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Canadian Journal of Veterinary Research logoLink to Canadian Journal of Veterinary Research
. 2009 Jul;73(3):224–236.

Diuretic effects of medetomidine compared with xylazine in healthy dogs

Md Hasanuzzaman Talukder 1, Yoshiaki Hikasa 1,✉
PMCID: PMC2705078  PMID: 19794896

Abstract

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 μg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine’s effect is less dose-dependent than xylazine’s effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation.

Introduction

Medetomidine, a potent α2-adrenoceptor agonist, has a selectivity ratio of 1620/1 for the α2/α1 adrenoceptors, which is approximately 10-fold that of xylazine (160/1) (1,2). It has a very low affinity for α1-adrenoceptors and interacts with central imidazoline receptors, in contrast to xylazine. This makes medetomidine potentially superior for use in small animals, particularly because of its antiarrhythmic property, which is mediated by imidazoline receptors associated with vagal tone stimulation (3). Imidazoline α2-adrenoceptor agonists may act via G-protein-coupled mechanisms (4). In spite of these differences, both medetomidine and xylazine are used similarly for their ability to produce reliable sedation, analgesia, and muscle relaxation in many species (2). On the other hand, both drugs are known to induce diuresis associated with changes in urine specific gravity, pH, creatinine concentration, and osmolality, as well as changes in the concentrations of sodium, potassium, and chloride in both urine and plasma in several species, including dogs (5–9). It has been claimed that the diuresis induced by both drugs is in part due to α2-adrenoceptor-mediated inhibition of the release of arginine vasopressin (AVP) in the blood (6–12). In addition, it has been reported that bolus intravenous (IV) injections of clonidine and moxonidine evoked a dose-dependent diuresis and natriuresis and an increase in urine and plasma concentrations of atrial natriuretic peptide (ANP) in rats (13). Imidazolines may also directly act on imidazoline receptors, α2-adrenoceptors, or both, located in the cortex and outer medulla of the rat kidney (14). Medetomidine has been reported to markedly induce ANP release in rats (15). However, there is no report that either medetomidine or xylazine stimulates ANP release in dogs. Circulating ANP acts on the kidney to cause diuresis and natriuresis by exerting direct actions on the proximal tubules and inner medullary duct cells and by inhibiting the release of renin and AVP and the synthesis and secretion of aldosterone in mice (16,17). To the best of our knowledge, factors involved in the diuresis other than AVP have not yet been elucidated in dogs. In addition, time- and dose-dependent data on the diuretic effects of medetomidine and xylazine in dogs are insufficient. This diuretic effect may limit the use of medetomidine and xylazine in animals with urinary tract obstruction, dehydration, or hypovolemia. The purpose of our study was to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs.

Materials and methods

Animals

Five healthy adult male dogs, 2 beagles, and 3 dogs of mixed breed, with a mean age of 6.2 y [standard deviation (s) = 2.7] and a mean weight of 10.44 kg (s = 2.01) were used. All the dogs were raised at a laboratory providing animal management facilities and fed a standard commercial dry canine food. Routine hematologic examination before the study showed all values to be within the normal physiological ranges. The experimental protocol was approved by the Animal Research Committee of Tottori University, Tottori, Japan.

Experimental protocol

The 5 dogs were assigned to each of 11 treatment groups in a randomized design. Each dog was given an intramuscular (IM) injection of the following: physiological saline solution (2.0 mL) (control); 5, 10, 20, 40, or 80 μg/kg of medetomidine hydrochloride (0.1% solution; Domitor, Meiji Seika, Tokyo, Japan); or 0.25, 0.5, 1, 2, or 4 mg/kg of xylazine hydrochloride (2% solution; Celactal, Bayer, Tokyo, Japan). The groups will be referred to as control, MED5, MED10, MED20, MED40, and MED80, and XYL0.25, XYL0.5, XYL1, XYL2, and XYL4. There was at least 1 wk between treatments for each dog.

Food was withheld for 12 h before drug injection, and food and water were withheld during each test period. After sample collection at 8 h, food and water were provided once, and then the dogs were again fasted for 12 h before the 24-h sample was collected the next day. We did not measure the volume of urine voided by the dogs after removal of the urinary catheter and before its placement the next day because we had observed that urine volume returned to baseline within 6 to 8 h after injection of medetomidine or xylazine. The sampling was performed in a room with the air temperature set at 25°C.

Sample collection

A 6- or 8-Fr silicon balloon catheter (All Silicon Foley Catheter; Create Medic Company, Yokohama, Japan) was inserted 1 h before treatment to empty the bladder and for subsequent urine sampling. The catheter was withdrawn after sampling at 8 h. The next day, at 22 h, the catheter was again inserted and the bladder emptied; a urine sample was collected at 24 h. Urine and blood samples were taken at the following 11 times: before injection of the agent (Pre) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, and 24 h after injection. The urine samples were centrifuged at 2000 × g for 5 min, and then the supernatant was collected and stored at −40°C until analyzed. Blood samples (5.5 mL) were collected from the jugular vein by means of a 21-gauge needle with a 6-mL disposable syringe; a 4.0-mL aliquot was mixed with ethylene diamine tetraacetic acid and aprotinin (Trasylol; Bayer, Leverksen, Germany) for AVP and ANP measurements, and the remaining 1.5 mL was mixed with heparin for osmolality measurement. The blood samples were immediately centrifuged at 2000 × g at 4°C for 15 min, and then the plasma was separated and kept at −40°C for analysis.

Analytical methods

Urine volume was measured at each time point in a measuring cylinder after collection from the urine bag. Specific gravity and pH were measured by a refractor photometer (Erma, Tokyo, Japan) and a pH meter (F-52; Horiba STEC, Santa Clara, California, USA), respectively. Urine creatinine concentration was measured with an assay kit (Wako Pure Chemical Industries, Osaka, Japan) by the Jaffe method, with the use of a spectrophotometer. In both urine and plasma, osmolality and electrolyte concentrations were measured by means of a vapor pressure osmometer (Vapro; Wescor, Logan, Utah, USA) and an Na–K–Cl ion-concentrations autoanalyzer (Dri-Chem 800V; Fuji Film Company, Tokyo, Japan), respectively.

Plasma AVP was extracted by solid-phase column extraction with the use of Sep-Pak cartridges (Waters, Milford, Massachusetts, USA). Each cartridge was attached to a plastic 10-mL syringe and kept in a test tube rack. Each column was washed first with 10 mL of 100% methanol and then twice with 10 mL of ultrapure water. Then a mixture of 0.5 mL of plasma and 1 mL of 0.1 M hydrochloric acid was poured into the syringe. After expulsion of the solution, the syringe was washed with 10 mL of 4% acetic acid, and all water was removed by use of the plunger. After putting 1 mL of 100% methanol into the syringe, AVP was collected in tubes. With the use of nitrogen gas and solvent-evaporation apparatus, all the AVP solution was desiccated and stored at −40°C until analyzed. Buffer solution (0.5 mL) was added to the desiccated AVP, and the tubes were shaken for 15 min by means of a shaking apparatus before measurement of the AVP concentration.

The urine and plasma AVP concentrations were measured by double-antibody radioimmunoassay (RIA) with a commercially available kit (Mitsubishi Chemical, Tokyo, Japan). The intra-assay coefficients of variation (CVs) were 10% and the limits of detection and quantification 0.063 to 8.0 pg/mL, respectively. Plasma ANP was also assayed with a double-antibody RIA kit (HANP kit; Eiken Chemical, Tokyo, Japan). The intra-assay CV was 15%, and the detection and quantification limits were 10 and 1280 pg/mL, respectively.

Data evaluation

All data obtained were analyzed together with Prism statistical software (version 4; GraphPad Software, San Diego, California, USA). One-way analysis of variance for repeated measures was used to examine the time effect within each group and the group effect at each time point. When a significant difference was found, the Tukey test was used to compare the means. The area under the curve (AUC) was calculated for each biochemical variable. The AUC was measured by calculating the sum of the trapezoids formed by the data points. The AUC data were plotted against the dose of medetomidine or xylazine, and simple linear regression analysis was applied. When a significant difference was found, the effect of the drug on the plasma level of the examined biochemical variable was claimed to be dose-dependent. Mean values are presented with standard error (sx̄) in parenthesis. The level of significance in all tests was set at P < 0.05.

Results

For all the variables, there were no significant differences between the groups at baseline (Pre: before injection of the agents). A diuretic effect was found with all the tested doses of both medetomidine and xylazine compared with physiological saline, and this effect persisted up to 4 h after injection (Figures 1A and 1B). All the doses of medetomidine and xylazine produced significant diuresis between 1 and 3 h compared with saline. Compared with the baseline values, the peak diuretic responses to MED80 and XYL4 were 11.56 (1.33) and 15.68 (1.92) mL/kg at 2 h, respectively. Linear regression of the total urine volume from 1 to 3 h (Figures 1C and 1D) was significant in the MED (P < 0.05) and XYL (P < 0.001) groups, indicating that both drugs caused diuresis in a dose-dependent manner but that the dose dependency was less with medetomidine than with xylazine. Similar results were observed with linear regression of the total urine volume from 0 to 4 h, 0 to 6 h, and 0 to 8 h. However, the time-related diuretic response differed somewhat between the MED and XYL groups: peak diuresis occurred at 2 h in the MED10, MED20, MED40, and MED80 groups but at 3 h in the MED5 group, and it occurred at 2 h in the XYL1, XYL2, and XYL4 groups but at 1 h in the XYL0.25 and XYL0.5 groups.

Figure 1.

Figure 1

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Urine volume before (Pre) and after intramuscular injection of medetomidine (MED), xylazine (XYL), or physiological saline (Control) to 5 dogs. A, B: Each point and vertical bar represent the mean and standard error (n = 5) of the rate of diuresis at various time points, and the letters indicate a significant difference from the “Pre” (baseline) value: a — P < 0.05; b — P < 0.01. The points, bars, and letters have the same meanings in Figures 2 through 8. C, D: Simple linear regression of total urine volume in the period 1 to 3 h after injection.

Urine specific gravity increased gradually over the first 8 h after saline injection, whereas it decreased significantly, in a dose- dependent manner, compared with the baseline values, in the drug groups (Figures 2A and 2B). The lowest values were similar after MED and XYL injection and were found between 1 and 3 h after injection: at 2 h in the MED5, MED10, and MED20 groups but at 3 h in the MED40 and MED80 groups and at 1 h in the XYL0.25 and XYL0.5 groups but at 2 h in the XYL1, XYL2, and XYL4 groups. These decreases corresponded with the increase in urine volume in the groups.

Figure 2.

Figure 2

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Urine specific gravity, pH, and creatinine concentration before and after injection.

Urine pH decreased significantly during the first 1 to 5 h after injection of either drug and then gradually returned to baseline values (Figures 2C and 2D). The lowest pH was observed at 5 h, in the MED80 and XYL4 groups. Thereafter, the pH increased over the values in the control group during 6 to 8 h after injection of either drug. Higher doses delayed the return to baseline.

The urine creatinine concentration decreased significantly in all the drug groups. The lowest means were found at 3 h, in the MED80 and XYL4 groups (Figures 2E and 2F). The slope of the recovery phases indicated that xylazine decreased the urine creatinine concentration in a dose-dependent manner. Higher doses of medetomidine delayed the return to baseline.

Urine osmolality decreased significantly compared with baseline values during the first 1 to 5 h after injection of either drug. The lowest means were observed at 2 to 3 h, with higher doses of either drug (Figures 3A and 3B). Xylazine decreased the urine osmolality in a dose-dependent manner. Plasma osmolality increased significantly compared with baseline values during the first 2 to 5 h after injection of either drug (Figures 3C and 3D). Medetomidine increased the plasma osmolality in a dose-dependent manner. Higher doses of both drugs delayed the return to baseline. The decreases in urine osmolality were likely related to the increases in plasma osmolality due to diuresis.

Figure 3.

Figure 3

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Urine and plasma osmolality before and after injection.

Compared with the baseline values, the mean urine concentrations of AVP were significantly lower at 1 to 4 h in the MED20, MED40, and MED80 groups, at 1 to 3 h in the XYL1 and XYL2 groups, and at 4 h in the XYL4 group (Figures 4A and 4B). Higher doses of medetomidine decreased the urine AVP concentration more than did higher doses of xylazine. In both the MED and the XYL groups, return to baseline values was delayed in a dose-dependent manner. The AVP concentrations then increased, to beyond the baseline values between 5 and 8 h, in both the MED and the XYL groups (Figures 4A and 4B). In the XYL groups the concentrations decreased initially in a dose-dependent manner. The slopes of the recovery phase indicated that both medetomidine xylazine decreased the urine AVP concentration in a dose-dependent manner. The total amounts of AVP excreted between 1 and 3 h after drug injection were significantly lower in the MED40 and MED80 groups than in the control group (Figure 4C). In contrast, there was no significant difference in the total amounts of AVP excreted between 1 and 3 h after the injection of xylazine compared with saline (Figure 4D). The amounts of AVP excreted between 1 and 3 h were decreased dose dependently in the MED groups and were also decreased, but not dose dependently, in the higher-dose XYL groups.

Figure 4.

Figure 4

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A, B: Urine arginine vasopressin (AVP) concentration before and after injection. C, D: Total amounts of AVP excreted between 1 and 3 h after injection.

The plasma AVP concentrations were significantly decreased from 0.5 to 2 h in the MED groups and were decreased, but not significantly, from 0.5 to 1 h in the XYL groups compared with the baseline values (Figures 5A and 5B). The concentrations then increased over the baseline values from 5 to 8 h in all the drug groups. Medetomidine suppressed the return to baseline in a dose-dependent manner. The AUC data revealed a significant decrease (P < 0.05) in AVP release from 0.5 to 2 h in the MED40 and MED80 groups, whereas xylazine did not cause a significant decrease at any dose (Figures 5C and 5D). Linear regression of the AUC data from 0.5 to 2 h was significant (P < 0.05) in the MED groups but not the XYL groups, indicating that medetomidine in contrast to xylazine suppressed plasma AVP release in a dose-dependent manner in the early phase after administration.

Figure 5.

Figure 5

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A, B: Plasma AVP concentration before and after injection. C, D: Area-under-the-curve (AUC) data for plasma AVP from 0.5 to 2 h after injection.

The plasma ANP concentrations were significantly increased in the MED40 and XYL2 groups 0.5 h after injection (Figures 6A and 6B). However, higher doses of medetomidine stimulated ANP release with greater potency than did higher doses of xylazine. The return to baseline was delayed in a dose-dependent manner in the MED groups. The AUC data revealed a significant increase (P < 0.05) in ANP release in the MED20, MED40, and MED80 groups from 0 to 8 h but no significant increase with xylazine (Figures 6C and 6D). The AUC data from 0 to 8 h was significant (P < 0.05) in the MED groups but not the XYL groups indicating that medetomidine in contrast to xylazine induced ANP release in a dose-dependent manner.

Figure 6.

Figure 6

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A, B: Plasma atrial natriuretic peptide (ANP) concentration before and after injection. C, D: The AUC data for plasma ANP from 0 to 8 h after injection.

The mean urine concentrations of sodium, potassium, and chloride decreased significantly from baseline after injection of medetomidine or xylazine. The lowest mean concentrations were found from 1 to 4 h after injection of either drug (Figure 7). Higher doses of medetomidine markedly decreased the concentrations of all 3 electrolytes, and the return to baseline values was delayed in a dose-dependent manner. Xylazine decreased the concentrations of all 3 electrolytes in a dose-dependent manner. The total amounts of excreted sodium, potassium, and chloride did not significantly change between 1 and 4 h after injection of either drug compared with saline. On the other hand, the mean plasma concentrations of all 3 electrolytes increased significantly from baseline 2 and 5 h after injection of higher doses of either drug (Figure 8).

Figure 7.

Figure 7

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Urine electrolyte concentrations before and after injection.

Figure 8.

Figure 8

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Plasma electrolyte concentrations before and after injection.

Discussion

This study demonstrated that medetomidine and xylazine have a profound diuretic effect in healthy dogs up to approximately 4 h after IM administration. Access to food and water after the sample collection at 8 h would not have greatly influenced diuresis at 24 h, because we observed that the urine volume returned to baseline in all groups within 6 to 8 h after injection of either drug. Our finding of a profound diuretic effect of these 2 drugs in dogs agrees with previous findings in dogs (5,6) and goats (7) that were given medetomidine and in cattle (8), horses (9), and rats (11) that were given xylazine. Other α2-adrenoceptor agonists, such as clonidine (17,18), moxonidine (19), BHT-933 (10), rilmenidine (20), and guanabenz (21), have also been shown to produce a diuretic response in anesthetized or conscious animals. In dogs, previous studies have found that intravenous (IV) administration of 10 or 20 μg/kg of medetomidine alone and 20 or 40 μg/kg of medetomidine combined with isoflurane produced diuretic effects (5,6). However, it has been reported that IM administration of 80 μg/kg of medetomidine alone did not significantly change urine volume in dogs (6), whereas we found that IM administration of 80 μg/kg of medetomidine significantly increased urine volume (6). This difference might be due to the use of the combination of medetomidine and isoflurane in the previous study (6).

To the best of our knowledge, this is the first report outlining the dose-dependent diuretic effect of medetomidine and xylazine in dogs and comparing these 2 drugs in the same animal species. The dose-dependent diuretic effect was more pronounced, and highly significant, in xylazine compared with medetomidine at the tested doses. This difference may be due to differences in receptor selectivity and specificity between the 2 drugs.

In our study, the decreases in urine specific gravity, urine osmolality, and urine creatinine concentration were almost simultaneous with the increase in urine volume after administration of either drug. This indicates that both medetomidine and xylazine produce a diuretic effect by decreasing reabsorption in the narrow tube of the kidney. The decreases in urine osmolality agreed with those previously reported for dogs given medetomidine (5,6) and rats given xylazine (11). In our study, both drugs significantly increased plasma osmolality in a dose-dependent manner, suggesting that the increased production of diluted urine due to renal excretion of water caused greater concentration of the serum, as confirmed by the elevated plasma electrolyte concentrations. Higher doses of both drugs tended to delay recovery from the lowered urine pH. Presumably the decrease in urine pH was due to arterial hypercapnea (22). The expected response of the kidney to acute hypercapnea is to slightly enhance renal tubular reabsorption of bicarbonate (22), which may in part be reflected as a decrease in urine pH. However, since the kidney may not respond rapidly to acute hypercapnea, other organic acids might partially cause the decrease in urine pH. The higher pH values late in the study may be attributable to a decrease in the secretion of renal tubular hydrogen ions or a decrease in bicarbonate reabsorption.

Our study revealed that the urine AVP concentration significantly decreased early after injection of higher doses of both drugs and increased later. Importantly, the total amount of AVP excreted 1 to 3 h after injection decreased significantly and in a dose-dependent manner with higher doses of medetomidine. On the other hand, the plasma AVP concentration decreased significantly between 0.5 and 2 h after injection of medetomidine but not xylazine. The AUC data revealed a significant decrease in AVP release from 0.5 to 2 h after injection of higher doses of medetomidine but no significant decrease after xylazine injection. In addition, linear regression of the normalized AUC data for plasma AVP from 0.5 to 2 h was significant for medetomidine but not for xylazine, indicating that plasma AVP release is suppressed in a dose-dependent manner early after administration of medetomidine. From these findings we confirmed that AVP alone was not responsible for the profound diuresis induced by the 2 drugs. With xylazine, although urine volume was highly dose-dependent at the tested doses, the total amounts of urine AVP excreted and the AUC data for plasma AVP did not significantly decrease between 1 and 3 h after injection, and linear regression of the AUC data did not show a dose dependency. In contrast, with medetomidine the total amounts of urine AVP excreted and the plasma AVP concentration decreased significantly during the same period.

So, definitely, there are different mechanisms for the diuresis induced by medetomidine and xylazine, in part related to the apparent inhibition of AVP release by medetomidine but not xylazine. Although the precise mechanism for the difference between medetomidine and xylazine in their effects on AVP release is unknown, it may be in part due to differences in receptor selectivity and actions mediated via the central nervous system (CNS), since the α2-adrenoceptor selectivity of medetomidine is approximately 10-fold that of xylazine and since medetomidine has central imidazoline-receptor affinity (1–4). Earlier studies showed that imidazoline α2-adrenoceptor agonists, such as moxonidine, clonidine, and clonidine’s analogue ST-91, mediate their action via both α2-adrenoceptors and imidazoline receptors (13,14,18).

The diuretic effects of α2-adrenoceptor agonists have been reported to involve their actions on AVP and the renin–angiotensin system (23). The α2-adrenoceptor agonists were reported to inhibit the secretion of AVP from the pituitary gland in dogs anesthetized with sodium pentobarbital and clonidine (24) and in rats anesthetized with ketamine and xylazine (11,25). A study in dogs under isoflurane anesthesia (6) found that IV injection of 20 and 40 μg/kg of medetomidine induced diuresis and a decrease in plasma AVP concentration, whereas IM injection of 80 μg/kg of medetomidine increased the plasma AVP concentration, which differs from our findings. This difference might be due to the combined effect of isoflurane and medetomidine in the previous study. We believe that the authenticity of our results is much greater because of our use of a single active agent. In addition, a previous study found that the plasma AVP concentration in dogs increased in association with surgery and anesthesia induced with IM acepromazine but decreased to baseline within half an hour, and diuresis occurred in the presence of a high plasma AVP concentration (26).

Much evidence indicates that activation of renal α2-adrenoceptors is the predominant mechanism by which selective α2-agonists produce diuresis in rats (10–12,25). The diuretic response may be due to inhibition of CNS secretion, renal tubular actions of AVP, or both (11,25). Furthermore, sedation with medetomidine and xylazine can affect the renin–angiotensin system directly or indirectly. In vitro experiments have demonstrated a decrease in renin production directly via specific renal α2-adrenoceptors in the isolated perfused rat kidney (23). However, the renin–angiotensin system may also be affected indirectly by α2-agonist-induced hypertension (3,11). Both medetomidine and xylazine may activate α2-adrenoceptors in the paraventricular nucleus of the hypothalamus, contributing to diuresis in dogs. In addition to a direct renal action, it is possible that the diuretic response elicited by the IV infusion of xylazine in ketamine-anesthetized rats is partially mediated by a pathway involving α2-adrenoceptors located in the CNS (25). More specifically, the increase in urine production induced by both medetomidine and xylazine may at least in part result from a central action of these drugs to inhibit the secretion of AVP. A number of studies have shown that activation of central adrenergic receptors, in particular the α2-adrenoceptor subtype, inhibits the release of AVP in conscious or anesthetized animals (11,23–25). At the cellular level, α2-adrenoceptor agonists such as clonidine and BHT-933 can inhibit AVP-stimulated cyclic adenosine monophosphate formation in rats and rabbits (10,12,27–29). Furthermore, an intrarenal infusion of clonidine in rats has been shown to produce rapid redistribution of aquaporin-2 (AQP-2) away from the luminal membrane of the medullary collecting duct to the cytosol and a reduction in AQP-2 mRNA, suggesting that α2-adrenoceptors regulate water excretion at least in part by effects on AQP-2 (30).

Xylazine and medetomidine have been reported to induce an increase in the serum glucose concentration by suppressing insulin release and stimulating glucagon release (5,6,8,9,31). We did not measure the plasma glucose concentration in this study because it had been reported previously by our laboratory in dogs (32). Osmotic diuresis attributable to glucosuria is unlikely to be an appreciable factor in the diuretic effect of these drugs in dogs because the plasma glucose concentration did not change the tubular maximum for glucose reabsorption (5).

In this study, the plasma ANP concentration peaked within half an hour of injection of medetomidine or xylazine. To the best of our knowledge, this is the first report that these drugs stimulate plasma ANP release in dogs. Higher doses of α2-agonists dominate hypertension via peripheral postsynaptic adrenoceptors that cause vasoconstriction, which results in a baroreceptor-mediated reflex bradycardia (3,4); this mechanism may be involved in the ANP release stimulated by medetomidine and xylazine. In addition, 2 partial α2-adrenoceptor agonists, clonidine and ST-91, potentially stimulate the release of ANP by activation of heart α2-adrenoceptors, imidazoline receptors, or both, and this may account for the elevated plasma ANP concentration and subsequent diuresis observed in vivo after administration of clonidine and its analogues (18). As revealed in our study, the significant release of ANP in response to higher doses of medetomidine in contrast to xylazine may be due to interaction of medetomidine with imidazoline receptors. Previous findings (13–16) and our results indicate that the peripheral actions of medetomidine are probably mediated by both α2-adrenoceptors and imidazoline receptors and may involve direct stimulation of ANP release, which may account for the increase in plasma ANP concentration after medetomidine injection in this study. Therefore, the plasma ANP concentration may have partially influenced the diuretic effects observed in our study.

The present study demonstrated that both medetomidine and xylazine significantly decreased the urine sodium, potassium, and chloride concentrations during profound diuresis, but the actual amounts of these electrolytes excreted in the urine did not significantly change compared with the control condition, indicating that the diluted urine was excreted after drug administration. In fact, the plasma electrolyte concentrations were increased in a dose-dependent manner after injection of either drug, indicating that the urinary excretion of these electrolytes did not significantly change during profound diuresis. It has been reported that medetomidine (5,6) and xylazine (11) may interfere with AVP-mediated tubular reabsorption of sodium because of dehydration after administration of these agents, as supported by the increased plasma osmolality in our experiment. Potassium is reabsorbed in the proximal tubule of the nephron, undergoes resorption by intercalated cells in the connecting segments and cortical ducts, and then is reabsorbed or secreted in the medullary collecting duct (33). Because the urine flow rate in the distal tubules has an important influence on urine potassium secretion, it is possible that an increased tubular flow rate was partially responsible for the increased concentration of potassium ions in the plasma after administration of medetomidine or xylazine. A temporal increase in the plasma chloride concentration may be attributable to direct effects of the 2 drugs on renal tubular function. However, other indirect factors, such as an initial decrease in cardiac output and renal blood flow or the strong acid–base regulatory effect associated with chloride, must be considered. Medetomidine- and xylazine-induced changes in electrolyte concentrations might be important in hypokalemic or hypochloremic dogs: it has been demonstrated that renal artery infusion of low doses of clonidine selectively increase water but not electrolyte excretion (34). Thus, the diuretic response to medetomidine and xylazine may be mediated via activation of complex peripheral and CNS α2-adrenoceptor systems.

In conclusion, this study showed that both medetomidine and xylazine had profound diuretic effects in healthy dogs. The dose-dependent diuretic response to xylazine was more profound than that to medetomidine at the tested doses. This is the first report outlining the dose-dependent diuretic action of these agents in dogs. From our findings in both urine and plasma, AVP alone may not be responsible for the dose-dependent diuretic effects of these 2 drugs. This study also demonstrated for the first time that medetomidine stimulates ANP release with greater potency than does xylazine, and this effect may partially influence the diuresis. There may be differences in the mechanism of the diuresis with the 2 drugs because diuresis is the net result of multiple hemodynamic, neural, hormonal, and local factors in the kidney, and there are definite differences between medetomidine and xylazine in the selectivity and specificity of α2-adrenoceptors and imidazoline receptors. Medetomidine and xylazine can both be used for effective diuresis accompanied by sedation.

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japanese Ministry of Education, Science, Sports and Culture (18580316; to Dr. Hikasa) and by the Scholarship Donation Fund 2005 from Meiji Seika, Tokyo, Japan (to Dr. Hikasa). The authors thank Mr. Hajime Takahashi for his technical assistance.

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