Effect of Naftopidil on Brain Noradrenaline-Induced Decrease in Arginine-Vasopressin Secretion in Rats

Journal of Pharmacological Sciences 132 (2016) 86e91

Contents lists available at ScienceDirect

Journal of Pharmacological Sciences

journal homepage: www.elsevier.com/locate/jphs

Full paper Effect of naftopidil on brain noradrenaline-induced decrease in arginine-vasopressin secretion in rats

* Masaki Yamamoto a, b, Takahiro Shimizu a, Shogo Shimizu a, Youichirou Higashi a, , Kumiko Nakamura a, Mikiya Fujieda b, Motoaki Saito a a Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan b Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan article info abstract

Article history: Naftopidil, an a1-adrenoceptor antagonist, has been shown to inhibit nocturnal polyuria in patients with Received 27 May 2016 lower urinary tract symptom. However, it remains unclear how naftopidil decreases nocturnal urine Received in revised form production. Here, we investigated the effects of naftopidil on arginine-vasopressin (AVP) plasma level 28 August 2016 and urine production and osmolality in rats centrally administered with noradrenaline (NA). NA (3 or Accepted 29 August 2016 30 mg/kg) was administered into the left ventricle (i.c.v.) of male Wistar rats 3 h after naftopidil pre- Available online 8 September 2016 treatment (10 or 30 mg/kg, i.p.). Blood samples were collected from the inferior vena cava 1 h after NA administration or 4 h after peritoneal administration of naftopidil; plasma levels of AVP were assessed by Keywords: Naftopidil ELISA. Voiding behaviors of naftopidil (30 mg/kg, i.p.)-administered male Wistar rats were observed Arginine-vasopressin during separate light- and dark cycles. Administration of NA decreased plasma AVP levels and elevated Noradrenaline urine volume, which were suppressed by systemic pretreatment with naftopidil (30 mg/kg, i.p.). Urine Brain osmolality decreased 1 h after NA administration. However, naftopidil by itself had no effect on plasma Nocturnal polyuria AVP levels or urodynamic parameters during light- and dark cycles. Our ﬁndings suggest that systemic administration of naftopidil could prevent central noradrenergic nervous system-mediated decline in AVP secretion and increase in urine production in rats. © 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

1. Introduction Arginine vasopressin (AVP), an antidiuretic hormone, is syn- thesized in the supraoptic and paraventricular nuclei of the hypo- Naftopidil is an a1-adrenoceptor antagonist that used in the thalamus and plays an important role in the maintenance of serum treatment of benign prostatic hyperplasia (BPH)-associated lower osmolality and volume through free water excretion. The release of urinary tract symptoms (LUTS) owing to its effects in reducing AVP into the plasma, induced by both osmotic and non-osmotic resistance in the prostatic urethra (1). In male patients with LUTS, stimuli, is modulated by brain adrenoceptors (5). In healthy naftopidil has also been shown to be effective against nocturia (2). adults, diurnal secretion of AVP into peripheral blood peaks during Furthermore, Yokoyama et al. (3) reported that nocturnal polyuria nighttime (6), and is regulated by the circadian rhythm. However, in male patients with LUTS significantly decreased upon naftopidil patients with nocturnal polyuria do not show significantly elevated administration, indicating that it can directly reduce nocturnal plasma AVP levels at nighttime, suggesting that abnormal diurnal urine production. Recently, another study found that naftopidil can variation in AVP secretion is highly prevalent in these patients (7,8). cross the bloodebrain barrier to easily enter the central nervous Spontaneously hypertensive rats (SHRs) are a valuable tool for system (4). However, the mechanism by which naftopidil decreases exploring the pathogenesis of hypertension-related bladder nocturnal urine production has still not been well understood. dysfunction. These rats exhibit increased voiding frequency and decreased bladder blood flow compared to the non-hypertensive Wistar rats (9,10). Saito et al. (11) revealed that naftopidil decreases micturition frequency and urine production in SHRs during þ * Corresponding author. Fax: þ81 888 80 2329ext2328. the light-cycle. It has been reported that basal and K -stimulated E-mail address: [email protected] (Y. Higashi). release of endogenous noradrenaline (NA) from the paraventricular Peer review under responsibility of Japanese Pharmacological Society. hypothalamic nucleus was increased in SHRs compared with http://dx.doi.org/10.1016/j.jphs.2016.09.002 1347-8613/© 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M. Yamamoto et al. / Journal of Pharmacological Sciences 132 (2016) 86e91 87 normotensive control rats, suggesting that noradrenergic neuronal through the cannula, had spread throughout the ventricular sys- activity is enhanced in the central nervous system of SHRs (12). tem, as described previously (17). For voiding behavior studies, rats Furthermore, inhibition of NA synthesis in the posterior hypothal- were administered naftopidil intraperitoneally at 10:00 am once a amus by 6-hydroxydopamine was demonstrated to lower blood day, for two days. pressure in SHRs (13). Based on these reports, we postulated that naftopidil either 2.4. Measurement of plasma AVP levels directly or indirectly regulates AVP secretion via brain adrenoceptors, leading to reduction in urine frequency and production at A total of 70 rats placed in a stereotaxic apparatus were night. In the present study, we examined whether naftopidil randomly divided into ten groups in order to measure their plasma modulates plasma AVP levels and urine production in rats centrally AVP levels: NA administered groups at 3 and 30 mg/kg per animal, administered with NA. i.c.v. (n ¼ 7 and 8, respectively); vehicle-1 (10 mL PBS-containing 0.1% ascorbic acid per animal, i.c.v.) administered group (n ¼ 7); 2. Materials and methods naftopidil administered groups at 10 and 30 mg/kg, i.p. (n ¼ 8 and 7, respectively); vehicle-2 (1.0 mL10% DMF, i.p.) administered group 2.1. Animals (n ¼ 6); 10 mg/kg naftopidil (i.p.) and NA (30 mg/kg, i.c.v.) administered group (n ¼ 8); 30 mg/kg naftopidil (i.p.) and NA (30 mg/kg, All animal care and experimental procedures complied with the i.c.v.) administered group (n ¼ 6); vehicle-2 and NA (30 mg/kg, i.c.v.) guiding principles for care and use of laboratory animals approved administered group (n ¼ 7); and vehicle-2 and vehicle-1 adminis- by Kochi University (No. I-00046), in accordance with the “Guide- tered group (n ¼ 6). lines for proper conduct of animal experiments” proposed by the Blood samples (5 mL) were collected from the inferior vena cava Science Council of Japan; these guidelines conform to the standards 1 h after NA or vehicle administration into the left ventricle. All of the National Institutes of Health. All efforts were made to blood samples were collected at 4:00 pm as described previously minimize the suffering of the animals and the number of animals (18), and were mixed with 1 mg/mL EDTA before centrifuged at needed to obtain reliable results. In all, 93 eight-week-old male 1600 g for 15 min at 4 C to obtain the plasma. The obtained Wistar rats (Japan SLC Inc., Hamamatsu, Japan) weighing plasma samples were mixed with a protease inhibitor cocktail 200e250 g were used in the experiments. The rats were housed in (0.5 mL/mL plasma), and were kept at 80 C. These samples were pairs in cages, in an air-conditioned room at 22e24 C under a concentrated to 400 mL using a centrifugal concentrator, before AVP constant dayenight rhythm (14/10 h lightedark cycle, lights on at levels were measured in duplicate using an ELISA kit (#ab133028; 05:00) for more than 2 weeks. They had ad libitum access to food Abcam, Cambridge, UK). The sensitivity of this assay (lower limit of (laboratory chow, CE-2; Clea Japan, Hamamatsu, Japan) and water. detection) was less than 3.39 pg/mL, and the intra-assay precision Upon reaching a body weight of 310e360 g, the rats were subjected was less than 5.9%. to the following experiments. 2.5. Voiding behavior studies 2.2. Intracerebroventricular administration of NA Rats were randomly divided into two groups for examination of In the morning (10:30e11:30), rats were placed in a stereotaxic voiding behaviors: naftopidil (30 mg/kg, i.p.) administered group apparatus (Narishige, Tokyo, Japan) under urethane anesthesia (n ¼ 5) and vehicle-2 administered group (n ¼ 5). Voiding behavior (1.0 g/kg, i.p.), as described previously in a published work of this studies were performed according to methods described in our laboratory (14). The skull was drilled for intracerebroventricular previous reports (11). The rats received food and water ad libitum administration of NA using a stainless-steel cannula (outer diam- from the time they were initially placed in metabolic cages. The rats eter of 0.3 mm). The stereotaxic coordinates of the tip of the can- were kept for 24 h for adaptation, and recorded for the next 24 h. nula were as follows (in mm): AP 0.8, L 1.5, V 4.0 (AP, anterior Micturition frequency and total urine output were evaluated from from the bregma; L, lateral from the midline; V, below the surface these recordings. of the brain), according to the rat brain atlas (15). The steel cannula was injected into the left lateral ventricle 3 h before NA adminis- 2.6. Urine production and osmolality tration as described below, and was retained until the end of the experiment. Fourteen rats were divided into the following groups: NA (30 mg/ kg, i.c.v.) administered group (n ¼ 5); NA (30 mg/kg, i.c.v.) and 2.3. Drug administration naftopidil (30 mg/kg, i.p.) administered group (n ¼ 5); and vehicle- 1 and vehicle-2 administered group (n ¼ 4). Before the experiment, NA and naftopidil were dissolved in 10 mM phosphate-buffered rats were catheterized at the bladder dome with a 22G needle for saline (PBS) containing 0.1% ascorbic acid (pH 7.4) and 10% N,N- urine collection, and a stainless cannula was inserted into the left dimethylformamide (DMF), respectively. NA (3 or 30 mg/kg) was lateral ventricle for administration of NA as described above. The slowly administered into the left lateral ventricle in a volume of catheterized bladder in the rat was emptied and the urethra was 10 mL/animal using a cannula connected to a 10-mL Hamilton sy- clamped to prevent urine leakage. Vehicle-1 or NA (30 mg/kg, i.c.v.) ringe (Hamilton, Reno, NV, USA) at a rate of 10 mL/min. Naftopidil was centrally administered 3 h after intraperitoneal pretreatment (10 or 30 mg/kg) was administered intraperitoneally in a volume of with vehicle-2 or naftopidil (30 mg/kg). Urine was collected 1 and 1.0 mL/animal. Subsequently, NA was slowly administered as 3 h after NA administration (at 4:00 pm and 6:00 pm, respectively). described above, 3 h following the application of naftopidil. The We also determined urine osmolality for the following groups: doses of naftopidil were determined according to previous reports NA (30 mg/kg, i.c.v.) administered group (n ¼ 5); NA (30 mg/kg, i.c.v.) from our and other laboratories that had used similar doses of and naftopidil (30 mg/kg, i.p.) administered group (n ¼ 5); and naftopidil in rats (4,11,16). Furthermore, we have checked the dose- vehicle-1 and vehicle-2 administered group (n ¼ 5). Urine was dependent efficacy of naftopidil in our preliminary study. The exact collected 1 and 3 h after NA administration (at 4:00 pm and 6:00 pm, location of the cannula injected in the brain was confirmed at the respectively), and was centrifuged at 1600 g for 15 min at 4 Cto end of each experiment by verifying that cresyl violet, injected remove impurities. The urine osmolality (mOsmolality/kg H2O) of 88 M. Yamamoto et al. / Journal of Pharmacological Sciences 132 (2016) 86e91 the supernatant was measured by means of an osmometer (OM- 16 2030; Aryray, Kyoto, Japan) based on the freezing point method (19). 12 2.7. Statistical analysis

/mL) 8 Data are expressed as mean ± SEM. Comparisons between two (pg or more groups were performed by unpaired t-test or analysis of 4 variance (ANOVA) followed by Bonferroni post hoc test, respectively. Differences with a p-value of 0.05 or less are considered Arginine-vasopressin 0 statistically signiﬁcant. Naf (mg/kg)0 10 30

2.8. Drug and chemicals Fig. 2. Effect of naftopidil on plasma level of AVP. Blood samples were obtained from the inferior vena cava 4 h after treatment with vehicle or naftopidil (10 or 30 mg/kg, Urethane, NA, and protease inhibitor cocktail were purchased i.p.). Naf: naftopidil. Results are presented as mean ± SEM. from Sigma Aldrich (St Louis, MO, USA). Naftopidil was purchased from Tokyo Chemical Industry (Tokyo, Japan). All other chemicals effectively abolished the NA-induced decrease in plasma AVP level were from Nacalai Tesque (Kyoto, Japan), except stated otherwise. (Fig. 3).

3. Results 3.4. Voiding behaviors in rats systemically administered with naftopidil 3.1. Effect of centrally administered NA on plasma level of AVP Results of the voiding behavior studies are shown in Table 1. fi We rst investigated whether centrally administered NA affects Basal levels of urine volume in rats treated with vehicle-2, collected plasma levels of AVP. It has been reported that AVP levels in plasma during light- and dark-cycles, were 8.4 ± 0.5 and 12.6 ± 2.2 mL, and in the brain exhibit marked changes during light- and dark- respectively. Treatment with 30 mg/kg naftopidil (i.p.) produced no cycles (20). Furthermore, Greeley et al. (18) revealed that significant difference in urine volume between rats administered e maximum plasma AVP levels (approximately 13 18 pg/mL) were with naftopidil (9.8 ± 1.0 mL during light-cycle, 12.1 ± 1.5 mL during observed during the midafternoon through the early evening in dark-cycle) and vehicle-2, regardless of the light- and dark-cycle. rats. As shown in Fig. 1, treatment with vehicle-1 had no effect on Similarly, basal levels of urinary frequency in the vehicle-treated ± the basal plasma levels of AVP (19.2 4.0 pg/mL), which were rats (7.0 ± 0.9 and 11.5 ± 1.2 times during light- and dark-cycles, consistent with the observations of Greeley et al. (18) and other respectively) were not significantly affected by naftopidil treat- m laboratories (21,22). On the other hand, NA (3 and 30 g/kg/animal, ment (5.4 ± 0.2 times during light-cycle, 8.6 ± 1.6 times during i.c.v.) dose-dependently decreased plasma AVP levels 1 h after its dark-cycle). administration (Fig. 1). 3.5. Effect of systemically administered naftopidil on urine 3.2. Effect of systemically administered naftopidil on plasma level of production and osmolality in rats centrally administered with NA AVP To investigate whether naftopidil affects urine production and To evaluate whether naftopidil by itself affects the plasma level its osmolality in rats treated with NA, urine was collected at 1 and of AVP, rats received i.p. injections of naftopidil. As shown in Fig. 2, 3 h after NA administration (30 mg/kg, i.c.v.; Table 2). Compared to fi there were no signi cant differences in plasma AVP level between the vehicle-1 and -2 treated control group, NA administration rats 4 h after treatment with vehicle-2 or naftopidil. resulted in a significant increase in urine volume that remained for at least 3 h after its administration. Remarkably, the increase in 3.3. Effect of systemically administered naftopidil on the centrally urine volume 3 h after NA administration was almost completely administered NA-induced decrease in plasma level of AVP suppressed when rats were pretreated with naftopidil (30 mg/kg, i.p.) 3 h before NA administration. In contrast, there were no Next, we investigated whether naftopidil affects the NA-induced reduction in plasma AVP level. Rats were pretreated with vehicle-2 40 or naftopidil (10 and 30 mg/kg, i.p.) 3 h before NA administration # (30 mg/kg, i.c.v.). Administration of naftopidil at a higher dose 30 25 20 20 (pg/mL) * * 15 10

10 * Arginine-vasopressin

(pg/mL) 0 5 NA (μg/kg) 0 30 30 30

Arginine-vasopressin 0 Naf (mg/kg)0 0 10 30

NA (μg/kg) 0 330 Fig. 3. Effect of naftopidil on the NA-induced decrease in plasma level of AVP. Rats were treated with vehicle or NA (30 mg/kg, i.c.v.) 3 h after pretreatment with vehicle or Fig. 1. Effect of centrally administered NA on plasma level of AVP. Blood samples were naftopidil (10 or 30 mg/kg, i.p.). Blood samples were obtained from the inferior vena obtained from the inferior vena cava 1 h after treatment with vehicle or NA (3 or 30 mg/ cava 1 h after NA administration. Results are presented as mean ± SEM. *p < 0.05 vs. kg, i.c.v.). Results are presented as mean ± SEM. *p < 0.05 vs. control rats treated with control rats treated with vehicle. Naf: naftopidil. #p < 0.05 vs. NA-treated rats, pre- vehicle. treated with vehicle or 10 mg/kg naftopidil. M. Yamamoto et al. / Journal of Pharmacological Sciences 132 (2016) 86e91 89

Table 1 Voiding behavior during light-cycle, dark-cycle, and the whole-day.

Urinary volume (mL) Micturition frequency (times)

Light-cycle Dark-cycle Whole-cycle Light-cycle Dark-cycle Whole-cycle

Vehicle 8.4 ± 0.5 12.6 ± 2.2 21.1 ± 1.9 7.0 ± 0.9 11.5 ± 1.2 18.5 ± 1.8 Naf 9.8 ± 1.0 12.1 ± 1.5 21.9 ± 2.4 5.4 ± 0.2 8.6 ± 1.6 14.0 ± 1.9 p-value 0.242 0.844 0.800 0.101 0.214 0.135

Vehicle: Wistar rats treated with 10% DMF (i.c.v.). Naf: Wistar rats treated with naftopidil (30 mg/kg, i.p.). p-Value: Vehicle-administered group vs. naftopidil-administered group. Data are shown as mean ± SEM. significant differences in urine volume collected at 1 h after NA we revealed that naftopidil decreases micturition frequency and administration between rats untreated and pretreated with nafto- urine production during the light-cycle in a rat model of pidil. Urine osmolality decreased significantly 1 h after NA treat- hypertension-related bladder dysfunction (11). It seemed that ment compared to control rats. However, there were no significant naftopidil either directly or indirectly increased the secretion of differences in urine osmolality collected 3 h after NA treatment. AVP in rats, thus contributing to the inhibition of urine produc- Although the decrease in urine osmolality was suppressed by naf- tion during sleep. In the current study, we showed that naftopidil topidil pre-administration, it was not statistically significant. suppressed the increase in urine production in rats centrally administered with NA, but did not affect urine production in rats 4. Discussion untreated with NA, during both light- and dark-cycles. Recently, naftopidil has been reported to be able to cross the bloodebrain In this study, we demonstrated that 1) centrally administered barrier and act on several regions in the central nervous system NA significantly decreased plasma level of AVP in a dose-dependent as well as the bladder (4,27,28). Therefore, the effects of naftopidil manner; 2) a decrease in plasma AVP level in rats induced by NA on urine production may be attributed to a direct inhibition of was dose-dependently suppressed by pre-administration of naf- dysregulated NA activity in the central nervous system, while, in topidil; and 3) while naftopidil suppressed NA-induced urine pro- this study, we did not examine whether central administration of duction in rats, it had no effect on the urine production in normal other a1-adrenoceptor antagonists such as tamsulosin and ter- condition. These findings suggest a novel mechanism by which azosin suppresses the NA-induced increase in urine production in naftopidil ameliorates nocturnal polyuria. rats. a1-Adrenoceptor antagonists are the most common drugs NA is an important neurotransmitter in the supraoptic nucleus, used in the treatment of male LUTS suggestive of BPH, which act and noradrenergic projection from the locus coeruleus is known to via the relaxation of prostatic smooth muscles. Tamsulosin, an a1- promote wakefulness in the hypothalamus (29). In a recent study adrenoceptor antagonist, improves the maximum urinary flow involving a rat model of sleep disturbance induced by repeated rate and the frequency of nocturia, without decreasing nocturnal administration of corticosterone, NA level was found to be mark- urine volume in BPH patients (23). Similarly, terazosin, another edly increased in the locus coeruleus and hypothalamus (30).On such an antagonist, also reduces the frequency of nocturia in BPH the other hand, improvement in sleep disturbance has been re- patients despite there being no detectable reduction in nocturnal ported to decrease the frequency of nocturia, accompanied by urine volume (24). In limited countries including Japan, China, reduction in nocturnal polyuria in the elderly (31). Thus, we and South Korea, naftopidil was administratively approved for the considered the NA-induced increase in urine production in our treatment of BPH and BPH-associated LUTS (25).Aclinicalstudy study as a model of nocturnal polyuria. This was supported by our comparing tamsulosin and naftopidil by Nishino and colleagues findings that systemic injection of naftopidil suppressed the in- (26) demonstrated that while both drugs had similar efficacy crease in urine production. However, little is known about the against BPH/LUTS, naftopidil was more effective against nocturia relationship between noradrenergic neuronal activation in the than tamsulosin. Furthermore, naftopidil has been reported to central nervous system and nocturnal polyuria. Therefore, further decrease urine production and the frequency of voids at night- studies are required to determine whether the former contributes time, regardless of incidences of sleep disturbance (3). Recently, to the latter.

Table 2 Inhibition of NA-induced decrease in urine production by naftopidil.

Urinary volume (mL) Urinary osmolality (mOsmolality/kgH2O) 1 h 3 h Total 1 h 3 h

Vehicle 0.5 ± 0.0 0.8 ± 0.0 1.3 ± 0.1 1965.4 ± 156.2 1964.5 ± 240.4 NA 0.9 ± 0.1* 1.5 ± 0.2* 2.5 ± 0.2* 1498.0 ± 97.4* 1719.7 ± 159.6 Naf + NA 0.7 ± 0.1 0.7 ± 0.0 # 1.4 ± 0.0 # 1748.2 ± 145.9 1941.0 ± 77.3

Vehicle: Wistar rats treated with DMF (i.c.v.) 3 h after pretreatment with PBS (i.p.). NA: Wistar rats treated with NA (30 mg/kg, i.c.v.) 3 h after pretreatment with PBS (i.p.). Naf + NA: Wistar rats treated with NA (30 mg/kg, i.c.v.) 3 h after pretreatment with naftopidil (30 mg/kg, i.p.). 1 h: the volume of urine that was collected 1 h after NA treatment (4:00 pm). 3 h: the volume of urine that was collected 3 h after NA treatment (6:00 pm). Total: the total volume of urine that was collected 1 and 3 h after NA treatment. Data are shown as mean ± SEM. *Signiﬁcantly different from the Vehicle group (p < 0.05). #Signiﬁcantly differently from the NA group (p < 0.05). 90 M. Yamamoto et al. / Journal of Pharmacological Sciences 132 (2016) 86e91

Previously, we and other laboratories have evaluated the effects References of naftopidil on urine production in both basic and clinical studies (3,11). While there is no information available that demonstrates (1) Takei R, Ikegaki I, Shibata K, Tsujimoto G, Asano T. Naftopidil, a novel alpha1- adrenoceptor antagonist, displays selective inhibition of canine prostatic the mechanisms by which naftopidil directly reduces urine pro- pressure and high affinity binding to cloned human alpha1-adrenoceptors. duction, it has been reported that naftopidil improves bladder ca- Jpn J Pharmacol. 1999;79:447e454. pacity by suppressing C-fiber afferent activity (32). In the present (2) Tanaka T, Kuratsukuri K, Yoshimura R, Adachi T, Yamaguchi T, Ohmachi T, et al. Efficacy of naftopidil for nocturia in male patients with lower urinary study, we found that naftopidil suppressed the decrease in plasma tract symptoms: comparison of morning and evening dosing. Int J Urol. AVP level in rats centrally administered NA. There are several re- 2015;22:317e321. a ports demonstrating that injection of NA into the cerebral ventri- (3) Yokoyama O, Aoki Y, Tsujimura A, Takao T, Namiki M, Okuyama A. 1-Adre- cles excites AVP-containing cells and stimulates release of AVP noceptor blocker naftopidil improves sleep disturbance with reduction in nocturnal urine volume. World J Urol. 2011;29:233e238. (5,33); nonetheless, NA has also been reported to inhibit AVP (4) Sugaya K, Nishijima S, Kadekawa K, Ashitomi K, Ueda T, Yamamoto H. Spinal fl release (16,34). In general, activation of a1-adrenoceptor excites mechanism of micturition re ex inhibition by naftopidil in rats. Life Sci. e neurons in the supraoptic nucleus and stimulates AVP release, 2014;116:106 111. (5) Radacs M, Gal fi M, Nagyeri G, Molnar AH, Varga C, Laszl o F, et al. Significance while b-adrenoceptor activation inhibits these neurons (35). It has of the adrenergic system in the regulation of vasopressin secretion in rat been suggested that the inhibitory effect of NA on AVP release may neurohypophyseal tissue cultures. Regul Pept. 2008;148:1e5. (6) George CP, Messerli FH, Genest J, Nowaczynski W, Boucher R, Kuchel Orofo- be mediated by a2-adrenoceptors, as the infusion of clonidine, an a Oftega M. Diurnal variation of plasma vasopressin in man. J Clin Endocrinol 2-adrenoceptor agonist, into the lateral cerebral ventricle mark- Metab. 1975;41:332e338. edly decreased the release of AVP in anesthetized dogs (36). Since (7) Natsume O. A clinical investigation of nocturnal polyuria in patients with these effects of the different adrenoceptor subtypes on AVP secre- nocturia: a diurnal variation in arginine vasopressin secretion and its rele- e fi vance to mean blood pressure. J Urol. 2006;176:660 664. tion are not consistent with the antagonistic speci city of nafto- (8) Hvistendahl GM, Frøkiaer J, Nielsen S, Djurhuus JC. Gender differences in pidil, it is necessary to clarify which subtype of adrenoceptor is nighttime plasma arginine vasopressin and delayed compensatory urine involved in the action of naftopidil in future investigations. To our output in the elderly population after desmopressin. J Urol. 2007;178: e fi fi 2671 2676. knowledge, this is the rst report demonstrating that the bene cial (9) Inoue S, Saito M, Takenaka A. Hydroxyfasudil ameliorates bladder dysfunction effect of naftopidil against NA-induced polyuria may be mediated in male spontaneously hypertensive rats. Urology. 2012;79: by its ameliorating action on NA-induced dysregulation in AVP 1186.e9e1186.e14. secretion from vasopressin-containing neurons into peripheral (10) Saito M, Ohmasa F, Tsounapi P, Inoue S, Dimitriadis F, Kinoshita Y, et al. Nicorandil ameliorates hypertension-related bladder dysfunction in the rat. blood. Furthermore, we found that central administration of NA Neurourol Urodyn. 2012;31:695e701. resulted in a significant reduction in urine osmolality. These results (11) Saito M, Shimizu S, Ohmasa F, Oikawa R, Tsounapi P, Dimitriadis F, et al. suggested that the observed changes in urine volume were Characterization of silodosin and naftopidil in the treatment of bladder dysfunction in the spontaneously hypertensive rat. Neurourol Urodyn. dependent on the renal action of AVP. 2013;32:393e399. In the present study, we utilized rats that have been acclimated (12) Qualy JM, Westfall TC. Release of norepinephrine from the paraventricular for two weeks on a 14/10-h lightedark cycle according to the hypothalamic nucleus of hypertensive rats. Am J Physiol. 1988;254: H993eH1003. breeding condition proposed by our Institute for Animal Research, (13) Kawasaki S, Takeda K, Tanaka M, Itoh H, Hirata M, Nakata T, et al. Enhanced while other researchers have adopted a 12/12-h lightedark cycle to norepinephrine release in hypothalamus from locus coeruleus in SHR. Jpn investigate plasma AVP level in rats (37,38). Since the rhythm of Heart J. 1991;32:255e262. (14) Shimizu T, Okada S, Yamaguchi-Shima N, Yokotani K. Brain phospholipase C- AVP secretion is maintained under dark conditions (39), we cannot diacylglycerol lipase pathway is involved in vasopressin-induced release of rule out the possibility that our particular lightedark cycle affected noradrenaline and adrenaline from adrenal medulla in rats. Eur J Pharmacol. the circadian change of plasma AVP level. Therefore, further in- 2004;499:99e105. (15) Paxinos G, Watson C. In: Paxinos G, Watson C, editors. The rat brain in ste- vestigations are necessary to clarify the mechanism by which naf- reotaxic coordinates. Burlington: Elsevier Academic Press; 2005. topidil inhibits the reduction in plasma AVP level in rats centrally (16) Kimura T, Shoji M, Iitake K, Ota K, Matsui K, Yoshinaga K. The role of central administered with NA. alpha 1- and alpha 2-adrenoceptors in the regulation of vasopressin release and the cardiovascular system. Endocrinology. 1984;114:1426e1432. (17) Kawamoto B, Shimizu S, Shimizu T, Higashi Y, Honda M, Sejima T, et al. Angiotensin II centrally induces frequent detrusor contractility of the bladder 5. Conclusions by acting on brain angiotensin II type 1 receptors in rats. Sci Rep. 2016;6: 22213. (18) Greeley Jr GH, Morris M, Eldridge JC, Kizer JS. A diurnal plasma vasopressin In summary, systemic pre-administration of naftopidil sup- rhythm in rats. Life Sci. 1982;31:2843e2846. pressed the decrease in plasma AVP level and the increase in urine (19) MahíaJ,BernalA,PuertoA.Inhibitionofnatriuresisinmedianeminence production in rats centrally administered with NA. However, naf- polydipsia: effects after intake of diets with different osmolalities and topidil by itself had no effect on either parameter. These findings after hypertonic NaCl administration. Acta Neurobiol Exp. 2013;73: 326e337. can contribute towards explaining the mechanism by which naf- (20) Windle RJ, Forsling ML, Guzek JW. Daily rhythms in the hormone content of topidil ameliorates nocturnal polyuria. the neurohypophysial system and release of oxytocin and vasopressin in the male rat: effect of constant light. J Endocrinol. 1992;133:283e290. (21) Appenrodt E, Bojanowska E, Janus J, Stempniak B, Guzek JW, Schwarzberg H. Effects of methylphenidate on oxytocin and vasopressin levels in pine- Conflicts of interest alectomized rats during light-dark cycle. Pharmacol Biochem Behav. 1997;58: 415e419. Motoaki Saito reports grants from Asahi Kasei Pharma, during (22) Keck ME, Hatzinger M, Wotjak CT, Landgraf R, Holsboer F, Neumann ID. Ageing alters intrahypothalamic release patterns of vasopressin and oxytocin the conduct of the study. in rats. Eur J Neurosci. 2000;12:1487e1494. (23) Koseoglu H, Aslan G, Ozdemir I, Esen A. Nocturnal polyuria in patients with lower urinary tract symptoms and response to alpha-blocker therapy. Urol- e Acknowledgements ogy. 2006;67:1188 1192. (24) Paick JS, Ku JH, Shin JW, Yang JH, Kim SW. Alpha-blocker monotherapy in the treatment of nocturia in men with lower urinary tract symp- This study was supported by research grants from Asahi Kasei toms: a prospective study of response prediction. BJU Int. 2006;97: e Pharma (Grant number 3814JA7091) and the Japan Society for the 1017 1023. fi (25) Hara N, Mizusawa T, Obara K, Takahashi K. The role of naftopidil in the Promotion of Science [Grant-in-Aid for Scienti c Research (C) management of benign prostatic hyperplasia. Ther Adv Urol. 2013;5: 24592431]. 111e119. M. Yamamoto et al. / Journal of Pharmacological Sciences 132 (2016) 86e91 91

(26) Nishino Y, Masue T, Miwa K, Takahashi Y, Ishihara S, Deguchi T. Comparison of (33) Bhargava KP, Kulshrestha VK, Srivastava YP. Central cholinergic and adren- two alpha1-adrenoceptor antagonists, naftopidil and tamsulosin hydrochlo- ergic mechanisms in the release of antidiuretic hormone. Br J Pharmacol. ride, in the treatment of lower urinary tract symptoms with benign prostatic 1972;44:617e627. hyperplasia: a randomized crossover study. BJU Int. 2006;97:747e751. (34) Ota K, Kimura T, Shoji M, Inoue M, Sato K, Ohta M, et al. Effects of intra- (27) Nishijima S, Sugaya K, Kadekawa K, Ashitomi K, Yamamoto H. Effect of cerebroventricular administration of adrenoceptor-agonists on the regulation chemical stimulation of the medial frontal lobe on the micturition reflex in of renal water and electrolytes handling through endocrine, renal and he- rats. J Urol. 2012;187:1116e1120. modynamic function. Tohoku J Exp Med. 1990;162:27e39. (28) Sugaya K, Nishijima S, Miyazato M, Ashitomi K, Hatano T, Ogawa Y. Effects of (35) Day TA, Randle JC, Renaud LP. Opposing alpha- and beta-adrenergic mecha- intrathecal injection of tamsulosin and naftopidil, alpha-1A and -1D adren- nisms mediate dose-dependent actions of noradrenaline on supraoptic ergic receptor antagonists, on bladder activity in rats. Neurosci Lett. vasopressin neurones in vivo. Brain Res. 1985;358:171e179. 2002;328:74e76. (36) Kimura T, Share L, Wang BC, Crofton JT. The role of central adrenoreceptors in (29) Mignot M, Skinner DC. Colocalization of GH, TSH and prolactin, but not ACTH, the control of vasopressin release and blood pressure. Endocrinology. with betaLH-immunoreactivity: evidence for pluripotential cells in the ovine 1981;108:1829e1836. pituitary. Cell Tissue Res. 2005;319:413e421. (37) Cafarchio EM, da Silva LA, Auresco LC, Ogihara CA, Almeida RL, Giannocco G, (30) Wang ZJ, Zhang XQ, Cui XY, Cui SY, Yu B, Sheng ZF, et al. Glucocorticoid re- et al. Cholinergic activation of neurons in the medulla oblongata changes ceptors in the locus coeruleus mediate sleep disorders caused by repeated urinary bladder activity by plasma vasopressin release in female rats. Eur J corticosterone treatment. Sci Rep. 2015;5:9442. Pharmacol. 2016;776:116e123. (31) Asplund R. Nocturia, nocturnal polyuria, and sleep quality in the elderly. (38) Xavier-Elsas P, de Luca B, Queto T, Vieira BM, Masid-de-Brito D, Dahab EC, J Psychosom Res. 2004;56:517e525. et al. Blockage of eosinopoiesis by IL-17A is prevented by cytokine and lipid (32) Yokoyama O, Yusup A, Oyama N, Aoki Y, Tanase K, Matsuta Y, et al. mediators of allergic inflammation. Mediat Inflamm. 2015;2015:968932. Improvement of bladder storage function by alpha1-blocker depends on the (39) Armstrong WE, Gallagher MJ, Sladek CD. Noradrenergic stimulation of su- suppression of C-fiber afferent activity in rats. Neurourol Urodyn. 2006;25: praoptic neuronal activity and vasopressin release in vitro: mediation by an 461e467. alpha 1-receptor. Brain Res. 1986;365:192e197.