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Available online at www.sciencedirect.com

Theriogenology 77 (2012) 430–436

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Uterine artery blood flow remains unchanged in pregnant mares inresponse to short-term administration of pentoxifylline

C.S. Baileya,*, R.B. Spera, J.L. Schewmakera,c, C.N. Buchanana, T.M. Beachlera,M.A. Pozorb, M.D. Whitacrea

a College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USAb College of Veterinary Medicine, University of Florida, Gainesville, Florida, USAc School of Veterinary Medicine, Ross University, Basseterre, St. Kitts, West Indies

Received 14 March 2011; received in revised form 5 August 2011; accepted 13 August 2011

Abstract

The objective of this study was to use Doppler ultrasound technology to determine whether pentoxifylline administrationincreased uterine blood flow in normal pregnant pony mares. Thirteen pregnant pony mares between 18 and 190 d of gestation(mean � SEM, 101 � 55) were utilized for the study during two trial periods. In each trial, pentoxifylline (17 mg/kg by mouthevery 12h, diluted in syrup) was administered to half of the mares for 3 d, while the other mares were treated with syrup only.Doppler measurements were obtained from the right and left uterine arteries from each mare for 2 d prior to treatment andthroughout the treatment period. The mean Resistivity Index (RI), Pulsatility Index (PI), Uterine Artery Diameter (D), and TotalArterial Blood Flow (TABF) from each day were compared over time and between groups. Administration of pentoxifylline didnot alter uterine blood flow parameters compared with controls (values for all treatment days combined were RI: 0.517 � 0.014vs 0.543 � 0.016; PI: 0.876 � 0.048 vs 0.927 � 0.057; D: 0.388 � 0.018 vs 0.379 � 0.023 cm; and TABF: 35.26 � 7.38 vs30.73 � 5.29 mL/min). Uterine blood flow increased over the course of the 5 d study, irrespective of treatment, and was higherin mares of greater gestational age than in early gestational mares (RI: r2 � 0.35; PI: r2 � 0.37; D: r2 � 0.66; and TABF: r2 �0.67 – P � 0.00001). We concluded that any immediate benefits of pentoxifylline administration in the pregnant mare were not

ediated through enhanced uterine artery blood flow.2012 Elsevier Inc. All rights reserved.

Keywords: Uterine blood flow; Equine pregnancy; Placentitis; Pentoxifylline; Color Doppler ultrasound; Horse

www.theriojournal.com

1. Introduction

As Doppler ultrasound technology becomes increas-ingly available to veterinary researchers and practitio-ners alike, it has been used to answer many questionsregarding blood perfusion in horses. Specifically, threemeasures of blood flow—the Resistivity Index (RI),Pulsatility Index (PI), and Total Arterial Blood Flow

* Corresponding author. Tel.: (919) 513-6149; fax: (919) 513-6336.

E-mail address: scott_bailey@ncsu.edu (S. Bailey).

093-691X/$ – see front matter © 2012 Elsevier Inc. All rights reserved.oi:10.1016/j.theriogenology.2011.08.018

(TABF) have been most commonly applied to quantifyblood flow via Doppler ultrasonography. The RI and PIare indirect measures of blood flow to an organ or tissueby accounting for the resistance in flow to that organ,whereas TABF measures blood flow within a singlecardiac cycle at a specific location. In the field ofequine reproduction, Pozor and coworkers applied thetechnology to study blood flow in the equine testis[1,2], whereas a series of studies by several groups haveutilized Doppler technology to study uterine blood flow

in cycling and pregnant mares [3–8]. In these studies,

431C.S. Bailey et al. / Theriogenology 77 (2012) 430–436

Doppler flow was described in the uterine artery underphysiologic conditions and in response to several inter-ventions, such as insemination, exogenous administra-tion of reproductive hormones, and anti-inflammatorymedication.

The general aim of the current study was to utilizeDoppler technology to determine whether short-termadministration of pentoxifylline would affect bloodflow measured at the uterine artery of pregnant mares.Pentoxifylline has been shown to be rapidly absorbedand readily bio-available in the horse and other species[9,10]. In treatment trials of equine placentitis, a lead-ing cause of pregnancy loss and neonatal disease inhorses [11], treatment with pentoxifylline and trim-ethoprim sulfamethoxazole delayed parturition comparedwith untreated animals [12]. Pentoxifylline, combinedwith trimethoprim sulfamethoxazole and altrenogest de-layed parturition and improved fetal viability [13]. How-ever, it remains unclear by which mechanism pentoxifyl-line might affect disease progression, or aid in treatmentof placentitis. A wide variety of potentially beneficialeffects have been ascribed to pentoxifylline in studiesinvolving horses and other species, including enhancedblood perfusion of inflamed tissues, inhibition of pro-inflammatory cytokines, and decreased bacterial attach-ment [14–19].

The objective of the current study was to applyDoppler ultrasound technology in the pregnant mare todetermine whether or not treatment with pentoxifyllineacutely increases uterine blood flow. We hypothesizedthat oral treatment with 17 mg/kg of pentoxifylline for3 d would result in decreased RI and PI and increasedTABF in the uterine arteries compared to untreatedmares.

2. Materials and methods

2.1. General design

Thirteen pregnant pony mares between 18 and 190 dof gestation were utilized for the study. Mares were 2 to15 y of age and were housed on pasture at the NCSUEquine Health Center at Southern Pines. All procedureswere in accordance with North Carolina State Univer-sity’s Institutional Animal Care and Use Committee’sguidelines for the humane treatment of research ani-mals. Mares were treated at two time points: in thesummer (Trial 1) and again in the fall (Trial 2).

Eight mares were enrolled in Trial 1. All mares wereexamined at the onset of the study to ensure they hadnormal physical exam parameters and were pregnant

with a single conceptus. Mares were age-matched

based on gestational age and randomly assigned totreatment groups (Group TREAT; n � 4 or GroupCONT; n � 4). All mares were examined using tran-srectal grayscale and Doppler ultrasound once dailybetween 11 AM and 5 PM for five consecutive days(Days 1–5). On Days 3–5, mares in Group TREATwere given 17 mg/kg of pentoxifylline orally (Pentoxi-fylline oral gel 4 g/30 cc, HDM Pharmacy, Lexington,KY, USA), diluted in syrup twice daily at 8 AM and 7PM, while mares in Group CONT received syrup only.

At the onset of Trial 2, twelve mares (seven maresfrom Trial 1, plus five additional mares) were examinedto confirm pregnancy and normal physical exam pa-rameters. Mares were age-matched by gestational ageand randomly assigned to two treatment groups (GroupTREAT; n � 6 and Group CONT; n � 6). All mareswere examined using transrectal Doppler ultrasoundbetween 7AM–10AM, 12PM–3PM and 5PM–7PM ontwo consecutive days (Days 1–2) to determine differ-ences in blood flow over the course of the day. On Days3–5, mares in Group TREAT were given 17mg/kg ofpentoxifylline twice daily orally, diluted in syrup, whilemares in Group CONT received syrup only. Mares inGroup TREAT were examined using transrectal Dopp-ler ultrasonography three times daily on Day 3–5.Mares in Group CONT were examined once daily be-tween 7AM and 10AM on Day 3, between 12 PM and3PM on Day 4, and between 5 PM and 7PM on Day 5.This protocol was designed based on prior work whichdid not find differences between animals examinedonce or multiple times per day (Bailey, unpublisheddata) and in an effort to avoid unnecessary risks arisingfrom repeated transrectal examinations.

2.2. Ultrasonography

To perform the examinations, mares were confinedin stocks modified to safely accommodate ponies. Therectum was evacuated and a 5–7 MHz linear probe(Sonosite MicroMaxx™; Bothell, WA, USA) wasintroduced into the rectum under manual guidance.The probe was placed against the lateral aspect of thecaudal aorta in the mid-abdomen and retracted grad-ually to the origin of the external iliac artery. At thispoint, the external iliac artery was traced until boththe uterine artery and deep circumflex artery wereidentified. The diameter (D) of the uterine artery wasmeasured at the level that it crossed the deep circumflexartery, approximately 2–5 cm distal from its origin.Color Doppler ultrasound (CDU) was used, as previ-ously described [6,20], to obtain blood flow measure-

ments of the uterine arteries. Briefly, a longitudinal

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432 C.S. Bailey et al. / Theriogenology 77 (2012) 430–436

section of the artery was identified by retroflexing theprobe slightly to face dorsomedially and the Dopplergate was placed within the artery for measurement.After completion of measurements on one side, theexaminer switched palpation arms to obtain measure-ments on the contralateral side (the right arm was usedfor the left artery and the left arm was used for the rightartery). The pulse-wave color Doppler ultrasound had asample gate setting slightly less than the diameter of theartery (1–3 mm) and angle correction was set between30 and 60 degrees. Three representative waveformswere obtained, and spectral analysis was performedusing the algorithm package provided with the ultra-sound unit to determine the Resistance Index (RI) andPulsatility Index (PI) and the Maximum Velocity(Vmax). These known parameters were then used tocalculate Total Arterial Blood Flow (TABF �[(Vmax�(RI*Vmax-Vmax))/PI]*(D/2)2�) [2,21]. Pa-ameters from three waveforms were averaged andsed for statistical analyses.

.3. Statistical analyses

Statistical analysis of the data was performed usinghe software package Statistix 8.1 (Statistix®, Analyt-cal Software Inc, Tallahassee FL, USA). Data fromach trial were analyzed separately and combined to-ether. Data were analyzed for differences betweeneasures taken from the right and left arteries, differ-

nces between days (Days 1–5), and differences be-ween treatment groups (Group TREAT and GroupONT). Data were additionally analyzed for interac-

ions between group and day and between group andestational age. In Trial 2, data were analyzed forifferences between time of day on Days 1 and 2Group TREAT and CONT) and differences betweenime of day relative to treatment on Days 3–5 (GroupREAT only). Analyses were performed on mean dailyalues for RI, PI, D, and TABF using an ANOVA withepeated measures test. A Tukey HSD All-Pairwiseomparisons Test was used to test for mean compari-

ons among days. Data were analyzed for effect ofestational age using a linear regression model. A sig-ificance level of P � 0.05 was established.

. Results

The mean gestational age for mares in this study was01 � 55 d. Due to progressive breeding dates, gesta-ional ages in Trial 1 and Trial 2 overlapped, rangingrom 18 to 84 d in Trial 1 and from 43–193 d in Trial

. Mean (� SEM) gestational ages in Trial 1 were 54 � (

d for Group TREAT and 45 � 5 for Group CONT.ean gestational ages in Trial 2 were 117 � 10 forroup TREAT and 119 � 10 for Group CONT. Thereere no differences in gestational ages between Group

n either Trial 1 or 2, or when data were combined (P �.6, 0.6, and 0.8 respectively). This was dropped fromubsequent analyses.

Reporting error resulted in the loss of data for D onay 1 in Trial 1. This day was excluded from analysis

or D and TABF.There was no difference between the right and left

ide for any measure (P � 0.2 for RI, PI, D, and TABF)in either Trial 1 or Trial 2. Average measures for bothsides were used for future calculations. In Trial 2, therewas no difference between measures (P � 0.4 for RI,PI, D and TABF) taken at various times of the day priorto (Days 1–2) or during (Days 3–5) treatment. Averagedaily measures were used for future analyses.

There was no difference in RI, PI, D, or TABFbetween groups in either Trial 1 or Trial 2 (P � 0.3 and

� 0.2 respectively). There was no difference in RI,I, D, or TABF between groups when data from both

rials were combined (Table 1; P � 0.4, 0.7, 0.8, and.2 respectively). An effect of Day was detected for Dnd TABF in both trials (P � 0.05 and 0.003 respec-ively for Trial 1 and P � 0.001 and 0.006 respectivelyor Trial 2). Within trials, no effect of Day was detectedor RI and PI. Analysis of all animals together revealedn effect of Day with improved uterine blood flow (aecrease in RI and PI and an increase in D and TABF)n Days 4 and 5 compared with Day 2 (Table 1; P �.008, 0.0057, 0.0064, and � 0.00001, respectively).ithin groups, no effect of Day was detected for RI or

I in either group. However, in Group CONT, D wasreater on Day 4 than Day 2, and TABF was greater onays 3, 4 and 5, compared with Day 2 (Table 1; P �.008 and 0.0004 respectively).

Resistance Index and PI decreased with increasingestational age (Fig. 1; r2 � 0.35 and 0.37 respectively,

P � 0.00001), whereas D and TABF increased withncreasing gestational age (Fig.1; r2 � 0.66 and 0.67espectively; P � 0.00001).

. Discussion

In this study, administration of pentoxifylline didot acutely increase blood flow to the uterine arteries inregnant mares, even at the elevated doses used. Theose of 17 mg/kg was approximately twice the currentecommended dose for horses [9,13,22]. The dose used

17 mg/kg) was selected based on the known pharma-

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433C.S. Bailey et al. / Theriogenology 77 (2012) 430–436

cokinetic properties of the drug, including a rapid de-cline in bioavailability with repeated doses [9], andbased on recent work in stallions, where Doppler tech-nology detected changes in testicular blood flow afteradministration of larger doses of pentoxifylline, but notstandard therapeutic doses [2]. Furthermore, 17 mg/kgwas also used in pregnant mares in another study [8]. In

Table 1Daily blood flow parameters (mean � SEM) by Group.

1 2

Group TREAT (n � 10)RI 0.553 � 0.031 0.542 � 0.0PI 0.959 � 0.110 0.942 � 0.0D 0.363 � 0.0TABF 24.2 � 8.1

Group CONT (n � 10)RI 0.551 � 0.025 0.572 � 0.0PI 0.956 � 0.101 1.013 � 0.0D 0.35 � 0.0TABF 22.0 � 8.2

Combined (n � 20)RI 0.553 � 0.020ab 0.557 � 0.0PI 0.957 � 0.073ab 0.978 � 0.0D 0.357 � 0.0TABF 23.1 � 5.6

Groups did not differ (P � 0.05) in any parameter.RI, Resistivity Index; PI, Pulsatility Index; D, Uterine Artery Diamea–c Within a row, means without a common superscript differed (P

Fig. 1. Effect of gestational age on uterine artery blood flow in pre

gestational age increased, whereas Uterine Artery Diameter and Total Arter

Trial 1, treatment intervals and examination intervalswere matched as closely as possible to work done in thestallion. Due to concerns that the examination fre-quency could potentially miss a vascular effect occur-ring shortly after administration of the drug, whichachieves peak serum concentrations approximately 1 hafter oral administration, frequency of examination was

Day

3 4 5

0.532 � 0.026 0.511 � 0.021 0.508 � 0.0290.921 � 0.082 0.855 � 0.068 0.851 � 0.1030.376 � 0.032 0.394 � 0.030 0.394 � 0.03229.3 � 12.40 35.9 � 13.14 40.6 � 13.84

0.545 � 0.026 0.542 � 0.031 0.541 � 0.0260.944 � 0.103 0.930 � 0.117 0.905 � 0.0830.362 � 0.040ab 0.395 � 0.043b 0.381 � 0.042ab

26.2 � 7.30b 36.4 � 11.68b 29.6 � 8.66b

0.538 � 0.018abc 0.526 � 0.018bc 0.525 � 0.019c

0.932 � 0.064abc 0.893 � 0.067bc 0.878 � 0.065c

0.369 � 0.025ab 0.394 � 0.026b 0.388 � 0.026ab

27.7 � 7.01b 36.2 � 8.56c 35.1 � 8.04bc

; TABF, Total Arterial Blood Flow.).

ares. Both the Resistivity Index and Pulsatility Index decreased as

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434 C.S. Bailey et al. / Theriogenology 77 (2012) 430–436

increased in Trial 2. The frequency of examination inTrial 2 was increased to three times daily to determinewhether uterine blood flow changed over the course ofthe day (Day 1 and 2) and whether a transient increasein uterine blood flow could be detected immediatelyafter administration of the drug (Day 3–5). Uterineblood flow did not change significantly over the courseof the day in untreated or in treated mares.

Our findings were consistent with results from sev-eral studies of blood flow to digital arteries in theequine foot and cerebral blood flow in humans afteradministration of pentoxifylline [23–25]. The results ofthe current study also supported those of previous stud-ies utilizing Doppler ultrasonography to measure uter-ine blood flow during normal equine pregnancy [6,26–28]. Mares enrolled in the current study at a latergestational age had increased blood flow (TABF) anddecreased resistance (RI and PI) compared to mares at anearlier stage of gestation. This effect resulted in largestandard deviations within treatment groups, which in-cluded mares at each gestational age. The variation be-tween mares of different gestational ages may have ob-scured small changes in uterine artery blood flow resultingfrom pentoxifylline administration, however, mares wereage matched based on gestational age prior to enrollmentin each trial in order to account for this factor.

The results from the present study were contrary tofindings in the testicular artery of stallions [2]. Short-term pentoxifylline administration increased testicularblood flow. Pentoxifylline administration was also as-sociated with increased blood flow to the equine foot[17], as well as other disease models in humans and rats[29,30]. Short-term administration of pentoxifyllinemay have had an effect on blood flow in smaller vesselsof the uterus and placenta, which was not readily de-tectable as a change in the uterine artery. However, RIand PI each measure flow through the vascular bedsdownstream from the point of measurement and shouldreflect changes in flow resulting from microvascularchanges or alterations in blood viscosity.

A recently published abstract by Ousey and cowork-ers suggested that long-term administration of pentoxi-fylline resulted in increased uterine artery blood flow inpregnant mares [8]. Interestingly, this study reportedthat chronic administration of pentoxifylline to maresbetween 70 and 120 d of gestation diminished thenormal decline in RI over the course of gestation,suggesting that pentoxifylline may actually increaseplacental vascular resistance in the pregnant mare. It isunclear, however, whether this finding could be a direct

drug effect or an effect of the decreasing bioavailability d

of the drug over time. A decrease in bioavailability wasinitially shown by Liska and coworkers in pharmaco-kinetic studies and hypothesized to result from either adecrease in absorption, increase in clearance, or anautoinduction of metabolic enzymes [9]. Autoinductionof metabolic enzymes in response to administration ofmethylxanthine derivatives has been demonstrated inhumans and suggested in dogs [31,32].

Comparison between these studies was complicatedby the fact that each had different methods and oftenalso different endpoints. Whereas uterine blood flowstudies have utilized Doppler ultrasound technology[4,8,20,27], a laser Doppler flowmeter was utilized inseveral other models [23,29,30]. Likewise, Pozor andcoworkers reported TABFR (Total arterial blood flowrate), a measure of blood flow per 100 g of tissue within1 min [2], Ousey and coworkers reported Uterine Ar-ery Blood Flow Volume (UA BFV) per kg bodyeight and RI [8], whereas Bollwein and coworkersariably reported RI or PI as endpoints in their studies3–7,20,26–28]. Thus, it is possible that the techniquend parameter used to determine blood flow could haveffected the results in each of these studies. There is a needo standardize research methodology and Doppler param-ters in order to enhance the applicability of the varioustudies performed with this technique. In the currenttudy, the authors attempted to utilize the most commonethodology and reported the three most common param-

ters. The technique described in the current study haseen well-documented in the pregnant mare and has beenensitive enough to show treatment differences, as well asestational age differences [4,5,27].

Perhaps a longer course of treatment would haveevealed differences between groups, as suggested byhe results of Ousey and coworkers [8], however itas not the goal of the current study to investigate a

hronic effect of pentoxifylline in the pregnant mare.ecause abortion often ensues rapidly in untreatedares, the goal of immediate therapy is to prevent

xpulsion of the fetus and enhance its wellbeing intero. Based on the current study, we inferred thatentoxifylline, which appeared to positively affect out-ome of treatment in mares with experimentally inducedlacentitis [12,13], did not act by enhancing uterine bloodow. Alternate mechanisms of action include anti-inflam-atory effects and disruption of bacterial binding to host

issues. Pentoxifylline has been shown to block the pro-nflammatory actions of IL-1 and TNF on neutrophils initro, thereby potentially decreasing tissue damage causedy neutrophils [18]. In addition, pentoxifylline may have

irect protective effects. In critically ill septic human pa-

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435C.S. Bailey et al. / Theriogenology 77 (2012) 430–436

tients, pentoxifylline has been shown to improve tissueoxygenation by increasing oxygen transport and oxygenuptake [15,16], whereas it has altered the flow propertiesof equine erythrocytes in vitro [33]. It has also been shownto improve bacterial clearance and significantly decreasebacterial colonization of the lung and kidney in rabbitsundergoing hemorrhage or endotoxemia [14].

In conclusion, administration of therapeutic doses ofentoxifylline did not alter uterine artery blood flow pa-ameters in this study when compared to untreated con-rols. Blood flow increased over the course of the 5 dtudy, irrespective of treatment and was higher in mares ofreater gestational age than in early gestational mares. Weoncluded that any immediate benefits of pentoxifyllinedministration in the pregnant mare are not mediatedhrough an enhancement of uterine blood flow.

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