1. 1213
Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax1,2
A. Pesqueira,* D. L. Harmon,* A. F. Branco,† and J. L. Klotz‡3
*Department of Animal and Food Sciences, University of Kentucky, Lexington 40546; †Universidade
Estadual de Maringa, Brazil; and ‡USDA-ARS, Forage-Animal Production Research Unit, Lexington, KY 40546
ABSTRACT: The ergot alkaloid ergovaline has dem-
onstrated a persistent and sustained contractile response
in several different vascular models. It was hypothesized
that different alkaloids isolated from tall fescue (Lolium
arundinaceum) will contribute to this contractile response
differently. The objective was to compare contractile-
response patterns of single additions of the ergoline
alkaloids lysergic acid, lysergol, and ergonovine and the
ergopeptine alkaloids ergotamine, ergocristine, ergocryp-
tine, ergocornine, and ergovaline (provided as tall fescue
seed extract). Lateral saphenous veins were collected
from 6 Holstein steers (BW = 397 ± 28 kg) immediately
after slaughter, sliced into cross-sections, and suspended
in myograph chambers containing oxygenated Krebs-
Henseleit buffer (95% O2/5% CO2; pH = 7.4; 37°C).
Treatments were added at 0 min and buffer was replaced
in 15-min intervals for a 120-min incubation. In addition
to maximum tension and time to reach maximum ten-
sion, percent relaxation and rate of relaxation were deter-
mined following maximum tension for each treatment.
All compounds tested produced significant contractile
responses (P < 0.05).All ergoline alkaloids reached max-
imum response in less time (P < 0.05) than the remain-
ing compounds and began to relax immediately after first
buffer change. Lysergic acid had the greatest (P < 0.05)
percent relaxation and ergonovine had the greatest (P <
0.05) rate of relaxation. The ergopeptine alkaloids ergo-
valine, ergotamine, ergocristine, ergocryptine, and ergo-
cornine had slower developing contractile responses with
a longer (P < 0.05) interval until maximum tension was
achieved compared to the ergoline alkaloids. Maximal
responses to all the ergopeptine alkaloids, however, all
persisted for the 120-min duration with negligible relax-
ation occurring. The different classes of alkaloids dif-
fered greatly in the type of contractile response generated
in the lateral saphenous vein. Persistence of contractile
response is thought to be the primary contributing factor
to the vasoconstriction observed in animals demonstrat-
ing signs of fescue toxicosis, where different ergot alka-
loids can contribute differently.
Key words: bovine, contractile response, ergoline alkaloids, ergopeptine alkaloids
© 2014 American Society of Animal Science. All rights reserved. J. Anim. Sci. 2014.92:1213–1218
doi:10.2527/jas2013-7142
INTRODUCTION
Tall fescue (Lolium arundinaceum) is commonly
infected with the endophytic fungus Neotyphodium coe-
nophialum (Bush et al., 1982; Lyons and Bacon, 1984).
This fungus produces numerous ergot alkaloids (Lyons
et al., 1986) that cause vasoconstriction, a primary sign
and cause of symptoms of the fescue toxicosis syndrome,
in grazing animals (Strickland et al., 2011). These al-
kaloids are classified by their chemical structure into 2
groups, ergoline alkaloids and ergopeptine alkaloids.
Ergovaline is the ergopeptine alkaloid produced
in the greatest quantity by the endophyte (Yates et al.,
1985; Lyons et al., 1986). Some of the other alkaloids
produced by N. coenophialum are the ergoline alkaloids
lysergic acid (LSA), lysergol (LYS), and ergonovine
(ERN) and the ergopeptine alkaloids ergotamine (ERT),
ergocristine (ERS), ergocryptine (ERP), and ergocor-
nine (ERO; Fig. 1). Previous research has reported an
interesting phenomenon in vasculature exposed to ergot
alkaloids. Solomons et al. (1989) reported a persistent
contractile response to ERT in the bovine dorsal pedal
1Mention of trade name, proprietary product, or specified equipment
does not constitute a guarantee or warranty by the USDAand does not
imply approval to the exclusion of other products that may be suitable.
2The authors would like to thank Adam J. Barnes of the Forage-
Animal Production Research Unit for his assistance in the laboratory.
3Corresponding author: james.klotz@ars.usda.gov
Received September 10, 2013.
Accepted December 26, 2013.
Published November 24, 2014

2. Pesqueira et al.1214
vein, and Dyer (1993) and Klotz et al. (2007) reported
sustained contractile responses to ergovaline in core and
peripheral bovine vasculature, respectively. Schöning et
al. (2001) demonstrated a near permanent receptor bind-
ing of ergovaline, with negligible dissociation in a rat tail
bioassay. The studies by Silberstein (1997), Schöning et
al. (2001), and Klotz et al. (2007) demonstrated slow dis-
sociation of ergot alkaloids from receptors and may be the
cause of vasoconstriction associated with fescue toxicosis.
Because N. coenophialum produces numerous ergot
alkaloids, it is hypothesized that different contractile
response patterns would contribute differently to the
vascular signs of fescue toxicosis. The objective of this
study was to observe the contractile response patterns
of the lateral saphenous vein to single additions of LSA,
LYS, ERN, ERT, ERS, ERP, ERO, and a tall fescue seed
extract (EXT) using a multimyograph.
MATERIALS AND METHODS
Procedures used in this study did not require ap-
proval from the University of Kentucky Animal Care
and Use Committee because no live animals were used.
Animals and Tissues
The cranial branch of the lateral saphenous vein
was collected from Holstein steers (n = 6; BW = 397 ±
28 kg) immediately after slaughter at the University
of Kentucky abattoir and processed according to the
methods of Klotz et al. (2006). Segments (4 to 5 cm
in length) of vein were removed and placed in a modi-
fied Krebs-Henseleit (oxygenated buffer solution, 95%
O2 + 5% CO2; pH = 7.4; mM composition = D-glu-
cose, 11.1; MgSO4, 1.2; KH2PO4, 1.2; KCl, 4.7; NaCl,
118.1; CaCl2, 3.4; and NaHCO3, 24.9; Sigma Chemical
Co., St. Louis, MO) for transport and were kept on ice
until processed. The venous segments had excess fat
and connective tissue carefully removed and then were
sliced into 2- to 3-mm cross-sections and examined
under a dissecting microscope (Stemi 2000-C; Carl
Zeiss Inc., Oberkochen, Germany) at 12.5x magnifica-
tion to confirm physical integrity of the tissue and to
verify the consistent segment size (Axiovision, version
20; Carl Zeiss Inc.). If abnormalities were found or an
inconsistent size was observed, the cross-section was
discarded and another segment was tested.
Myograph Experiments
Duplicate cross-sections from each animal were
horizontally suspended into a tissue bath (DMT610M
Multichamber myograph; Danish Myo Technologies,
Atlanta, GA) containing 5 mL of continuously gassed
(95% O2 + 5% CO2) modified Krebs-Henseleit buffer
(37°C). The transport buffer was modified for myo-
graph incubations, with the addition of desipramine
(3 × 10–5 M; D3900; Sigma Chemical Co.) and pro-
pranolol (1 × 10–6 M; P0844; Sigma Chemical Co.) to
inactivate neuronal uptake of catecholamines and to
block β-adrenergic receptors, respectively, as described
by Klotz et al. (2006). The baseline tension used to
equilibrate the tissue segments was 1 g for 90 min and
the buffer solution was replaced at 15-min intervals
throughout the entire experiment. The tissue segments
were exposed to a 500-μL aliquots of norepinephrine
(1 × 10–4 M) to assure responsiveness and for subse-
quent normalization of the tissue response data. Viable
tissues were washed every 15 min until the original 1-g
resting tension (baseline) was achieved.
Ergot alkaloids can be classified by their chemical
structure (Evans et al., 2004a,b) into groups (Fig. 1).
Ergopeptine alkaloids 1) ergovaline (provided as EXT
that was analyzed, validated, and described in detail by
Figure 1. Chemical structure of the water insoluble ergopeptine alkaloids (ergovaline, ergocristine, ergocryptine, ergocornine, and ergotamine) and the
water soluble ergoline alkaloids (lysergic acid, lysergol, and ergonovine).

3. Sustained contractile response 1215
Foote et al. [2012]), 2) ERS (Research Plus, Barnegat,
NJ), 3) ERP (E5625; Sigma Chemical Co.), 4) ERO
(E131; Sigma Chemical Co.), and 5) ERT (45510; Al-
drich, Milwaukee, WI) and ergoline alkaloids 6) LSA
(Acros Organics, Geel, Belgium), 7) LYS (R751650;
Aldrich), and 8) ERN (E6500; Sigma Chemical Co.).
After recovery from the norepinephrine viability assess-
ment, the cross-sections of the veins from each animal
were exposed to a single addition of a 25-μL aliquot of
1 × 10–4 M LSA, LYS, ERN, ERT, ERS, ERP, and ERO
and 1 × 10–6 M ergovaline in EXT (as measured by the
ultra-performance liquid chromatography/tandem mass
spectrometry [Acquity UPLC-TQD; Waters, Inc., Mil-
ford, MA]). Each alkaloid was tested in duplicate lateral
saphenous vein preparations from each steer.
The incubation buffer was replaced in 15-min in-
tervals for a 120-min incubation. At the end of the in-
cubation period, after a 1-min interval, the tissues were
exposed to a second 500-μL aliquot of norepinephrine
(1 × 10–4 M) to ensure tissue responsiveness at the con-
clusion of the experiment.
Data and Statistical Analyses
The contractile response was recorded as grams of
tension in response to exposure to norepinephrine, LSA,
LYS, ERN, ERT, ERS, ERP, ERO, and EXT. The data
were digitally recorded using a Powerlab/8sp (ADIn-
struments, Colorado Springs, CO) and Chart software
(version 7.2; ADInstruments). For each vessel segment,
the maximum tension was determined at each 15-min
interval during the 120-min incubation period follow-
ing the initial norepinephrine addition and corrected for
baseline tension (subtraction of the baseline value). Data
from each cross-section were normalized to the maxi-
mum contractile response generated by norepinephrine
from the same cross-section by dividing the baseline
corrected values by the baseline corrected norepineph-
rine value and multiplying by 100. This minimized dif-
ferences in contractile response due to different sized
veins and animal-to-animal variation (Klotz et al., 2006).
The time at maximum and minimum (after the max-
imum tension was achieved) tension (min), the specific
tension at those times (g), and in which 15-min interval
during the 120-min incubation period they were locat-
ed occurred were determined for each channel. Once a
vessel segment reached a maximum tension in the 120-
min incubation period, rate of relaxation was calculat-
ed by subtracting the baseline-corrected maximum and
minimum tensions and dividing it by the increment of
time that it took to reach the minimum tension. Also,
percent relaxation for each channel was obtained by
subtracting the baseline-corrected maximum and the
minimum tensions and dividing this difference by the
maximum tension and multiplying by 100.
Contractile response over the 120-min incubation
period, time to maximum, time to minimum, rate of re-
laxation, and percent of relaxation data were compared
between the alkaloids tested. The experimental model
used was completely randomized design analyzed with
mixed models in SAS (version 9.2; SAS Inst. Inc., Cary,
NC). Contractile response data were analyzed with re-
peated measures over time with an autoregressive co-
variance structure. The experimental unit was the vein,
and the alkaloid added to the chamber was the treatment.
Mean separation was conducted for all data considered
if the probability of a greater F-statistic in the ANOVA
was significant for the effect tested. The LSD feature in
SAS was used to evaluate individual mean differences
and was considered significant at P < 0.05.
RESULTS AND DISCUSSION
The ergoline alkaloids (for structures see Fig. 1) had
a larger initial contractile response than ergopeptine al-
kaloids, with LSAreaching a maximum (P < 0.05) in the
first 15-min interval and LYS and ERN reaching maxi-
mums (P < 0.05) in the second 15-min interval (Fig. 2).
These contractile responses began to immediately de-
crease after reaching the maximums, with ERN and LYS
decreasing (P < 0.05) towards the baseline value with
each subsequent 15-min interval. Vasoactivity of veins
exposed to LSA decreased (P < 0.05) more rapidly than
LYS and ERN after reaching maximum response and re-
turned to baseline tension by 45 min (Fig. 2).
Conversely, none of the ergopeptine alkaloids eval-
uated in the current experiment relaxed back to the base-
line value during the whole 120-min incubation (Fig. 3).
As for the ergopeptine alkaloids, ERO, ERP, and ERT
took 45 min to reach maximum (P < 0.05) contractile
response, and ERS needed 75 min to reach (P < 0.05)
maximum response (Fig. 3). Previous studies using seg-
ments of the cranial branch of the lateral saphenous vein
of bovines showed that ergovaline and ERT are potent
vasoconstrictors (Klotz et al., 2007) and that LSA was
not was not a potent vasoconstrictor (Klotz et al., 2006),
and repetitive additions of ergovaline (1 × 10–7 M) re-
sulted in a significant increase in the contractile response
(Klotz et al., 2008) compared to the baseline tension.
The data cited suggest that there is a bioaccumulative ef-
fect of repeated ergovaline exposures on the saphenous
veins exposed in vitro (Klotz et al., 2009). This bioaccu-
mulation is hypothesized to be a result of the sustained
contractile response observed in the current study and
the irreversible receptor binding of ergovaline reported
by Schöning et al. (2001).

4. Pesqueira et al.1216
It is hypothesized that the sustained contractile re-
sponse caused by ergopeptine alkaloids could be relat-
ed to the accumulative ability of some ergot alkaloids.
This effect may be explained by the strength of their
receptor affinity. Dihydroergotamine mesylate (DHE)
is a synthesized ergot alkaloid similar to ERT, and both
have similar vasoactivity on the cranial vascular bed;
however, they differ in their effect on peripheral blood
vessels, where DHE is more potent in veins and ERT
more potent in arteries (Müller-Schweinitzer, 1992).
Dihydroergotamine mesylate and the other alkaloids
have an affinity for norepinephrine, epinephrine, do-
pamine, and serotonin receptors (Saper and Silberstein,
2006). The observed effect of ergot alkaloids is related
to the activity of these receptors, yet the mechanisms
of this action are not well defined. The biologic activity
of DHE and all ergot alkaloids differ from their plasma
concentrations, which means that even at low con-
centrations their activity may persist for days (Saper
and Silberstein, 2006). The possible explanations are
the binding effect where DHE has a slow dissociation
from the receptor sites and the slow release of DHE
back into circulation caused by nonspecific binding to
other receptor sites (Saper and Silberstein, 2006). This
theory could explain the binding effect of the ergopep-
tine alkaloids to the vascular tissue, resulting in the
sustained contractile response observed during the 2-h
incubation period in the current experiment.
Klotz et al. (2009) hypothesized that ergovaline ac-
cumulates in vascular tissue, repeatedly exposed in vitro,
but that LSA does not accumulate. Ergovaline increased
the contractile response in the vascular tissue, but LSA
did not cause the same effect, even in repeated exposures
and increasing concentrations. The results obtained in
the current study observed similar response to LSA ex-
posure, where ergoline alkaloids returned to the baseline
tension during the incubation period and the ergopeptine
alkaloids caused the saphenous vein to remain in a con-
tracted state. The contractile response of ergovaline was
observed in studies using cross-sections of bovine lat-
eral saphenous veins (Klotz et al., 2007), bovine uterine
arteries (Dyer, 1993), and rat caudal arteries (Schöning
et al., 2001), which similarly showed the tissue did not
return to baseline tension. The observed failure of multi-
ple vasculature models from a variety of species to relax
after an in vitro exposure to ergovaline is likely due to
the high affinity for ergovaline and a slow dissociation,
similar to mechanisms discussed above for DHE.
Contractile response data were integrated with time
data to test the interaction between each ergot alkaloid
and time. These data show that the ergopeptine alkaloids
have a lower percent of relaxation and the contractile
response was mostly maintained during the 120-min in-
cubation period (Table 1) with a single addition of the
alkaloids. The time to minimum occurred faster in ves-
sels exposed to ergopeptine alkaloids, and the time to
maximum was greater (P < 0.05) for the ergopeptine
alkaloids (Table 1). This was due to the fact that vessels
exposed to ergoline alkaloids continued to relax during
the majority of the incubation while vessels exposed
to ergopeptine alkaloids continued to constrict for the
majority of the incubation. Ergonovine had the greatest
rate of relaxation (P < 0.05), ERS had the lowest rate of
relaxation, and LSA had the greatest percent of relax-
ation (Table 1). None of the ergopeptine alkaloids in-
cluding EXT differed in percent relaxation and only dif-
fered slightly in rate of relaxation (Table 1). The rate of
relaxation was different between the ergoline alkaloids,
where LSA and LYS had similar rates (P > 0.05) but
ERN had a higher value (P < 0.05). Ergocristine had the
Figure 2. Contractile response (normalized to the 1 × 10–4 M norepi-
nephrine maximum) of lateral saphenous veins to a single additions of 1 ×
10–4 M ergoline alkaloids ergonovine (ERN), lysergic acid (LSA), and ly-
sergol (LYS) in a 120-min experiment with buffer replacement occurring at
15-min intervals.
Figure 3. Contractile response (normalized to the 1 × 10–4 M norepi-
nephrine maximum) of lateral saphenous veins to a single additions of 1 ×
10–4 M ergopeptine alkaloids ergocornine (ERO), ergocryptine (ERP), ergo-
cristine (ERS), and ergotamine (ERT) in a 120-min experiment with buffer
replacement occurring at 15-min intervals.

5. Sustained contractile response 1217
lowest rate of relaxation (P < 0.05) of all the alkaloids,
which is consistent with the observation that it took 99.3
min to reach a maximum response leaving little time for
relaxation in the remaining 120-min incubation. These
data support previous studies (Klotz et al., 2006, 2008)
regarding the theory that ergopeptines have a greater va-
soactivity than the ergoline alkaloids, especially LSA.
Tall fescue seed extract was presented separately
(Fig. 4) because it could not be added at the same concen-
tration as the other alkaloids evaluated, and although it
contains mostly ergovaline (97% of measured alkaloids),
it is technically a mixture of different ergot alkaloids.
Foote et al. (2012) described the exact alkaloid content
of EXT and compared the contractile response produced
by EXT to the same concentrations of pure ergovaline in
bovine lateral saphenous veins. The contractile respons-
es between the pure ergovaline and EXT did not differ,
indicating that the other detected alkaloids were present
at levels below those required to induce a biological re-
sponse in this bioassay. The EXT containing 1 × 10–6 M
ergovaline used in the current study is from the same lot
of EXT used in the Foote et al. (2012) study. Although
the contractile response over time to EXT (Fig. 4) was
not compared directly to the other ergopeptine alkaloids
evaluated in the current study, the response did not appear
to differ much in magnitude from ERP, ERO, ERS, or
ERT (Fig. 3) even though the concentration of EXT was
2-fold less. This is additional evidence that ergovaline is
the most vasoactive of the ergopeptine alkaloids produced
by N. coenophialum. Furthermore, the response to a 1 ×
10–6 M ergovaline addition through the EXT was not dif-
ferent from 1 × 10–6 M additions of ERP, ERO, or ERT in
the time to maximum response, rate of relaxation, or per-
cent relaxation (Table 1). In the current study, the maxi-
mum response to 1 × 10–4 M EXT was recorded at 65 min.
In lower concentrations (10–10 M), ergovaline was shown
to require a minimum of 120 min to reach the maximal
contractile response in bovine uterine and umbilical arter-
ies (Dyer, 1993) This time shortened as the concentration
increased and even after 3 h of repeatedly changing the
bath fluid with fresh Krebs solution the tissue did not be-
gin to relax (Dyer, 1993). In the current study, the lateral
saphenous vein began to relax from the maximum (P <
0.05) at the end of the 120-min incubation period. This
difference in time of relaxation could be due to the differ-
ent anatomic origin and vessel type (artery versus vein) of
the tissues used in the experiments.
In conclusion, this study indicates that ergot alka-
loids classified as ergolines do not have a persistent
binding effect and do not cause a sustained contractile
response in the cranial branch of the bovine lateral sa-
phenous vein. The contractile response caused by ergo-
lines is highest during the first 15- to 30-min interval fol-
lowed by constant relaxation during the remaining 120-
min incubation period. Obversely, the ergopeptine alka-
loids have a sustained contractile response that slowly
increased during the first three to five 15-min intervals.
Table 1. Percent relaxation, time to minimum, time to maximum, and rate of relaxation of bovine lateral saphenous
veins exposed to ergoline and ergopeptine alkaloids1
Variable LSA LYS ERN ERO ERP ERS ERT EXT SEM P-value
Time to reach maximum tension,2 min 14.30C 25.70C 18.30C 52.00B 66.60B 99.30A 62.70B 65.00B 7.77 <0.001
Time to reach minimum tension,3 min 97.60A 90.10A 94.20A 57.90B 38.70B 12.40C 44.90B 41.20B 7.59 <0.001
Relaxation,4 % 119.15A 53.10B 59.72B 13.80C 11.47C 3.11C 14.08C 11.44C 4.34 <0.001
Rate of relaxation,5 g/min 0.07B 0.07B 0.14A 0.03C 0.02CD 0.006D 0.03C 0.02CD 0.01 <0.001
A–DMeans within a row with different subscripts differ (P < 0.05).
1Based on a single 1 × 10–4 M addition of lysergic acid (LSA), lysergol (LYS), ergonovine (ERN), ergocornine (ERO), ergocryptine (ERP), ergocristine
(ERS), or ergotamine (ERT) or 1 × 10–6 M tall fescue seed extract (EXT).
2The interval of time from the addition of the alkaloid until the maximum tension was recorded within the 120-min incubation period.
3The interval of time following the point of observed maximum tension until the minimum tension was recorded within the 120-min incubation period.
4The percent relaxation was determined by subtracting the baseline-corrected maximum and the minimum tensions and dividing by the maximum tension
and multiplying by 100.
5The rate of relaxation was determined once a vessel segment reached a maximum tension in the 120-min incubation period, by subtracting the baseline-
corrected maximum and minimum tensions, and dividing by the increment of time that it took to reach the minimum tension.
Figure 4. Contractile response (normalized to the 1 × 10–4 M norepi-
nephrine maximum) of lateral saphenous veins to a single addition of 1 ×
10–6 M tall fescue seed extract (EXT; dilution based on measured ergovaline
concentration) in a 120-min experiment with buffer replacement occurring at
15-min intervals.

6. Pesqueira et al.1218
Furthermore, the ergopeptines did not relax markedly
during the incubation period. The absence of relaxation
by the lateral saphenous vein after the ergopeptine al-
kaloids were removed from the buffer is an indication
of the ability of these toxins to cause vasoconstriction,
possibly accumulate, and delay the animal’s recovery
from fescue toxicosis. To mitigate the vascular effects
of fescue toxicosis, future research should be directed at
analyzing the ergot alkaloid receptor affinity mechanism
and how to manipulate this effect.
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