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Canadian Journal of Veterinary Research logoLink to Canadian Journal of Veterinary Research
. 2014 Oct;78(4):304–315.

Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats

Yusuke Murahata 1, Yuya Miki 1, Yoshiaki Hikasa 1,✉
PMCID: PMC4170770  PMID: 25356000

Abstract

This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 μg/kg BW prazosin; or 40, 160, or 480 μg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats.

Introduction

The effects of α2-adrenoceptor agonists in cats include reliable, dose-dependent sedation, analgesia, and muscle relaxation (1). Pharmacologically, the α2-adrenoceptors have been classified into 3 subtypes (α2A, α2B, and α2C) based on the differences in drug affinity (2). The α2D-adrenoceptors in cattle and rodents are considered as a species homologue of the α2A-adrenoceptors (3). Xylazine has been widely used as a sedative in veterinary practice (4). The α2/α1 adrenoceptor selectivity ratio of xylazine is 160/1 (5); whereas, it does not have selectivity for the 3 α2-adrenoceptor subtypes (6).

Xylazine is known to induce diuresis in dogs (7,8), cattle (9), horses (10–13), and rats (14–19). Recently, we found that both medetomidine and xylazine induce profound diuresis in cats by decreasing the reabsorption of water in the kidneys (20). In a previous study, we demonstrated that xylazine had a dose-dependent diuretic effect, but medetomidine did not, suggesting that some factors such as the difference in α2- and α1-adrenoceptor selectivity or imidazoline receptor selectivity in the renal system may be involved in the diuretic mechanism.

The α2-adrenoceptor antagonists atipamezole and yohimbine have been clinically used to reverse the sedative and analgesic effects of α2-adrenoceptor agonists (1,21). The α2/α1 adrenoceptor selectivity ratios of atipamezole and yohimbine are 8526/1 and 40/1, respectively (22). The affinities of atipamezole and yohimbine are similar for the α2A-, α2B-, and α2C-adrenoceptors, but atipamezole has an approximately 100-fold higher affinity for the α2D-adrenoceptor compared to yohimbine (21). Prazosin has a selectivity of 1000:1 for the α1/α2 adrenoceptor (23). In contrast, atipamezole has an imidazoline structure, whereas yohimbine and prazosin are non-imidazoline agents (24). These differences among atipamezole, yohimbine, and prazosin may influence their antagonistic effects for xylazine-induced diuresis in cats.

Because the regulation of water excretion has implications for a number of clinical situations, xylazine-induced diuresis will influence the hydration conditions in normal cats. Especially urinary tract obstruction, dehydration, or hypovolemia may require limiting the use of xylazine in cats. In such cases, α2-adrenoceptor antagonists may be used to reverse the diuretic actions. Therefore, it is important to examine the antagonistic effects for urination associated with xylazine use. However, to the best of our knowledge, there are no published reports on the effects of α-adrenoceptor antagonists on xylazine-induced diuresis in cats. This study aimed to investigate and compare the antagonistic effects of a single dose of prazosin and 3 different doses of either atipamezole or yohimbine on xylazine-induced diuresis in clinically normal cats.

Materials and methods

Animals

Three healthy male (2 neutered) and 2 healthy female (1 neutered) adult mixed-breed cats with a mean age of 2.8 y (SD = 0.84) and a mean weight of 3.4 kg (SD = 0.76) were used in this study. They were fed a standard commercial dry food formulated for cats and raised in a laboratory with appropriate animal management facilities. Examinations done prior to the experiments revealed that all cats were clinically normal, with physical examination, hematologic, and urinary values within respective reference limits. The study protocol was approved by the Animal Research Committee of Tottori University.

Experimental procedures

The 5 cats were assigned to receive each of the 9 treatment groups in a modified randomized design. In group 1, each cat was administered a physiological saline solution (0.1 mL/kg) intramuscularly (IM) as the non-medicated control treatment. In groups 2 to 9, each cat received 2 mg/kg IM xylazine hydrochloride as the 1st treatment (Celactal; Bayer Yakuhin Ltd., Osaka, Japan) at the beginning of the experiment. In group 2 each cat received 2nd intravenous (IV) treatment of 0.1 mL/kg physiological saline; group 3 each cat received 160 μg/kg prazosin hydrochloride (Sigma-Aldrich Japan K.K., Tokyo, Japan); group 4 each cat received 40 μg/kg atipamezole hydrochloride (Antisedan Nippon Zenyaku Kogyo Co., Fukushima, Japan); group 5 each cat received 160 μg/kg atipamezole hydrochloride; group 6 each cat received 480 μg/kg atipamezole hydrochloride; group 7 each cat received 40 μg/kg yohimbine hydrochloride (Sigma-Aldrich Japan K.K.); group 8 each cat received 160 μg/kg yohimbine hydrochloride; and group 9 each cat received 480 μg/kg yohimbine hydrochloride were administered 0.5 h later. Prazosin was dissolved in sterile water to obtain a concentration of 1.6 mg/mL. Yohimbine was dissolved in sterile water to obtain a concentration of 5.0 mg/mL. The groups are denoted as SAL, XYL, PRA, ATI 40, ATI 160, ATI 480, YOH 40, YOH 160, and YOH 480. A gap of at least 1 wk was maintained between successive treatments for each cat.

Food and water were withheld for 12 h before the start of each experiment. Food and water were provided after sample collection at 8 h after injection. The experiments were done in a room where the room temperature was maintained at 25°C.

Sample collection

A day before treatment, all cats were anesthetized using propofol (Propofol 1%; Intervet K.K., Tokyo, Japan), as described elsewhere (25). A 17-gauge central venous catheter (SMAC plus; Covidien Japan, Tokyo, Japan) was introduced into a jugular vein of each cat. Lidocaine (Xylocaine injection 2%; AstraZeneca K.K., Osaka, Japan) was used to assist with local analgesia at the catheterization site. A 4-Fr polyvinyl chloride catheter (Atom Multipurpose Tube; Atom Medical Corp., Tokyo, Japan) and 6-Fr silicon balloon catheter (All Silicone Foley Balloon Catheter; Create Medic Co., Kanagawa, Japan) were inserted in the urinary bladder of male and female cats, respectively. Each cat was subsequently placed in a separate cage. In order to keep the bladder catheter in place, the cats were continually put on a diaper and Elizabethan collar except for when cats were provided food and water. In addition, a soft catheter was used, and the tip of catheter was appropriately put in the bladder. One hour before the start of the experiments, the bladder of each cat was emptied by suction through the indwelling catheter in preparation for subsequent collection of urine sample. Urine and blood samples were collected 10 times [before injection of the treatment (time 0; baseline) and 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h after injection] from each cat. Blood samples (2.5 mL) and urine samples were collected from the central venous and urinary catheters, respectively. Behavioral responses were observed simultaneously with the collection of blood and urine samples. An aliquot (2.0 mL) of each blood sample was mixed with ethylenediamine tetraacetic acid (EDTA) for measurement of plasma arginine vasopressin (AVP) concentrations, and the remaining 0.5 mL was mixed with heparin for other measurements. Blood samples were immediately centrifuged at 2000 × g at 4°C for 15 min, and the plasma was separated and stored at −80°C until analysis. Urine samples were centrifuged at 2000 × g for 5 min, and the supernatant was subsequently collected and stored at −40°C until analysis.

Analytical methods

Urine volume, specific gravity, and pH; urine and plasma creatinine and electrolyte (sodium, potassium, and chloride) concentrations, as well as osmolality; and plasma AVP concentrations were measured via procedures described elsewhere (7). The osmolar clearance was calculated as follows: (urine osmolality × urine volume)/plasma osmolality. Free water clearance was calculated as follows: urine volume–osmolar clearance. The glomerular filtration rate (GFR) was assessed via creatinine clearance and calculated as follows: (urine creatinine concentration × urine volume)/plasma creatinine concentration. From these formulas, urine volume was calculated from total urine volume for 0.5 or 1 h for each time point. The fractional clearance of electrolytes was calculated as follows: (urine electrolyte concentration/plasma electrolyte concentration) × (plasma creatinine concentration/urine creatinine concentration) × 100.

Data evaluation

Statistical analysis was performed using commercially available statistical programs (GraphPad software, version 5; GraphPad Software, San Diego, California, USA). A 1-way analysis of variance (ANOVA) was used to examine the time effect within each treatment and the treatment effect at each time point. When a significant difference was detected, Tukey’s test was used to compare the means. Total urine volume was plotted against atipamezole or yohimbine doses and simple linear regression analysis was applied. The effect of the drug was considered to be dose-related when a significant difference was detected. The area under the curve (AUC) was measured by calculating the sum of trapezoids formed by the data points. Pearson’s correlation coefficient was used to examine the correlation between the total urine volume and AUC of plasma AVP. Results were expressed as mean ± standard error. For all tests, values of P < 0.05 were considered significant.

Results

All cats in the XYL and PRA groups showed transiently profound sedation including sternal and lateral recumbency for approximately 1 h, and subsequently light sedation with slight drowsiness for 2 to 3 h after xylazine administration. Both atipamezole and yohimbine dose-dependently antagonized the sedative effect of xylazine, but the highest dose of both treatments transiently induced abnormal behaviors, such as excitement, vocalization, salivation, or defecation. Vomiting was observed before sedation in all xylazine-administered cats.

For urine and plasma variables, there were no significant differences between the groups at baseline. No significant changes in urine volume or other biochemical and hormonal variables were observed in the SAL group. Urine volume significantly and similarly increased in the XYL and PRA groups compared with the baseline values (Figure 1A). The peak diuresis was observed at 2 h after injection. Comparison with the peak mean value of urine volume at 2 h with the XYL group showed that the all ATI groups and YOH 480 group significantly inhibited xylazine-induced diuresis (Figures 1B and 1C). Total urine volume for 0.5 to 5 h significantly increased in the XYL and PRA groups compared with SAL group (Figure 2A). The ATI 160, 480, and YOH 480 groups showed significantly inhibited xylazine-induced increases in the total urine volume. The linear regression of the total urine volume for 0.5–5 h after injection was significant in the YOH groups (Figure 2C), but not in the ATI groups (Figure 2B), indicating that yohimbine dose-dependently inhibited xylazine-induced diuresis, in contrast to atipamezole, at the tested doses. Similar results were observed in case of linear regression analysis of the total urine volume from 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 6, 0.5 to 7, and 0.5 to 8 h.

Figure 1.

Figure 1

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Urine volume for 5 cats before (0) and after intramuscular (IM) injection of physiological saline (SAL) or xylazine followed by saline (XYL) or by prazosin (PRA), atipamezole (ATI), or yohimbine (YOH) 0.5 h later; the last 2 drugs in doses of 40, 160, and 480 μg/kg. A, B, C: Each time point and vertical bar represents the mean and standard error (n = 5) of the diuresis rate at various time points. The lower-case letters indicate a significant difference from the baseline (0) value (a — P < 0.05; b — P < 0.01) or from the value for the XYL group (c — P < 0.05; d — P < 0.01).

Figure 2.

Figure 2

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Total urine volume for 5 cats 0.5 to 5 h after injection of prazosin or various doses of atipamezole or yohimbine. A — The symbols indicate a significant difference from the value for the SAL group (*P < 0.01) or from the value for the XYL group (†P < 0.05; ††P < 0.01). B, C — Simple linear regression of total urine volume for 5 cats 0.5 to 5 h after injection of various doses of atipamezole or yohimbine.

Urine pH significantly increased at 6 h in the XYL group and 5 h in the PRA group (Table I). In both the ATI and YOH groups, urine pH did not significantly change. Urine specific gravity significantly decreased from 1 to 4 h in both the XYL and PRA groups compared with baseline values. The ATI 480 and YOH 480 groups showed significantly inhibited xylazine-induced decreases in urine specific gravity.

Table I.

Urine pH and urine specific gravity in cats after an injection of saline (SAL) 0.1 mL/kg IM or xylazine 2 mg/kg IM followed 0.5 h later by an injection of saline (XYL) 0.1 mL/kg IV; prazosin (PRA) 160 μg/kg IV; atipamezole (ATI) 40, 160, or 480 μg/kg IV; or yohimbine (YOH) 40, 160, or 480 μg/kg IV

Time after xylazine injection (h)
Variable, group 0 0.5 1 2 3 4 5 6 7 8
Urine pH
 SAL 6.3 ± 0.3 6.3 ± 0.3 6.4 ± 0.3 6.6 ± 0.4 6.4 ± 0.3 6.4 ± 0.3 6.1 ± 0.2 6.3 ± 0.2 6.3 ± 0.2 6.4 ± 0.1
 XYL 6.2 ± 0.1 6.3 ± 0.1 6.9 ± 0.2 7.0 ± 0.1 7.0 ± 0.2 7.0 ± 0.1 6.8 ± 0.2 7.2 ± 0.3a 7.1 ± 0.3 6.8 ± 0.2
 PRA 6.5 ± 0.2 6.3 ± 0.1 6.9 ± 0.2 6.6 ± 0.2 6.9 ± 0.1 7.2 ± 0.1 7.5 ± 0.1a 7.2 ± 0.2 7.0 ± 0.2 6.8 ± 0.3
 ATI 40 6.0 ± 0.3 6.2 ± 0.2 6.5 ± 0.2 6.7 ± 0.3 6.6 ± 0.3 6.7 ± 0.3 6.7 ± 0.4 6.8 ± 0.5 6.8 ± 0.5 6.7 ± 0.4
 ATI 160 6.1 ± 0.1 6.3 ± 0.1 6.3 ± 0.1 6.6 ± 0.3 6.4 ± 0.1 6.4 ± 0.1 6.5 ± 0.1 6.5 ± 0.2 6.3 ± 0.2 6.4 ± 0.1
 ATI 480 6.1 ± 0.1 6.3 ± 0.2 6.4 ± 0.2 6.7 ± 0.3 6.7 ± 0.4 6.6 ± 0.4 6.5 ± 0.3 6.5 ± 0.2 6.5 ± 0.1 6.3 ± 0.1
 YOH 40 6.0 ± 0.2 6.0 ± 0.1 6.2 ± 0.1 6.3 ± 0.2 6.4 ± 0.1 6.6 ± 0.2 6.4 ± 0.2 6.4 ± 0.1 6.2 ± 0.2 6.1 ± 0.1
 YOH 160 5.9 ± 0.1 6.0 ± 0.1 6.4 ± 0.1 6.4 ± 0.1 6.3 ± 0.2 6.5 ± 0.2 6.5 ± 0.2 6.5 ± 0.2 6.5 ± 0.2 6.4 ± 0.1
 YOH 480 5.8 ± 0.2 6.1 ± 0.2 6.2 ± 0.2 6.2 ± 0.2 5.9 ± 0.2 5.9 ± 0.2 6.0 ± 0.1 6.3 ± 0.2 6.4 ± 0.2 6.4 ± 0.2
Urine specific gravity
 SAL 1.035 ± 0.003 1.035 ± 0.003 1.036 ± 0.003 1.037 ± 0.003d 1.039 ± 0.002d 1.037 ± 0.002 1.035 ± 0.002 1.037 ± 0.002 1.037 ± 0.002 1.035 ± 0.003
 XYL 1.043 ± 0.006 1.038 ± 0.004 1.016 ± 0.002b 1.007 ± 0.001b 1.011 ± 0.002b 1.018 ± 0.003b 1.030 ± 0.002 1.035 ± 0.003 1.036 ± 0.004 1.039 ± 0.003
 PRA 1.034 ± 0.003 1.032 ± 0.002 1.012 ± 0.003b 1.003 ± 0.001b 1.009 ± 0.002b 1.015 ± 0.004b 1.021 ± 0.003 1.024 ± 0.002 1.030 ± 0.004 1.032 ± 0.003
 ATI 40 1.031 ± 0.001 1.029 ± 0.002 1.022 ± 0.004 1.025 ± 0.005 1.019 ± 0.005 1.021 ± 0.004 1.026 ± 0.003 1.029 ± 0.002 1.033 ± 0.002 1.035 ± 0.003
 ATI 160 1.033 ± 0.002 1.030 ± 0.004 1.021 ± 0.005 1.027 ± 0.006 1.025 ± 0.004 1.024 ± 0.004 1.026 ± 0.005 1.031 ± 0.003 1.035 ± 0.002 1.036 ± 0.001
 ATI 480 1.045 ± 0.003 1.041 ± 0.005 1.033 ± 0.006 1.038 ± 0.005d 1.040 ± 0.005d 1.041 ± 0.005c 1.041 ± 0.004 1.041 ± 0.004 1.039 ± 0.002 1.042 ± 0.003
 YOH 40 1.039 ± 0.004 1.032 ± 0.001 1.022 ± 0.004 1.008 ± 0.003b 1.010 ± 0.004b 1.026 ± 0.005 1.034 ± 0.005 1.041 ± 0.004 1.041 ± 0.005 1.045 ± 0.005
 YOH 160 1.035 ± 0.003 1.037 ± 0.003 1.023 ± 0.006 1.016 ± 0.005 1.017 ± 0.003 1.021 ± 0.004 1.028 ± 0.003 1.031 ± 0.003 1.035 ± 0.002 1.037 ± 0.003
 YOH 480 1.038 ± 0.002 1.036 ± 0.002 1.030 ± 0.002 1.037 ± 0.002d 1.034 ± 0.003d 1.035 ± 0.003 1.034 ± 0.003 1.036 ± 0.002 1.035 ± 0.002 1.033 ± 0.002
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Each value represent mean concentration ± standard error (n = 5).

a,b

Value differs significantly (a P < 0.05; b P < 0.01) from the baseline value (0 h).

c,d

Within a time point, value differed significantly (c P < 0.05; d P < 0.01) from the XYL group.

Urine osmolality significantly and similarly decreased in the XYL and PRA groups compared with baseline values (Table II). The ATI 160, 480, and YOH 480 groups significantly inhibited xylazine-induced decrease in urine osmolality. Plasma osmolality did not significantly change in any of the groups compared with the baseline values, but the mean value at 3 h in the XYL group significantly increased compared with that in the SAL group. The mean value at 3 h in the YOH 480 group was significantly lower than that in the XYL group. Osmolar clearance did not significantly change in any of the groups. Free water clearance significantly and similarly increased in the XYL and PRA groups compared with the baseline values. All doses of ATI and YOH 480 groups significantly inhibited the xylazine-induced increase in free water clearance. Glomerular filtration rate did not significantly change in any of the groups.

Table II.

Plasma and urine osmolality (mmol/kg), osmolar clearance (mL/kg/min), free water clearance (mL/kg/min), and glomerular filtration rate (mL/kg/min) in cats after an injection of saline (SAL) 0.1 mL/kg IM or xylazine 2 mg/kg IM followed 0.5 h later by an injection of saline (XYL) 0.1 mL/kg IV; prazosin (PRA) 160 μg/kg IV; atipamezole (ATI) 40, 160, or 480 μg/kg IV; or yohimbine (YOH) 40, 160, or 480 μg/kg IV

Time after xylazine injection (h)
Variable, group 0 0.5 1 2 3 4 5 6 7 8
Urine osmolality
 SAL 1543 ± 156 1507 ± 153 1518 ± 161c 1570 ± 146d 1611 ± 135d 1520 ± 82 1433 ± 114 1494 ± 112 1459 ± 134 1368 ± 145
 XYL 1808 ± 257 1569 ± 189 631 ± 123b 236 ± 5b 464 ± 60b 845 ± 128b 1426 ± 57 1537 ± 87 1480 ± 144 1648 ± 109
 PRA 1623 ± 154 1459 ± 115 631 ± 129b 206 ± 19b 489 ± 128b 863 ± 188a 1112 ± 141 1219 ± 106 1476 ± 153 1515 ± 140
 ATI 40 1371 ± 84 1193 ± 76 944 ± 153 1044 ± 205 828 ± 207 958 ± 177 1183 ± 79 1273 ± 84 1345 ± 107 1456 ± 118
 ATI 160 1509 ± 128 1245 ± 168 921 ± 185 1242 ± 224d 1155 ± 187 1076 ± 169 1165 ± 188 1387 ± 138 1534 ± 118 1540 ± 56
 ATI 480 1938 ± 152 1636 ± 200 1327 ± 203 1593 ± 207d 1784 ± 142d 1759 ± 173c 1831 ± 124 1804 ± 105 1673 ± 70 1781 ± 72
 YOH 40 1523 ± 108 1360 ± 38 902 ± 160 367 ± 97b 457 ± 136b 1082 ± 170 1415 ± 187 1617 ± 168 1701 ± 215 1833 ± 198
 YOH 160 1619 ± 125 1564 ± 127 1003 ± 260 768 ± 238 828 ± 144 1022 ± 166 1265 ± 132 1319 ± 109 1454 ± 140 1489 ± 159
 YOH 480 1684 ± 102 1515 ± 98 1205 ± 71b 1522 ± 109d 1462 ± 92d 1491 ± 87 1394 ± 91 1427 ± 102 1333 ± 76 1346 ± 92
Plasma osmolality
 SAL 318.6 ± 1.9 317.8 ± 1.7 317.6 ± 2.0 318.0 ± 2.2 316.8 ± 1.3c 316.2 ± 1.0 317.0 ± 1.3 316.0 ± 1.1 317.4 ± 1.8 318.0 ± 1.2
 XYL 319.2 ± 1.6 319.6 ± 1.1 323.0 ± 1.1 324.8 ± 1.7 326.6 ± 1.3 322.6 ± 1.5 322.6 ± 1.4 323.4 ± 1.5 323.0 ± 1.5 323.8 ± 1.3
 PRA 317.2 ± 2.5 317.4 ± 2.8 319.4 ± 2.5 322.8 ± 2.5 323.8 ± 1.8 321.8 ± 2.6 321.6 ± 2.1 321.6 ± 2.1 321.6 ± 2.1 321.6 ± 2.0
 ATI 40 318.0 ± 2.0 318.8 ± 2.2 321.2 ± 2.2 321.0 ± 1.9 320.4 ± 2.4 321.0 ± 2.7 321.8 ± 2.9 319.4 ± 3.0 320.6 ± 3.1 320.2 ± 3.1
 ATI 160 316.6 ± 1.7 318.6 ± 2.2 317.6 ± 1.5 318.6 ± 1.9 317.6 ± 2.1 319.4 ± 1.7 318.2 ± 1.4 320.0 ± 2.1 319.6 ± 1.8 319.4 ± 1.4
 ATI 480 318.4 ± 1.8 319.4 ± 2.1 323.2 ± 3.5 320.2 ± 3.2 319.0 ± 2.7 318.0 ± 2.1 320.6 ± 2.0 321.6 ± 1.6 321.4 ± 1.3 322.0 ± 2.0
 YOH 40 317.6 ± 2.3 319.0 ± 1.5 319.4 ± 0.8 321.8 ± 1.9 319.4 ± 1.7 321.0 ± 1.7 321.8 ± 1.8 321.6 ± 2.0 320.2 ± 1.2 322.6 ± 1.1
 YOH 160 315.4 ± 1.9 316.4 ± 1.1 316.4 ± 0.9 317.8 ± 1.2 318.2 ± 0.9 317.6 ± 0.5 317.2 ± 1.1 317.8 ± 1.2 317.4 ± 1.1 319.0 ± 1.9
 YOH 480 317.2 ± 1.1 317.2 ± 1.2 321.2 ± 1.7 317.0 ± 0.7 316.6 ± 0.5c 317.0 ± 1.3 317.6 ± 1.5 319.0 ± 1.3 319.6 ± 1.4 319.8 ± 2.0
Osmolar clearance
 SAL 0.065 ± 0.005 0.064 ± 0.006 0.061 ± 0.006 0.065 ± 0.007 0.064 ± 0.007 0.058 ± 0.009 0.052 ± 0.009 0.049 ± 0.008 0.048 ± 0.006 0.045 ± 0.004
 XYL 0.055 ± 0.010 0.053 ± 0.008 0.059 ± 0.010 0.064 ± 0.008 0.060 ± 0.007 0.058 ± 0.009 0.049 ± 0.008 0.043 ± 0.003 0.038 ± 0.005 0.044 ± 0.004
 PRA 0.050 ± 0.001 0.053 ± 0.003 0.066 ± 0.002 0.050 ± 0.005 0.056 ± 0.006 0.057 ± 0.009 0.048 ± 0.008 0.050 ± 0.008 0.049 ± 0.008 0.048 ± 0.007
 ATI 40 0.049 ± 0.004 0.044 ± 0.009 0.059 ± 0.006 0.066 ± 0.006 0.056 ± 0.003 0.046 ± 0.007 0.048 ± 0.006 0.036 ± 0.003 0.037 ± 0.002 0.039 ± 0.001
 ATI 160 0.059 ± 0.007 0.057 ± 0.008 0.064 ± 0.001 0.056 ± 0.006 0.052 ± 0.004 0.045 ± 0.003 0.046 ± 0.005 0.043 ± 0.002 0.043 ± 0.005 0.045 ± 0.002
 ATI 480 0.066 ± 0.010 0.069 ± 0.006 0.072 ± 0.008 0.060 ± 0.006 0.061 ± 0.008 0.060 ± 0.004 0.060 ± 0.005 0.062 ± 0.009 0.056 ± 0.005 0.050 ± 0.004
 YOH 40 0.044 ± 0.005 0.044 ± 0.004 0.061 ± 0.006 0.053 ± 0.006 0.037 ± 0.004 0.037 ± 0.002 0.038 ± 0.003 0.037 ± 0.002 0.040 ± 0.004 0.041 ± 0.004
 YOH 160 0.062 ± 0.003 0.061 ± 0.006 0.062 ± 0.007 0.061 ± 0.007 0.066 ± 0.008 0.050 ± 0.005 0.049 ± 0.003 0.041 ± 0.004 0.043 ± 0.002 0.043 ± 0.005
 YOH 480 0.062 ± 0.006 0.065 ± 0.005 0.057 ± 0.003 0.067 ± 0.009 0.064 ± 0.006 0.060 ± 0.004 0.051 ± 0.002 0.051 ± 0.004 0.047 ± 0.003 0.048 ± 0.004
Free water clearance
 SAL −0.051 ± 0.005 −0.050 ± 0.006 −0.048 ± 0.006 −0.052 ± 0.007d −0.051 ± 0.007 −0.046 ± 0.007 −0.041 ± 0.008 −0.039 ± 0.007 −0.037 ± 0.005 −0.035 ± 0.004
 XYL −0.046 ± 0.010 −0.042 ± 0.007 −0.026 ± 0.009 0.024 ± 0.002a −0.014 ± 0.007 −0.033 ± 0.008 −0.038 ± 0.006 −0.032 ± 0.003 −0.029 ± 0.005 −0.035 ± 0.003
 PRA −0.039 ± 0.002 −0.041 ± 0.002 −0.022 ± 0.011 0.029 ± 0.005a −0.001 ± 0.017 −0.028 ± 0.012 −0.032 ± 0.004 −0.036 ± 0.005 −0.036 ± 0.005 −0.037 ± 0.005
 ATI 40 −0.041 ± 0.003 −0.031 ± 0.006 −0.033 ± 0.005 −0.032 ± 0.015c −0.016 ± 0.014 −0.025 ± 0.004 −0.034 ± 0.004 −0.027 ± 0.002 −0.028 ± 0.002 −0.031 ± 0.001
 ATI 160 −0.046 ± 0.006 −0.042 ± 0.007 −0.035 ± 0.007 −0.040 ± 0.006d −0.036 ± 0.003 −0.029 ± 0.004 −0.030 ± 0.006 −0.033 ± 0.002 −0.034 ± 0.004 −0.036 ± 0.002
 ATI 480 −0.055 ± 0.009 −0.055 ± 0.007 −0.052 ± 0.008 −0.046 ± 0.005d −0.049 ± 0.006 −0.048 ± 0.003 −0.049 ± 0.004 −0.051 ± 0.007 −0.045 ± 0.004 −0.041 ± 0.003
 YOH 40 −0.035 ± 0.005 −0.034 ± 0.003 −0.036 ± 0.007 0.008 ± 0.010a 0.003 ± 0.009a −0.024 ± 0.002 −0.028 ± 0.002 −0.029 ± 0.001 −0.032 ± 0.003 −0.034 ± 0.003
 YOH 160 −0.049 ± 0.003 −0.049 ± 0.005 −0.035 ± 0.009 −0.014 ± 0.017 −0.037 ± 0.009 −0.031 ± 0.003 −0.036 ± 0.003 −0.031 ± 0.004 −0.032 ± 0.003 −0.033 ± 0.005
 YOH 480 −0.050 ± 0.005 −0.051 ± 0.005 −0.042 ± 0.002 −0.053 ± 0.008d −0.050 ± 0.004 −0.046 ± 0.002 −0.039 ± 0.002 −0.039 ± 0.004 −0.036 ± 0.003 −0.036 ± 0.003
Glomerular filtration rate
 SAL 2.42 ± 0.11 2.65 ± 0.14 2.54 ± 0.24 2.88 ± 0.34 2.71 ± 0.15 2.51 ± 0.24 2.21 ± 0.28 2.21 ± 0.19 2.24 ± 0.17 2.37 ± 0.27
 XYL 2.34 ± 0.31 2.29 ± 0.13 2.46 ± 0.27 2.22 ± 0.19 1.84 ± 0.07 1.83 ± 0.13 1.72 ± 0.14 1.68 ± 0.09 1.57 ± 0.12 1.83 ± 0.08
 PRA 2.21 ± 0.14 2.23 ± 0.20 2.29 ± 0.25 1.66 ± 0.16 2.00 ± 0.26 1.80 ± 0.22 1.64 ± 0.22 1.82 ± 0.15 1.80 ± 0.20 1.83 ± 0.17
 ATI 40 1.91 ± 0.14 1.78 ± 0.23 2.27 ± 0.09 2.26 ± 0.10 2.27 ± 0.19 1.73 ± 0.23 1.92 ± 0.15 1.56 ± 0.12 1.77 ± 0.17 1.80 ± 0.09
 ATI 160 2.25 ± 0.10 2.16 ± 0.17 2.43 ± 0.11 1.99 ± 0.13 1.87 ± 0.12 1.75 ± 0.14 1.71 ± 0.10 1.69 ± 0.09 1.72 ± 0.13 1.98 ± 0.16
 ATI 480 2.63 ± 0.18 2.61 ± 0.10 2.41 ± 0.26 2.19 ± 0.13 2.11 ± 0.19 2.04 ± 0.06 2.06 ± 0.12 2.27 ± 0.19 2.21 ± 0.11 2.13 ± 0.09
 YOH 40 2.18 ± 0.10 2.05 ± 0.19 2.66 ± 0.16 2.01 ± 0.11 1.60 ± 0.23 1.54 ± 0.12 1.53 ± 0.06 1.57 ± 0.04 1.71 ± 0.14 1.75 ± 0.19
 YOH 160 2.49 ± 0.14 2.69 ± 0.15 2.24 ± 0.16 2.40 ± 0.31 2.09 ± 0.07 2.08 ± 0.12 2.04 ± 0.10 1.99 ± 0.08 2.25 ± 0.17 2.20 ± 0.19
 YOH 480 2.15 ± 0.17 2.25 ± 0.17 2.23 ± 0.11 2.55 ± 0.22 2.35 ± 0.10 2.39 ± 0.10 2.18 ± 0.15 2.23 ± 0.07 2.18 ± 0.11 2.14 ± 0.12
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Each value represent mean concentration ± standard error (n = 5).

a,b

Value differs significantly (a P < 0.05; b P < 0.01) from the baseline value (0 h).

c,d

Within a time point, value differed significantly (c P < 0.05; d P < 0.01) from the XYL group.

Plasma AVP concentrations significantly and similarly increased at 4 to 7 h in the XYL and PRA groups compared with the baseline values after the xylazine-induced increase in urine volume had stopped (returned to the baseline; Figure 3A). Plasma AVP concentrations in the ATI 480 and YOH 480 groups significantly increased at 1 h compared with the value in the XYL group (Figures 3B and 3C). The AUC value for plasma AVP from 0.5 to 2 h significantly increased in the ATI 480 and YOH 480 groups compared with the SAL or XYL group (Figure 4). There were no correlations between the total urine volume and the AUC of plasma AVP from 0.5 to 2 h in any of the groups.

Figure 3.

Figure 3

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Plasma AVP concentration (A, B, C) for 5 cats before and after injection of saline or xylazine. SAL — physiological saline; XYL — xylazine followed by saline; PRA — prazosin; ATI — atipamezole; YOH — yohimbine. The lower-case letters indicate a significant difference from the baseline (0) value (a — P < 0.05; b — P < 0.01) or from the value for the XYL group (c — P < 0.05; d — P < 0.01).

Figure 4.

Figure 4

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Area under the curve (AUC) data for plasma AVP concentration for 5 cats after injection of the prazosin or various doses of atipamezole or yohimbine from 0.5 to 2 h. The symbols indicate a significant difference from the value for the SAL group (*P < 0.05) or from the value for the XYL group (†P < 0.05).

Plasma sodium, potassium, and chloride concentrations did not significantly change in any of the groups (Table III). The fractional clearance of sodium tended to increase at 3 to 5 h similarly in the XYL and PRA groups. The mean value of the fractional clearance of sodium at 4 h in the XYL group significantly increased compared with the value in the SAL group. The fractional clearance of sodium did not significantly change in any of the ATI groups. Significant increases were also observed at 3 h in the YOH 160 group and at 4 h in the YOH 40 group compared with the baseline values. The fractional clearance of potassium significantly increased at 5 to 8 h in the PRA group compared with the baseline values. The fractional clearance of potassium significantly decreased at 4 h in the ATI 160 and ATI 480 groups and at 4 and 7 h in the YOH 480 group compared with the XYL group. The fractional clearance of chloride did not significantly change in any of the groups.

Table III.

Plasma sodium, potassium, and chloride concentrations (mmol/L) and fractional clearance of sodium, potassium, and chloride (%) in cats after an injection of saline (SAL) 0.1 mL/kg IM or xylazine 2 mg/kg IM followed 0.5 h later by an injection of saline (XYL) 0.1 mL/kg IV; prazosin (PRA) 160 μg/kg IV; atipamezole (ATI) 40, 160, or 480 μg/kg IV; or yohimbine (YOH) 40, 160, or 480 μg/kg IV

Time after xylazine injection (h)
Variable, group 0 0.5 1 2 3 4 5 6 7 8
Plasma sodium
 SAL 154.2 ± 0.7 154.0 ± 0.6 154.4 ± 1.0 154.6 ± 0.8 154.4 ± 0.7 154.2 ± 0.7 154.8 ± 0.8 155.0 ± 0.7 155.0 ± 0.7 155.2 ± 0.7
 XYL 154.0 ± 0.8 152.2 ± 1.1 151.6 ± 1.0 153.0 ± 0.9 154.2 ± 0.7 154.2 ± 1.2 155.4 ± 0.8 155.0 ± 0.6 155.0 ± 0.7 154.8 ± 0.9
 PRA 153.2 ± 0.5 150.8 ± 0.9 151.2 ± 1.0 152.0 ± 1.0 153.4 ± 0.9 154.8 ± 0.5 155.0 ± 0.5 154.8 ± 0.7 154.2 ± 0.5 154.0 ± 0.3
 ATI 40 156.0 ± 0.9 153.0 ± 0.6 153.8 ± 0.9 153.6 ± 0.8 155.8 ± 1.2 156.0 ± 1.0 156.8 ± 0.8 155.8 ± 0.9 155.8 ± 1.0 156.0 ± 1.2
 ATI 160 154.2 ± 0.7 151.8 ± 0.4 153.8 ± 0.7 152.8 ± 0.8 153.0 ± 0.7 153.2 ± 0.4 153.8 ± 0.7 153.4 ± 0.6 154.2 ± 0.6 153.6 ± 0.7
 ATI 480 155.6 ± 1.7 152.8 ± 1.2 155.4 ± 1.3 156.6 ± 1.9 155.0 ± 1.1 154.8 ± 1.0 154.8 ± 1.4 155.0 ± 0.9 154.6 ± 0.7 154.8 ± 0.8
 YOH 40 153.2 ± 0.9 150.8 ± 1.1 151.2 ± 1.0 153.4 ± 0.6 153.8 ± 0.7 154.8 ± 0.8 154.0 ± 0.6 154.8 ± 0.9 154.4 ± 0.6 154.8 ± 0.6
 YOH 160 154.0 ± 0.6 152.2 ± 0.6 154.2 ± 0.7 154.2 ± 0.7 154.6 ± 1.2 155.2 ± 1.0 155.4 ± 1.1 155.6 ± 1.0 154.8 ± 1.1 155.6 ± 1.0
 YOH 480 154.2 ± 0.8 153.2 ± 0.9 155.8 ± 0.7 154.8 ± 0.6 155.0 ± 0.6 154.8 ± 1.0 154.8 ± 0.7 155.2 ± 0.7 155.6 ± 0.9 155.6 ± 0.9
Plasma potassium
 SAL 3.72 ± 0.09 3.66 ± 0.08 3.66 ± 0.05 3.78 ± 0.13 3.90 ± 0.12 3.76 ± 0.12 3.82 ± 0.13 3.80 ± 0.14 3.78 ± 0.14 3.72 ± 0.13
 XYL 3.56 ± 0.09 3.66 ± 0.07 3.76 ± 0.05 3.74 ± 0.13 3.76 ± 0.13 3.74 ± 0.06 3.76 ± 0.10 3.84 ± 0.11 3.72 ± 0.13 3.86 ± 0.10
 PRA 3.76 ± 0.21 3.68 ± 0.11 3.60 ± 0.11 3.72 ± 0.16 3.52 ± 0.19 3.54 ± 0.17 3.56 ± 0.12 3.48 ± 0.21 3.54 ± 0.16 3.64 ± 0.09
 ATI 40 3.84 ± 0.18 3.80 ± 0.04 3.70 ± 0.20 3.82 ± 0.12 3.68 ± 0.07 3.72 ± 0.08 3.90 ± 0.19 3.74 ± 0.07 3.70 ± 0.06 3.76 ± 0.15
 ATI 160 3.68 ± 0.17 3.60 ± 0.09 3.44 ± 0.15 3.54 ± 0.09 3.66 ± 0.10 3.88 ± 0.15 3.76 ± 0.13 3.84 ± 0.16 3.88 ± 0.16 3.80 ± 0.19
 ATI 480 4.02 ± 0.14 3.84 ± 0.12 3.46 ± 0.19 3.76 ± 0.26 4.02 ± 0.18 4.00 ± 0.12 3.84 ± 0.10 3.80 ± 0.07 3.82 ± 0.06 3.78 ± 0.12
 YOH 40 3.66 ± 0.18 3.70 ± 0.15 3.82 ± 0.15 3.72 ± 0.15 3.74 ± 0.24 3.90 ± 0.17 3.82 ± 0.15 3.78 ± 0.11 3.84 ± 0.24 3.86 ± 0.23
 YOH 160 3.88 ± 0.11 3.64 ± 0.07 3.62 ± 0.13 3.70 ± 0.08 3.66 ± 0.17 3.72 ± 0.11 3.68 ± 0.12 3.74 ± 0.10 3.68 ± 0.07 3.76 ± 0.08
 YOH 480 3.76 ± 0.14 3.84 ± 0.06 3.42 ± 0.18 3.70 ± 0.17 3.94 ± 0.08 4.06 ± 0.20 3.86 ± 0.13 3.90 ± 0.14 4.06 ± 0.15 3.84 ± 0.18
Plasma chloride
 SAL 117.8 ± 0.8 117.2 ± 0.7 117.6 ± 0.6 116.8 ± 0.3 118.0 ± 0.7 118.0 ± 0.3 118.2 ± 0.2 118.4 ± 0.2 118.8 ± 0.5 118.6 ± 0.5
 XYL 116.6 ± 1.8 115.2 ± 2.1 114.2 ± 2.4 115.8 ± 1.6 116.6 ± 1.8 116.6 ± 1.6 117.4 ± 1.9 117.8 ± 1.8 117.6 ± 1.6 118.4 ± 1.7
 PRA 118.0 ± 1.7 115.6 ± 2.0 115.8 ± 1.6 115.8 ± 2.4 117.8 ± 2.2 118.8 ± 1.8 119.4 ± 1.7 119.4 ± 1.8 118.6 ± 1.8 119.8 ± 1.4
 ATI 40 120.4 ± 0.9 118.6 ± 0.7 119.0 ± 0.5 118.4 ± 1.0 119.6 ± 0.9 120.6 ± 0.7 121.6 ± 0.2 120.6 ± 0.8 120.8 ± 0.8 121.2 ± 1.0
 ATI 160 117.6 ± 1.1 115.8 ± 1.0 117.2 ± 0.6 117.6 ± 0.7 118.0 ± 0.7 117.8 ± 0.9 118.4 ± 0.7 118.2 ± 0.7 119.0 ± 0.4 120.0 ± 0.9
 ATI 480 119.8 ± 1.5 117.0 ± 1.5 118.4 ± 1.1 119.8 ± 1.2 119.8 ± 1.0 119.0 ± 0.8 119.0 ± 0.7 118.8 ± 0.9 118.2 ± 0.6 119.4 ± 0.8
 YOH 40 117.6 ± 1.9 115.2 ± 2.1 115.6 ± 2.1 117.2 ± 1.7 118.0 ± 2.0 119.6 ± 2.1 119.0 ± 1.9 120.0 ± 1.5 119.6 ± 2.2 120.0 ± 1.7
 YOH 160 119.0 ± 0.7 117.2 ± 0.8 118.2 ± 0.9 118.6 ± 0.9 119.2 ± 1.2 120.2 ± 1.1 119.4 ± 1.2 120.4 ± 1.4 119.6 ± 1.3 120.6 ± 1.4
 YOH 480 118.2 ± 1.0 117.0 ± 1.0 118.4 ± 1.1 118.8 ± 1.4 118.6 ± 1.1 119.6 ± 1.3 119.2 ± 1.2 119.4 ± 1.4 120.2 ± 1.6 121.0 ± 1.3
Fractional clearance of sodium
 SAL 0.31 ± 0.05 0.28 ± 0.04 0.29 ± 0.03 0.27 ± 0.02 0.26 ± 0.03 0.25 ± 0.04c 0.27 ± 0.07 0.28 ± 0.06 0.29 ± 0.06 0.31 ± 0.07
 XYL 0.26 ± 0.07 0.26 ± 0.05 0.51 ± 0.11 0.76 ± 0.22 1.31 ± 0.31 1.42 ± 0.49 0.87 ± 0.21 0.73 ± 0.21 0.62 ± 0.16 0.62 ± 0.16
 PRA 0.39 ± 0.15 0.31 ± 0.11 0.71 ± 0.22 0.67 ± 0.18 0.94 ± 0.20 1.37 ± 0.37 1.06 ± 0.34 0.95 ± 0.19 0.70 ± 0.19 0.65 ± 0.14
 ATI 40 0.29 ± 0.05 0.31 ± 0.04 0.55 ± 0.08 0.77 ± 0.12 0.77 ± 0.18 1.06 ± 0.36 0.89 ± 0.27 0.76 ± 0.27 0.56 ± 0.15 0.54 ± 0.09
 ATI 160 0.26 ± 0.07 0.30 ± 0.06 0.52 ± 0.10 0.69 ± 0.09 0.79 ± 0.17 0.66 ± 0.10 0.73 ± 0.12 0.74 ± 0.12 0.63 ± 0.17 0.39 ± 0.09
 ATI 480 0.34 ± 0.11 0.35 ± 0.08 0.67 ± 0.19 0.95 ± 0.36 0.85 ± 0.21 0.91 ± 0.21 0.90 ± 0.21 0.78 ± 0.17 0.65 ± 0.17 0.50 ± 0.19
 YOH 40 0.11 ± 0.02 0.17 ± 0.03 0.25 ± 0.03 0.43 ± 0.06 0.35 ± 0.09 0.66 ± 0.16a 0.61 ± 0.15 0.48 ± 0.11 0.39 ± 0.09 0.37 ± 0.11
 YOH 160 0.23 ± 0.03 0.23 ± 0.03 0.47 ± 0.08 0.57 ± 0.11 1.16 ± 0.22b 0.75 ± 0.13 0.69 ± 0.13 0.49 ± 0.10 0.36 ± 0.06 0.32 ± 0.05
 YOH 480 0.25 ± 0.03 0.29 ± 0.05 0.39 ± 0.06 0.44 ± 0.10 0.50 ± 0.14 0.38 ± 0.08 0.52 ± 0.11 0.49 ± 0.11 0.41 ± 0.11 0.42 ± 0.09
Fractional clearance of potassium
 SAL 16.5 ± 1.0 14.8 ± 0.9 16.5 ± 2.0 15.0 ± 1.8 13.8 ± 1.4 14.7 ± 1.2 14.0 ± 0.9 14.6 ± 1.6 12.8 ± 1.4 11.3 ± 1.4
 XYL 13.5 ± 2.8 12.6 ± 2.7 12.9 ± 1.7 14.5 ± 0.9 17.7 ± 3.1 27.5 ± 7.4 26.7 ± 4.3 22.3 ± 2.9 21.5 ± 2.5 19.9 ± 4.4
 PRA 9.7 ± 1.0 9.8 ± 1.7 21.7 ± 3.4 16.7 ± 2.5 18.3 ± 2.6 17.6 ± 1.7 25.4 ± 5.6a 26.0 ± 3.0a 24.3 ± 2.0 25.3 ± 2.7a
 ATI 40 10.7 ± 1.9 10.7 ± 2.0 19.3 ± 3.2 16.2 ± 2.4 12.0 ± 1.2 13.4 ± 1.4 14.9 ± 1.6 15.8 ± 1.3 15.7 ± 2.0 17.9 ± 1.4
 ATI 160 11.6 ± 1.2 11.0 ± 1.4 13.8 ± 1.2 16.5 ± 2.8 13.0 ± 1.2 10.4 ± 1.2c 13.3 ± 0.9 19.1 ± 2.3 18.4 ± 0.9 18.8 ± 2.8
 ATI 480 10.0 ± 2.8 12.1 ± 2.1 17.2 ± 3.2 14.8 ± 3.2 11.6 ± 1.7 11.7 ± 1.4c 14.3 ± 1.5 17.7 ± 2.0 19.3 ± 2.1 18.9 ± 3.5
 YOH 40 7.4 ± 0.8 9.5 ± 1.1 11.6 ± 1.6 15.5 ± 2.6 12.4 ± 1.3 14.9 ± 1.3 17.7 ± 3.6 17.3 ± 1.6 13.8 ± 2.0 19.1 ± 2.6a
 YOH 160 13.3 ± 1.5 12.8 ± 1.2 20.2 ± 2.6 18.2 ± 1.8 19.8 ± 4.0 14.7 ± 2.6 16.8 ± 2.7 13.5 ± 2.5 12.2 ± 2.2 11.5 ± 1.7
 YOH 480 12.5 ± 2.9 13.8 ± 2.4 14.4 ± 1.5 13.4 ± 1.3 12.1 ± 1.5 10.9 ± 1.3c 12.2 ± 2.2 12.4 ± 2.5 9.0 ± 1.6d 10.3 ± 2.0
Fractional clearance of chloride
 SAL 0.73 ± 0.11 0.60 ± 0.11 0.57 ± 0.10 0.59 ± 0.12 0.58 ± 0.13 0.55 ± 0.14 0.59 ± 0.17 0.56 ± 0.15 0.52 ± 0.13 0.48 ± 0.13
 XYL 0.41 ± 0.14 0.30 ± 0.05 0.37 ± 0.04 0.51 ± 0.16 1.06 ± 0.28 1.55 ± 0.59 0.92 ± 0.20 0.66 ± 0.16 0.57 ± 0.13 0.54 ± 0.11
 PRA 0.68 ± 0.22 0.50 ± 0.15 0.56 ± 0.15 0.57 ± 0.14 0.82 ± 0.21 1.30 ± 0.34 1.07 ± 0.34 0.98 ± 0.16 0.67 ± 0.15 0.52 ± 0.10
 ATI 40 0.68 ± 0.17 0.49 ± 0.08 0.55 ± 0.10 0.64 ± 0.11 0.68 ± 0.18 1.15 ± 0.45 0.99 ± 0.34 0.78 ± 0.24 0.59 ± 0.14 0.50 ± 0.09
 ATI 160 0.73 ± 0.14 0.51 ± 0.09 0.69 ± 0.14 0.77 ± 0.11 0.83 ± 0.19 0.57 ± 0.09 0.66 ± 0.13 0.57 ± 0.09 0.60 ± 0.16 0.44 ± 0.11
 ATI 480 0.85 ± 0.26 0.55 ± 0.12 0.91 ± 0.26 1.24 ± 0.51 0.93 ± 0.22 0.86 ± 0.29 0.81 ± 0.31 0.70 ± 0.26 0.53 ± 0.20 0.50 ± 0.21
 YOH 40 0.40 ± 0.09 0.29 ± 0.06 0.23 ± 0.04 0.40 ± 0.04 0.32 ± 0.09 0.79 ± 0.24 0.69 ± 0.22 0.53 ± 0.15 0.37 ± 0.08 0.35 ± 0.09
 YOH 160 0.80 ± 0.11 0.43 ± 0.07 0.46 ± 0.10 0.63 ± 0.15 1.39 ± 0.25 1.10 ± 0.16 0.99 ± 0.21 0.60 ± 0.12 0.48 ± 0.08 0.51 ± 0.10
 YOH 480 0.83 ± 0.09 0.48 ± 0.08 0.48 ± 0.06 0.65 ± 0.11 0.84 ± 0.25 0.59 ± 0.13 0.57 ± 0.14 0.45 ± 0.06 0.39 ± 0.06 0.43 ± 0.07
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Each value represent mean concentration ± standard error (n = 5).

a,b

Value differs significantly (a P < 0.05; b P < 0.01) from the baseline value (0 h).

c,d

Within a time point, value differed significantly (c P < 0.05; d P < 0.01) from the XYL group.

Discussion

The results of this study indicate that both atipamezole and yohimbine, but not prazosin, have antagonistic effects on xylazine-induced diuresis in healthy cats. These effects are consistent with the results of studies on the antagonistic action of atipamezole or yohimbine on xylazine- or medetomidine-induced diuresis in dogs (8,26) and rats (14,16–19). Prazosin has inconsistent results for decrease in the elevated urinary output caused by some α2-adrenoceptor agonists in rats (19,27,28). Our results indicated that the xylazine-induced diuretic effect in cats is not mediated by the α1-adrenoceptor because it was not antagonized by prazosin. In the present study, yohimbine dose-dependently inhibited xylazine-induced diuresis, in contrast to atipamezole, at the tested doses. Atipamezole is known to be a highly selective and specific antagonist compared with yohimbine for centrally and peripherally located α2-adrenoceptors (22). Thus, the difference in responses to atipamezole and yohimbine may have been attributable to the differences in α2-adrenoceptor selectivity, and high-dose of atipamezole may have shown a ceiling effect. Atipamezole has an imidazoline structure in contrast to yohimbine, but assessing the influence of these actions on xylazine-induced diuresis in this study was not possible.

In the present study, urine pH significantly increased in the XYL and PRA groups. These results differed from our previous findings that showed that xylazine did not significantly increase urine pH in cats (20). This difference may be because of the fact that cats in the previous study were administered fluids prior to xylazine treatment.

The changes in urine specific gravity and osmolality corresponded to the increase in urine volume after xylazine administration and antidiuretic action of atipamezole and yohimbine. In addition, higher doses of atipamezole and yohimbine potently reversed the xylazine-induced changes and tended to accelerate recovery from the decreases in urine specific gravity and osmolality.

Osmolar clearance in the present study did not significantly change in any of the groups. In contrast, there was an almost perfect correlation between the increase in free water clearance and the increase in urine volume after xylazine administration. A previous study on rats proposed that xylazine or clonidine caused increase in both osmolar clearance and free water clearance (19,29,30). Moreover, the clonidine-induced increase in free water clearance is blocked by prazosin (29). However, our results in cats revealed that the diuretic effect of xylazine was caused only by an increase in free water clearance, which was blocked by atipamezole and yohimbine, α2-adrenoceptor antagonists, but not by prazosin, α1-adrenoceptor antagonist. Therefore, our results suggest that the mechanism of xylazine-induced diuresis in cats differs from that in rats.

In the present study, the plasma AVP significantly increased in the XYL group after the diuretic effect had returned to the baseline. Plasma AVP secretion is controlled by osmotic stimulus and also cardiovascular reflexes that respond to decrease blood pressure and/or blood volume. In addition, AVP is considerably more sensitive to small changes in osmolality than to similar percentage changes in blood volume (31). Our results showed that plasma osmolality significantly increased at 3 h after peak diuresis in the XYL group. Therefore, stimulation of plasma AVP release after diuresis may cause by osmoreceptor-AVP feedback system. Both atipamezole and yohimbine tended to prevent the increase in plasma AVP concentrations after xylazine-induced diuretic effect. Furthermore, the highest dose of both treatments caused a transient but significant increase in the AUC value for plasma AVP from 0.5 to 2 h. One possible explanation for this change is that the mean values of plasma osmolality increased, but not significantly, at 1 h in the ATI 480 and YOH 480 groups, because a change in plasma osmolality of only 1% is sufficient to increase plasma AVP concentrations (31). A second explanation is that an overdose of α2-adrenoceptor antagonists may lead to hypotension. A previous study in dogs under sedation by medetomidine combined with midazolam and opioids revealed that mean arterial pressure significantly decrease after atipamezole administration (32). Although the precise mechanism of the increase in plasma AVP after the administration of higher doses of atipamezole and yohimbine is unknown, this increase may be involved in the anti-diuretic action of only high doses of both agents, for xylazine-induced diuresis in cats.

The AUC value for plasma AVP from 0.5 to 2 h did not significantly change in the XYL group compared with the SAL group. Further, there was no association between the total urine volume and the AUC of plasma AVP from 0.5 to 2 h in any of the groups. These results suggest that the xylazine-induced diuretic effect in the present study may have been independent of the changes in plasma AVP concentration. An in vitro study (33) revealed that α2-adrenoceptor agonists (dexmedetomidine and clonidine) inhibited AVP-stimulated osmotic water permeability, which was reversed by α2-adrenoceptor antagonists (yohimbine and atipamezole), except prazosin, in the rat collecting duct. Therefore, the antagonistic effects of atipamezole and yohimbine on xylazine-induced diuresis observed in this study may have been attributed to the changes in water permeability of α2-adrenoceptors in the collecting duct.

Plasma sodium and chloride concentrations did not significantly change in any of groups in this study. We have previously shown that plasma sodium concentration significantly increased after administration of high xylazine doses (8 mg/kg IM) in cats (20). A previous study has also reported that plasma potassium significantly increased after administration of 2 mg/kg IM xylazine and higher doses of atipamezole and yohimbine prevented the xylazine-induced increase in plasma potassium concentration in dogs (8). Our result showed that, in contrast to dogs, plasma potassium concentration did not increase in cats. Therefore, it is suggested that plasma ionic regulation to maintain an appropriate plasma potassium concentration is well-controlled in cats compared with dogs.

Fractional clearance of sodium and potassium significantly increased after diuresis had peaked following xylazine administration, suggesting that this event is a rebound phenomenon. High doses of both atipamezole and yohimbine prevented the xylazine-induced increases in fractional clearance of sodium and potassium in the present study. These results indicate that the anti-diuretic actions of atipamezole and yohimbine contributed to reduce the xylazine-induced changes in fractional clearances of sodium and potassium. Fractional electrolyte excretion tests have been used for evaluation of renal dysfunction, particularly tubule impairments, in veterinary nephrology (34). Therefore, when xylazine is administered in cats, the influence of xylazine on the interpretation of urinalysis should be considered, even if α2-adrenoceptor antagonists are used.

In the present study, 3 different doses of both atipamezole and yohimbine were evaluated for determining the effective dose in antagonizing xylazine-induced diuresis in normal cats. Administration of 2 mg/kg xylazine approximately increased urine volume to 7 times in the peak diuresis, and subsequently caused dehydration in cats. Although this adverse effect of xylazine is independent of changes in glomerular filtration rate, we need to consider it for antagonizing the diuresis, especially in cats with urinary tract obstruction, dehydration, or hypovolemia. A moderate dose of atipamezole (160 μg/kg) for 2 mg/kg xylazine can be clinically recommended because this dose produces an anti-diuretic effect without causing frequent behavioral side effects and hormonal changes. High doses of atipamezole and yohimbine (480 μg/kg) are certain to counteract the diuretic action of xylazine, but these doses are not recommended normally because they induced abnormal behaviors such as excitement, vocalization, salivation, or defecation. On the other hand, there are limitations in this study, because the sample size is small and the cats were heterogeneous. In addition, we could not measure the arterial blood pressure and arterial blood gas analysis in this study. More studies with the use of larger populations would be necessary to determine the clinical influence of diuresis via α2-adrenoceptors in cats.

In conclusion, both atipamezole and yohimbine showed profound anti-diuretic effects for xylazine-induced diuresis but prazosin did not. Although, in contrast to yohimbine, atipamezole did not dose-dependently inhibit diuretic action it had a greater inhibitory effect compared with yohimbine at our tested doses. The xylazine-induced diuretic effect in cats may be mediated by α2-adrenoceptors but not by α1-adrenoceptors. Increases in plasma AVP concentration after administration of high doses of both atipamezole and yohimbine may be involved in the anti-diuretic actions of both agents for xylazine-induced diuresis in cats. Both drugs can be used as antagonists against xylazine-induced diuresis in clinically normal cats.

Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (to Y. Hikasa) and by a Tottori University President Discretion Grant (to Y. Hikasa).

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