 26), [4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-cis-octahydroquinoxalin-1-yl]furan-2-ylmethanone [(+)-cyclazosin, Roche Bioscience] (8, 12, 21), and 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY 7378 Research Biochemicals International, Natick, MA) (9). Urethane was dissolved in distilled water (0.5 g/ml solution). RS-100329 and (+)-cyclazosin were dissolved in 100% DMSO (20 mM solutions), and BMY 7378-HCl was dissolved in artificial CSF (10 and 100 mM solutions). Drug doses were calculated for the base of each compound. Drugs were administered in small volumes (<5 µl), and then the intrathecal catheter was flushed by artificial CSF (7.5 µl).

Multiple doses of drugs or vehicles starting with the smallest amounts were injected in each animal. Increasing amounts were administered after bladder contractions recovered to control. Injections were spaced at intervals of at least 30 min even when bladder activity was not altered.

Evaluation and statistical analysis. The effects of RS-100329, (+)-cyclazosin, and BMY 7378 were evaluated on the amplitude and frequency of reflex-bladder contractions recorded under isovolumetric conditions. The effects of vehicle solutions [100% DMSO for RS-100329 and (+)-cyclazosin and artificial CSF with pH adjusted to 1.6 or 4.0 for BMY 7378] were also examined. All values are expressed as means ± SE. For statistical data analysis, ANOVA and paired t-test were used to compare the values before and after drug administration. Two-way ANOVA and unpaired t-test were applied to compare the differences between the effects of drug and vehicle solution. For all statistical tests, P < 0.05 was considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals with implanted intrathecal catheters (n = 30) exhibited rhythmic bladder contractions (mean amplitude: 33 ± 2 cmH2O; range: 17-51 cmH2O) at a mean frequency of 0.84 ± 0.04 contractions/min (range: 0.43-1.34 contractions/min) under isovolumetric conditions when the bladder was filled with 0.8-1.5 ml of saline.

Effects of vehicles (100% DMSO or acidic CSF) on bladder activity. The vehicle for RS-100329 and (+)-cyclazosin (up to 5 µl of 100% DMSO followed by 7.5 µl artificial CSF injection) did not alter the frequency of bladder contractions, but a large volume of vehicle decreased the amplitude of bladder contractions (see Fig. 2). The volume of vehicle for 50- and 100-nmol doses reduced bladder-contraction amplitude by 4.1 ± 1.2% (n = 10) and by 30.1 ± 11.0% (n = 11), respectively. Therefore, two-way ANOVA (followed by unpaired t-test) was used to compare the dose-response curves for vehicle (100% DMSO) with the dose-response curves for RS-100329 or (+)-cyclazosin. The dose-response curves for BMY 7378 and its vehicle (artificial CSF adjusted to pH 1.6 or 4) were compared in the same manner, although the vehicle for BMY 7378 did not change bladder activity at any volume (n = 3-6).

Effects of RS-100329, (+)-cyclazosin, or BMY 7378 on bladder activity. RS-100329 in 25-, 50-, and 100-nmol doses decreased the amplitude of bladder contractions by 16-85% (average: 38 ± 9%), 18-100% (average: 52 ± 10%), and 84-100% (average: 95 ± 2%), respectively, whereas smaller doses of the drug (6.25 and 12.5 nmol) had no effect (Figs. 1 and 2A). The depressant effect occurred within 1 min after the administration of the drug and persisted for 7-53 min depending on the dose (25 nmol, average: 15 ± 2 min; 50 nmol, average: 18 ± 3 min; 100 nmol, average: 34 ± 4 min). RS-100329 in the 50-nmol dose significantly increased (average: 51 ± 14%, range: 4-131%) the frequency of bladder contractions; however, smaller doses (6.25, 12.5, and 25 nmol) and a larger dose (100 nmol) had no significant effect (Figs. 1 and 2B).


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  		Fig. 1.   The effects of RS-100329 (6.25, 25, and 50 nmol intrathecal) on bladder activity under isovolumetric conditions in a urethane-anesthetized rat. Note that the 25 and 50 nmol of the drug decreased the bladder-contraction amplitude and 50 nmol increased the bladder-contraction frequency, whereas the small dose (6.25 nmol) had no effect on bladder activity.



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  		Fig. 2.   Graphs showing the effects of intrathecal (it) administration of RS-100329 (n = 7-10), (+)-cyclazosin (n = 3-9), and vehicles (100% DMSO, n = 8-11) for these drugs on amplitude and frequency of bladder contractions under isovolumetric conditions in urethane-anesthetized rats. *P < 0.05, **P < 0.01 (comparison between vehicle and each drug by unpaired t-test following 2-way ANOVA). *Significant differences between measurements taken before and after each drug injection (by paired t-test).

The effects of (+)-cyclazosin were variable between animals and not dose dependent (Fig. 3). The 50-nmol dose significantly decreased the amplitude of bladder contractions (average: 45 ± 11%, range: 6-79%) and increased the bladder-contraction frequency (average: 57 ± 20%, range: 19-145%) for periods ranging from 5 to 14 min (average: 9 ± 1 min); whereas smaller and larger doses (25 and 100 nmol) had no significant effect (Fig. 2, A and B) compared with vehicle. However, it should be noted that there was considerable variation in the effect of the 100-nmol dose that in three experiments completely blocked bladder contractions and in three other experiments had minimal effects on bladder-contraction amplitude. Thus the effects of the 100-nmol dose of (+)-cyclazosin on bladder-contraction frequency could be evaluated in only three rats (Fig. 2B). In these animals, the drug produced 35% increase in frequency, which was not statistically significant (P = 0.1361).


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  		Fig. 3.   The effects of (+)-cyclazosin (25 and 50 nmol it) on bladder activity under isovolumetric conditions in an urethane-anesthetized rat. Note that 50 nmol of the drug increased the bladder-contraction frequency. The bladder-contraction amplitude was slightly reduced in this rat; however, the effect of the drug on amplitude varied in different animals. The 25 nmol did not change either the bladder-contraction amplitude or frequency.

BMY 7378 (25, 50, and 100 nmol) did not significantly alter the amplitude or the frequency of bladder contractions (Fig. 4).


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  		Fig. 4.   Graphs showing the effects of it administration of BMY 7378 (n = 6) and drug vehicle (acidic cerebrospinal fluid, n = 3-6) on amplitude and frequency of bladder contractions under isovolumetric conditions in urethane-anesthetized rats. BMY 7378 produced no significant effect on either parameter (comparison between vehicle and drug by unpaired t-test following 2-way ANOVA).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In our previous studies in anesthetized rats (4, 35), phenylephrine (an alpha 1-adrenoceptor agonist) increased the intercontraction interval (i.e., the time between bladder contractions) and pressure threshold for inducing micturition during continuous infusion cystometrograms. Under isovolumetric conditions, the drug abolished bladder activity. On the other hand, doxazosin (a nonselective alpha 1-adrenoceptor antagonist) decreased intercontraction intervals during cystometrograms and increased the bladder-contraction frequency and decreased bladder-contraction amplitude under isovolumetric conditions. These results indicated that two types of spinal alpha 1-adrenergic mechanisms are involved in reflex-bladder activity: 1) inhibitory control of the bladder-contraction frequency presumably due to modulation of afferent processing in the spinal cord and 2) excitatory modulation of bladder-contraction amplitude due to regulation of the descending limb of the spinobulbospinal bladder-reflex pathway. The present experiments have provided insights into the alpha 1-adrenoceptor subtypes involved in these modulatory mechanisms.

Intrathecal administration of RS-100329, an alpha 1A-adrenoceptor antagonist, suppressed bladder-contraction amplitude in a dose-dependent manner, indicating that the descending limb of the micturition-reflex pathway is facilitated by bulbospinal noradrenergic inputs acting on alpha 1A-adrenoceptors. Certain doses of RS-100329 or (+)-cyclazosin, an alpha 1B-adrenoceptor antagonist, significantly increased the bladder-contraction frequency, indicating that alpha 1A- or alpha 1B-adrenoceptors modulate the spinal processing of afferent input from bladder mechanoreceptors. It is likely that these adrenergic modulatory mechanisms regulate N-methyl-D-aspartate (NMDA) and non-NMDA glutamatergic synapses that play an essential role in the micturition-reflex pathway (31-33).

Although RS-100329, which has a high affinity and selectivity for the alpha 1A-adrenoceptor versus the alpha 1B- and alpha 1D-adrenoceptor subtypes (26), suppressed bladder-contraction amplitude in a dose-dependent manner, only the 50-nmol dose significantly increased the frequency of bladder contractions. Smaller and larger doses (25 and 100 nmol) were ineffective. The lack of effect on this parameter by the largest dose (100 nmol) raises the possibility that alpha 1A-adrenoceptors are not involved or that the high dose nonselectively affected other transmitter mechanisms to negate the effects of the lower dose.

In contrast to the prominent effect of RS-100329 on bladder activity, the alpha 1D-antagonist BMY 7378 had no significant effect. This indicates that alpha 1D-adrenoceptors do not play an important role in controlling reflex-bladder activity under the conditions of our experiments. On the other hand, the role of alpha 1B-adrenoceptors is less clear. The effects of (+)-cyclazosin were complicated. The 50-nmol dose had significant effects on bladder-contraction amplitude and frequency, whereas lower and higher doses did not produce significant changes. There may be several reasons for this unusual dose-response relationship. First, the vehicle (100% DMSO) may have interfered with the effect of the drug. Second, (+)-cyclazosin may not be sufficiently selective at alpha 1B-adrenoceptors. Radioligand binding studies indicated that (+)-cyclazosin was a potent and selective ligand for the alpha 1B-adrenoceptor subtype (8), whereas functional studies indicated that (+)-cyclazosin displayed low potency and did not act as a competitive antagonist (21). The lack of any effect on either parameter by 100 nmol may be due to the interaction with other receptor(s). Furthermore, in the present studies, the largest volume of the vehicle (100% DMSO) for RS-100329 and (+)-cyclazosin significantly decreased the amplitude of bladder contractions. Therefore, the vehicle could have interacted synergistically with the drugs to enhance the depression of bladder-contraction amplitude and conversely to antagonize the facilitatory drug effects on the frequency of bladder contractions.

The present results suggesting that alpha 1A-adrenoceptors are the most important and that alpha 1B-adrenoceptors are of lesser importance in the regulation of reflex-bladder activity are consistent with the previous studies using a radioligand binding assay (24), which revealed that in the rat lumbar spinal cord, the alpha 1A- and alpha 1B-adrenoceptor populations comprised 70% and 30%, respectively, of the total population of alpha 1-adrenoceptors in the spinal ventral and dorsal horns and that alpha 1D-adrenoceptors were expressed at very low levels.

In other spinal systems, alpha 1A-adrenoceptors also seem to play a major role. For example, in vivo experiments in rats indicated that spinal alpha 1A-adrenoceptors mediated the spontaneous tail flicks induced by 8-hydroxy-2-(di-n-propylamino)tetralin (1), and experiments on the rat lumbar spinal cord slice preparation revealed that alpha 1A-adrenoceptors were essential for adrenergic facilitation of spinal motoneuron activity (23). On the contrary, Wilson and Minneman (27) reported that in the in vitro cervical spinal cord preparation, 42% of alpha 1-adrenoceptors were inactivated by chloroethylclonidine, an alpha 1B/1D-adrenoceptor antagonist, suggesting a somewhat lower proportion of alpha 1A-adrenoceptors at this level of the cord.

Because bladder activity in the present studies was evaluated under isovolumetric conditions in which reflex-bladder contractions occurred against a closed outlet, it might be questioned whether this bladder activity is elicited via different mechanisms than "normal" voiding reflexes. For example, isovolumetric contractions might activate high-threshold bladder afferents that, in turn, stimulate nociceptive pathways in the spinal cord. Thus the effects of adrenergic drugs on this type of bladder activity might reflect adrenergic modulation of visceral nociceptive mechanisms rather than the control of normal micturition. However, we believe that this is unlikely because isovolumetric bladder contractions, like voiding reflexes, are dependent on similar central mechanisms including glutamatergic transmission and a spinobulbospinal-reflex pathway (31-33). In addition, doxazosin, a nonselective alpha 1-adrenoceptor antagonist, decreased micturition pressure in conscious rats during continuous-infusion cystometrograms (CMGs) with an open urethral outlet (11), and phenylephrine, alpha 1-adrenoceptor agonist, altered the profile of bladder contractions in anesthetized rats during continuous CMGs with the bladder catheter inserted through a ureter (14). Thus alpha 1-adrenergic drugs are still effective in modulating the activity of rat bladder even under conditions in which voiding is unobstructed and bladder afferent activity is entirely nonnoxious.

In summary, the present results taken together with previous studies (4, 35) indicate that two types of spinal alpha 1-adrenergic mechanisms are involved in the control of reflex activity in anesthetized rats: 1) alpha 1A- or alpha 1B-adrenergic inhibitory control of afferent processing in the spinal cord and 2) alpha 1A-adrenergic excitatory modulation of the descending limb of bladder-reflex pathway (Fig. 5). These two mechanisms possibly involving alpha 1A- and alpha 1B-adrenoceptors acting in concert would facilitate urine storage by increasing bladder capacity and also enhance voiding efficiency by increasing parasympathetic nerve activity and the amplitude of bladder contractions.


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  		Fig. 5.   Scheme showing putative mechanisms using alpha 1-adrenoceptor subtypes in the L6-S1 spinal cord that contribute to the control of reflex activity of the urinary bladder in the rat. PGN, preganglionic neurons; PMC, pontine micturition center. Descending noradrenergic pathways from the brain stem may excite inhibitory interneurons to regulate the sensory pathways from the bladder and excitatory interneurons to regulate the efferent pathway to the bladder.

Perspectives

In clinical urology, nonselective alpha 1-adrenergic antagonists have been used in the treatment of benign prostatic hypertrophy (15). This therapy was initially designed to block adrenergic receptors in the proximal urethra and prostate gland and thereby reduce urethral resistance and increase urine flow. It was discovered that the drugs not only improved urine flow but also reduced irritative bladder symptoms. However, the changes in urinary flow rates were not correlated with the improvement in symptoms (15). This raises the possibility that the two effects might occur by different mechanisms. The reduction in abnormal bladder sensations could be mediated by a suppression of unstable bladder contractions due to an effect on efferent pathways to the bladder. This could occur as a result of actions at various sites including 1) the spinal cord, as suggested by the present experiments, 2) at presynaptic alpha 1-adrenergic facilitatory receptors on efferent parasympathetic nerve terminals in the bladder wall (20, 22), or 3) at alpha 1-adrenergic facilitatory receptors in bladder parasympathetic ganglia (13). Thus alpha 1-adrenergic receptors at various sites in the peripheral and central nervous system, as well as in smooth muscle, may play a role in voiding function.


    ACKNOWLEDGEMENTS

We acknowledge Drs. A. P. D. W. Ford and T. J. Williams (Center for Biological Research, Roche Bioscience, Palo Alto, CA) for the gift of the drugs used in the present studies and helpful discussions during this project.


    FOOTNOTES

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-49430 and DK- 51402 (W. de Groat) and a research grant from Roche Bioscience (W. de Groat).

Address for reprint requests and other correspondence: M. Yoshiyama, Dept. of Neurology, Chiba Univ. Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan (E-mail: PXN15164{at}nifty.ne.jp).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3 August 2000; accepted in final form 13 December 2000.


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DISCUSSION
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Am J Physiol Regul Integr Comp Physiol 280(5):R1414-R1419
0363-6119/01 $5.00 Copyright © 2001 the American Physiological Society


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