Download Vasoconstrictor responses of coronary resistance arteries in

Vasoconstrictor responses of coronary resistance
arteries in exercise-trained pigs
M. HAROLD LAUGHLIN AND JUDY M. MULLER
Departments of Veterinary Biomedical Sciences and Medical Physiology,
The Dalton Cardiovascular Research Center, and Division of Cardiology,
College of Medicine, University of Missouri, Columbia, Missouri 65211
albumin; spontaneous tone; vascular smooth muscle; acetylcholine; endothelin; Bay K 8644; nitroprusside
CORONARY BLOOD FLOW and capillary exchange capacities are increased in the hearts of exercise-trained pigs
(17, 23). The increased transport capacity of the coronary circulation is associated with changes in local
control of coronary resistance (17, 23) and vasoreactivity of coronary arteries (21, 22) and the control of
intracellular calcium by the sarcoplasmic reticulum in
coronary vascular smooth muscle (25, 26). The myogenic response, the ability of blood vessels to constrict
in response to elevations in intraluminal pressure and
dilate when intraluminal pressure decreases, appears
to be an intrinsic property of resistance arteries and is
believed to be critically important in control of vascular
resistance in the microcirculation (3, 5, 6, 9, 13, 18).
Coronary resistance arteries isolated from exercise-
884
trained (Trn) pigs exhibit increased myogenic reactivity
(20). Specifically, comparison of pressure-diameter
curves of isolated, cannulated arteries revealed that
arteries from Trn pigs constrict more than arteries from
control pigs as intraluminal pressure was raised to and
above 60 mmHg. The mechanisms responsible for the
enhanced myogenic reactivity in coronary resistance
arteries have not been determined.
DiCarlo et al. (4) reported that exercise training in
dogs produced enhanced sensitivity of coronary resistance arteries to norepinephrine. The results of this
study (4), considered together with those by Muller et
al. (20), suggest the hypothesis that exercise training
produces increased sensitivity of coronary resistance
arteries to all vasoconstrictor stimuli, including the
response to stretch (myogenic response). Thus increased myogenic reactivity after exercise training may
reflect a generalized enhancement of all vasoconstrictor responses in coronary resistance arteries. The purpose of this study was to test this hypothesis. Responses of coronary resistance arteries to receptormediated and voltage-gated calcium channel-mediated
vasoconstrictions were examined in coronary resistance arteries isolated from exercise trained and sedentary pigs. An in vitro, isolated artery preparation was
used to determine vasoconstrictor responses, independent of confounding neural or humoral influences, that
might be found in the intact heart.
MATERIALS AND METHODS
Experimental animals. Adult female miniature swine
weighing 25–40 kg were obtained from the breeder (Charles
River) and randomly divided into groups of Trn pigs and
sedentary control (Sed) pigs. The Trn pigs were placed on the
same progressive treadmill training program used by Muller
et al. (20), which is a modification of the program designed by
Tipton et al. (27). Sed pigs were confined to their pens during
the training period (16–20 wk). This is the same training
program our laboratory has used for miniature swine in
previous studies (17, 20–23, 25, 26).
Training program. All animals used in this study were
housed and maintained in accordance with standards set
forth by the American Association for Laboratory Animal
Care and the University of Missouri Institutional Animal
Care and Use Committee. In week 1 of training, Trn pigs
walked on the treadmill for 5 min at 2.5 mph to warm-up.
After the warm-up, the pigs ran on the treadmill at 5 miles/h
(mph) for 15 min (sprint) and at 3 mph for 20–30 min
(endurance). Pigs were fed after treadmill training bouts as
positive reinforcement of the behavior (17, 19, 21–23). The
intensity and duration of exercise bouts increased steadily so
that by the week 12 of training the pigs ran 85 min/day, 5
days/wk. At this time, the 85-min training bouts consisted of a
5-min warm-up at a speed of 2.5 mph, a 15-min sprint run at
0161-7567/98 $5.00 Copyright r 1998 the American Physiological Society
http://www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017
Laughlin, M. Harold, and Judy M. Muller. Vasoconstrictor responses of coronary resistance arteries in exercisetrained pigs. J. Appl. Physiol. 84(3): 884–889, 1998.—
Coronary resistance arteries isolated from exercise-trained
pigs have been shown to exhibit enhanced myogenic reactivity (J. M. Muller, P. R. Myers, and M. Harold Laughlin. J.
Appl. Physiol. 75: 2677–2682, 1993). The purpose of this
study was to test the hypothesis that exercise training results
in enhanced vasoconstrictor responses of these arteries to all
vasoconstrictor stimuli [specifically acetylcholine (ACh), endothelin-1 (ET-1), KCl, and the Ca21 channel-agonist Bay K
8644]. Female Yucatan miniature swine were trained (Trn) on
a motor-driven treadmill (n 5 16) or remained sedentary
(Sed, n 5 15) for 16–20 wk. Arteries 50–120 µm in diameter
were isolated and cannulated with micropipettes, and intraluminal pressure was set at 60 cmH2O throughout experiments.
Vasoreactivity was evaluated by examining constrictor responses to increasing concentrations of ACh (1029 to 1024 M),
ET-1 (10210 to 1028 M), KCl (bath replacement with isotonic
physiological saline solution containing 30 or 80 mM), and
Bay K 8644 (1029 to 1026 M). Constricted diameters are
expressed relative to the passive diameter observed after 100
µM SNP. All four constrictors produced similar decreases in
diameter in arteries from both groups [ACh: 0.52 6 0.07 (Trn)
and 0.54 6 0,06 (Sed); ET-1: 0.66 6 0.05 (Trn) and 0.70 6 0.07
(Sed); KCl: 0.66 6 0.05 (Trn) and 0.70 6 0.07 (Sed); Bay K
8644: 0.86 6 0.05 (Trn) and 0.76 6 0.05 (Sed)]. Present results
combined with previous observations indicate that exercise
training does not alter vasoconstrictor responses of porcine
coronary resistance arteries but specifically increases myogenic reactivity. Thus the underlying cellular mechanisms for
myogenic tone are altered by training but not receptormediated mechanisms (ACh and ET-1) nor voltage-gated
Ca21 channels (KCl and Bay K 8644) in coronary resistance
arteries.
EXERCISE TRAINING AND CORONARY RESISTANCE ARTERIES
Louis, MO) unless otherwise specified. Drugs were dissolved
in PSS-albumin and administered to the bath surrounding
the artery. PSS-albumin contained 10 mg/ml bovine serum
albumin (bovine, fraction V: 98–99% albumin, US Biochemical) as described previously (7, 13, 19, 20).
Experimental procedure. Vessels were allowed to equilibrate at an intraluminal pressure of 60 cmH2O for 1 h, during
which time the temperature of the chamber was raised to and
maintained at 37 6 1°C with a circulating water bath. During
the 1-h equilibration period, the PSS-albumin was replaced
three times with fresh PSS-albumin (37°C).
Sensitivity to receptor-mediated vasoconstrictor agonists
was evaluated by examining responses to acetylcholine (ACh)
and endothelin-1 (ET-1), direct vascular smooth muscle vasoconstrictor agents in pig coronary arteries. These vasoconstrictor agonists were selected because they are receptormediated constrictors that preliminary experiments revealed
consistently produced vasoconstriction. Concentration-response curves were obtained by cumulative additions of small
aliquots of concentrated stock solution directly into the bath;
drug concentrations (1029 to 1024 M ACh; 10210 to 1028 M
ET-1) were increased after the response to the preceding dose
was maximal. To examine contractions mediated by voltagegated calcium channels, responses to KCl and Bay K 8644
were examined. Concentration-response curves were obtained by cumulative additions of small aliquots of concentrated stock solution directly into the bath; drug concentrations (5 to 100 mM KCl; 1029 to 1026 M Bay K 8644) were
increased after the response to the preceding dose was
maximal. Arteries that did not respond (20% constriction) to
KCl and ACh or ET-1 were deleted from the study. Spontaneous tone was not used as a selection criterion in this study.
Arteries that developed spontaneous tone (15% constriction)
were generally used for other protocols. Some arteries did not
constrict in response to addition of KCl to the bath. To
determine whether this lack of responsiveness was due to the
cumulative addition of KCl to the bath, responses to bath
replacement with isotonic PSS containing 30 or 80 mM KCl
were examined in arteries from eight Sed and eight Trn pigs.
Finally, at the end of each experiment, each artery was
exposed to 100 µM sodium nitroprusside (SNP) in PSSalbumin solution to determine maximal diameter at 60
cmH2O intraluminal pressure. Diameters were normalized to
this measurement as described previously by Kuo et al. (9, 12,
13) and Muller et al. (20). This pressure, 60 cmH2O, was
selected because in vivo microvascular pressure measurements obtained by Chilian et al. (2) in the beating cat
ventricle indicate that intravascular pressure in vessels of
this size is ,60 cmH2O.
Data analysis. Vasomotor responses are presented as absolute diameters and as normalized diameters. The diameter
measured at 60 cmH2O intraluminal pressure in the presence
of 100 µM SNP was defined as the reference diameter and
was assigned a value of 1.0. All normalized diameter measurements are expressed relative to this diameter, as described by
Kuo et al. (9, 10, 11, 13). Responses were compared between
Trn and Sed groups by analysis of variance (ANOVA) for
repeated measures. Diameters measured at each dose were
compared between Trn and Sed groups with ANOVA for
repeated measures by using SuperANOVA software. No post
hoc tests were employed because ANOVA did not indicate that
differences existed between groups. Significance of differences between mean values for treadmill performance times,
citrate synthase activity, and heart weight-to-body weight
ratio were determined by an unpaired t-test. In all statistical
analyses, n is the number of pigs. Significance was defined as
P , 0.05.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017
speeds of 6–8 mph, a 60-min endurance run at speeds of 4–6
mph, and a 5-min warm-down at a speed of 2 mph. Actual
running speeds during the sprint and endurance runs depended on the ability of each pig to perform on the treadmill.
Treadmill performance test. At the beginning and again at
the end of the training period, treadmill performance tests
were administered to both Trn and Sed pigs to evaluate
exercise tolerance. The treadmill performance test consisted
of four stages of exercise (17). In stage 1 the pigs ran 3.1 mph
with 0% grade for 5 min. In stage 2 the pigs continued to run
at 3.1 mph for 10 min, and the grade was increased to 10%. In
stage 3 speed was increased to 4.3 mph, whereas the grade
remained at 10%. The pigs ran for 10 min in this stage. In the
final stage (stage 4) the pigs ran up a 10% grade at 6 mph
until exhaustion. A three-lead electrocardiogram was used to
measure heart rates continuously throughout the test. Total
exercise times were also recorded.
Oxidative enzyme capacity. Samples were taken from the
middle of the triceps brachii muscles, frozen, and stored at
270°C until processed. Citrate synthase activity was measured in the samples by using the spectrophotometric assay
described by Srere (24).
Preparation of coronary resistance arteries. After completion of exercise training (or sedentary confinement), pigs were
sedated with ketamine (30 mg/kg) and anesthetized with
pentobarbital sodium (30 mg/kg). The hearts were rapidly
removed and placed in cold physiological saline solution (PSS;
4°C). The weight of the heart was recorded, and a portion of
the left ventricular wall was isolated and placed in a dissection chamber containing cold PSS. Resistance arteries 50–
120 µm in intraluminal diameter and ,1 mm in length were
isolated from the surrounding tissue 0.5–3.0 mm below the
epicardial surface with the aid of a dissecting microscope.
Resistance arteries were placed in a Plexiglas chamber
containing PSS-albumin solution equilibrated with room air
at ambient temperature. Each end of the vessel was cannulated with a glass micropipette (,50 µm diameter and filled
with filtered PSS-albumin) and secured with 11–0 ophthalmic suture. The vessel was stretched to the length measured
before removal from the myocardium. The glass micropipettes were connected to independent reservoirs, and intraluminal pressure was set at 60 cmH2O, with zero intraluminal
flow, by raising the reservoirs 60 cm above the vessel chamber. Pressures were measured through side arms of the two
reservoirs with low-volume displacement transducers (model
BP100 transducer, AD Instruments). If the arteries would not
maintain pressure (due to leaks), they were removed from the
chamber and discarded. The cannulated vessel was viewed
through an inverted microscope (Nikon Diaphot TMD) with a
320–40 lens, numerical aperture of 0.4 (ELWD). The microscope was coupled to a video camera (Panasonic WV 1,500x)
and TV monitor (Panasonic TR930B). An image of the vessel
was displayed on the TV monitor, and intraluminal diameter
measurements were made continuously by using a video
tracking device (Texas A & M) as described previously (12, 13,
20, 21). The tracking system was calibrated with a stage
micrometer showing 10-µm divisions. The resolution of the
system allowed measurement of changes in vessel diameter
as small as 2 µm. The tracking device produced a direct
current signal that was recorded on a computer dataacquisition system (MacLab) at a sampling rate of 4 samples/s.
The PSS used in these experiments consisted of (in mM)
145 NaCl, 4.7 KCl, 2.0 CaCl2, 1.17 MgSO4, 1.2 NaH2PO4, 5.0
glucose, 2.0 pyruvate, 0.02 EDTA, and 3.0 3-(N-morpholino)propanesulfonic acid buffer. The PSS pH was adjusted to 7.4
and filtered through 0.22-µm filters (Fisher Scientific, Pittsburgh, PA). All drugs were obtained from Sigma Chemical (St.
885
886
EXERCISE TRAINING AND CORONARY RESISTANCE ARTERIES
RESULTS
DISCUSSION
The purpose of this study was to test the hypothesis
that exercise training results in enhanced vasoconstrictor responses of coronary resistance arteries to all
vasoconstrictor stimuli (specifically, ACh, ET-1, KCl,
and the calcium channel-agonist Bay K 8644 were
examined). An in vitro approach was used to evaluate
the effects of exercise training on contractile responses
Table 1. Characteristics of animals and treadmill performance test heart rate data
Characteristics of Animals
Trn
Sed
Heart
wt, g
Body
wt, kg
Heart wt/body wt,
g/kg
Citrate SA of TLH,
µmol · min21 · g21
Citrate SA of Delt,
µmol · min21 · g21
194.7 6 5.7*
163.9 6 6.6
33.8 6 1.2
34.1 6 2.8
5.9 6 0.2*
5.0 6 1.0
17.0 6 1.0*
11.2 6 1.0
23.1 6 1.2*
17.1 6 1.0
Performance Testing
Heart rates, beats/min
Trn
Sed
Stage 1
Stage 2
Stage 3
Stage 4
Total time,
min
146 6 12*
199 6 17
175 6 14*
232 6 18
221 6 22*
267 6 3
237 6 8*
264 6 5
37.8 6 3.0
23.8 6 1.9
Values are means 6 SE; n 5 18 trained (Trn) and 18 sedentary (Sed) pigs. Heart wt/Body wt, heart weight-to-body weight ratio; SA, citrate
synthase activity; TLH, long head of triceps brachii; Delt, deltoid. Heart rates for treadmill performance tests, conducted after training (Sed)
period, are presented during 4 progressive stages of testing (stages 1–4), as described in text. Total run time during treadmill performance
tests before 16–22 wk of training was 24.6 6 1.3 and 24.6 6 2.3 min for Trn and Sed pigs, respectively. * Significantly different between Trn and
Sed values, P , 0.05.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017
Physiological state of animals. As expected, the training program resulted in significant increases in the
endurance of the Trn pigs (17, 20–23, 25, 26). Thus, by
week 16 of training, Trn pigs were able to complete
85-min running bouts on the treadmill whereas during
the first week of training fatigue generally occurred
after 30–40 min of treadmill exercise. Further indication of the effectiveness of training are given in Table 1.
Heart weight, heart weight-to-body weight ratio, and
citrate synthase activity of skeletal muscles were significantly higher in the Trn pigs. Trn pigs also had significantly longer running times during performance testing. Heart rates were significantly lower in Trn pigs
during all stages of treadmill performance testing
(Table 1).
Characteristics of isolated coronary resistance arteries. Mean intraluminal diameter measured at 60 cmH2O
in the presence of 100 µM SNP was similar in resistance arteries isolated from Trn (115 6 5 µm) and Sed
(109 6 5 µm) pigs. The range of passive intraluminal
diameter was from 73 to 221 µm and from 67 to 202 µm
in vessels from Trn and Sed pigs, respectively.
Only vessels that constricted at least 20% to vasoconstrictor agents were included in data analysis. In
keeping with this selection criterion, no response to
vasoconstrictor agents was observed in 4 of 43 vessels
from Trn pigs and in 2 of 45 arteries from Sed pigs.
During the initial equilibration period at 60 cmH2O,
most vessels from Trn and Sed pigs developed similar
spontaneous tone. In the Trn group the mean normalized diameter after equilibration was 0.93 6 0.01 µm,
and in the Sed group the diameter was 0.94 6 0.01 µm.
Spontaneous tone, $5% of normalized diameter, was
present in 22 of 39 arteries from Trn pigs and in 18 of 43
arteries from Sed pigs. Thus the incidence of spontaneous tone and of nonresponsive arteries was similar in
vessels from Trn and Sed pigs. It should be noted that
in a previous study from our laboratory (20), which
focused on myogenic responsiveness, arteries were
selected that constricted $15% in response to increas-
ing intraluminal pressure. This selection criterion was
not used in the present study.
Responses to receptor-mediated vasoconstrictor agents.
ACh produced dose-dependent constriction in arteries
from both groups (Fig. 1). ACh sensitivity and maximal
ACh-induced contraction of arteries isolated from Trn
and Sed pigs were similar. ET-1 also produced dosedependent constriction in arteries from both groups,
and sensitivity and maximal ET-1-induced contraction
were also similar (Fig. 2). ET-1 is a more potent
vasoconstrictor agent than ACh, as reflected by the fact
that constriction was apparent at doses of 10210 M
ET-1. Doses of ET-1 greater than 1029 M generally
caused complete constriction.
Cumulative addition of KCl generally produced dosedependent constriction in arteries from both groups
(data not shown). However, KCl occasionally produced
no response or even vasodilation in some vessels. To
determine whether these results were influenced by the
hypertonic conditions produced by cumulative addition
of KCl to the bath, we conducted a series of experiments
in which the bath was replaced with isotonic PSS
containing 30 or 80 mM KCl. The results of this
experiment are shown in Fig. 3. In both Trn and Sed
groups, replacement of PSS produced greater constriction with both 30 and 80 mM KCl than did cumulative
addition of KCl. These results indicate that the response of coronary resistance arteries to changes in
membrane potential produced by KCl is similar in Trn
and Sed animals. Finally, Bay K 8644, a selective L-type
calcium channel-agonist, produced dose-dependent constriction in arteries from both groups (Fig. 4).
EXERCISE TRAINING AND CORONARY RESISTANCE ARTERIES
of coronary resistance arteries to ACh and ET-1, agents
that induce contraction via receptor-mediated mechanisms, and to two agents that induce contraction via
opening of voltage-gated calcium channels in the vascular smooth muscle sarcolemma, KCl and Bay K 8644.
The results indicate that vasoconstrictor responses
signaled by receptor-mediated mechanisms (ACh and
ET-1) and by voltage-gated calcium channels (KCl and
Bay K 8644) were similar in coronary resistance arteries isolated from Sed and Trn pigs. These results,
combined with the previously observed increase in the
myogenic response in coronary resistance arteries isolated from exercise-trained pigs (20), suggest that
exercise training specifically increases myogenic reac-
Fig. 2. Vasoconstrictor responses to increasing doses of endothelin in
coronary resistance arteries from Sed and Trn pigs. Diameters were
normalized to diameter measured in response to 100 µM nitroprusside at 60 cmH2O. Values are means 6 SE.
Fig. 3. Vasoconstrictor responses to 30 and 80 mM KCl in coronary
resistance arteries from Sed and Trn pigs. Diameters were normalized to diameter measured in response to 100 µM nitroprusside at 60
cmH2O. Values are means 6 SE; n 5 8 Sed and 8 Trn animals. rep,
Replacement of bath with isotonic PSS-albumin (PSSA) containing
30 or 80 mM KCl; add, cumulative addition of KCl.
tivity. It is important that the pigs in the present study
were trained by using a training program identical to
that of Muller et al. (20). Present results also indicate
that the underlying cellular mechanisms responsible
Fig. 4. Vasoconstrictor responses to increasing doses of Bay K 8644
(M) in coronary resistance arteries from Sed and Trn pigs. Values are
means 6 SE. Results are expressed as absolute diameters (A), and
diameter relative to initial diameter was determined in presence of
30 mM KCl (B). PSSA contained 30 mM KCl.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017
Fig. 1. Vasoconstrictor responses to increasing doses of acetylcholine
in coronary resistance arteries from sedentary (Sed) and exercisetrained (Trn) pigs. Diameters were normalized to diameter measured
in response to 100 µM nitroprusside at 60 cmH2O. Values are
means 6 SE. n, No. of animals.
887
888
EXERCISE TRAINING AND CORONARY RESISTANCE ARTERIES
arteries to vasoconstrictor agents (Figs. 1–4). This lack
of effect of training on vascular smooth muscle in these
arteries is consistent with a lack of effect of training on
direct vascular smooth muscle vasodilator responses of
this size of coronary resistance arteries (21). Muller et
al. (21) reported that endothelium-dependent vasodilation is enhanced after training. Present results combined with these previous results indicate that the only
direct vascular smooth muscle vasomotor response of
coronary resistance arteries that is altered by exercise
training is myogenic reactivity (20). Presently, available data do not allow us to determine the significance
of these changes to the control of coronary blood flow.
Even in the absence of a change in total coronary blood
flow per se, it is possible that the enhancement of these
two opposing control mechanisms in the coronary microcirculation results in improved control of myocardial
perfusion (8, 10, 11).
The authors thank Miles A. Tanner, Pam Thorne, Tammy Knox,
Tammy Strawn, and Denise Stowers for important technical contributions to this work.
This work was supported by National Heart, Lung, and Blood
Institute Grant HL-52490.
Address for reprint requests: M. Laughlin, E102 Veterinary Medical Bldg., Univ. of Missouri, Columbia, MO 65211.
Received 28 July 1997; accepted in final form 12 November 1997.
REFERENCES
1. Bove, A. A., and J. D. Dewey. Proximal coronary vasomotor
reactivity after exercise training in dogs. Circulation 71: 620–
625, 1985.
2. Chilian, W. M., C. L. Eastham, and M. L. Marcus. Microvascular distribution of coronary vascular resistance in beating left
ventricle. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H779–
H788, 1986.
3. D’Angelo, G., and G. A. Meininger. Transduction mechanisms
involved in the regulation of myogenic activity. Hypertension 23:
1096–1105, 1994.
4. DiCarlo, S. E., R. W. Blair, V. S. Bishop, and H. L. Stone.
Daily exercise enhances coronary resistance vessel sensitivity to
pharmacological activation. J. Appl. Physiol. 66: 421–428, 1989.
5. Halpern, W., G. Osol, and G. Coy. Mechanical behavior of
pressurized in vitro prearteriolar vessels determined with a
video system. Ann. Biomed. Eng. 12: 463–479, 1984.
6. Harder, D. Pressure-induced myogenic activation of cat cerebral
arteries is dependent on intact endothelium. Circ. Res. 60:
102–107, 1987.
7. Jackson, P. A., and B. R. Duling. Myogenic response and wall
mechanics of arterioles. Am. J. Physiol. 257 (Heart Circ. Physiol.
26): H1147–H1155, 1989.
8. Jones, C. J. H., L. Kuo, M. J. Davis, D. V. Defily, and W. M.
Chilian. Role of nitric oxide in the coronary microvascular
responses to adenosine and increased metabolic demand. Circulation 91: 1807–1813, 1995.
9. Kuo, L., W. M. Chilian, and M. J. Davis. Coronary arteriolar
myogenic response is independent of endothelium. Circ. Res. 66:
860–866, 1990.
10. Kuo, L., W. M. Chilian, and M. J. Davis. Interaction of
pressure- and flow-induced responses in porcine coronary resistance vessels. Am. J. Physiol. 261 (Heart Circ. Physiol. 30):
H1706–H1715, 1991.
11. Kuo, L., W. M. Chilian, and M. J. Davis. Longitudinal gradients for endothelium-dependent and -independent vascular responses in the coronary microcirculation. Circulation 92: 518–
525, 1995.
12. Kuo, L., W. M. Chilian, M. J. Davis, and M. H. Laughlin.
Endotoxin impairs flow-induced vasodilation of porcine coronary
arterioles. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H1838–
H1845, 1992.
13. Kuo, L., M. J. Davis, and W. M. Chilian. Myogenic activity in
isolated subepicardial and subendocardial coronary arterioles.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017
for the enhanced myogenic reactivity do not involve the
L-type calcium channels in the sarcolemma or receptorsecond messenger signaling systems used by ACh or
ET-1 in vascular smooth muscle cells in coronary
resistance arteries.
The hypothesis for this study was based on results
from previous studies that indicate that exercise training alters coronary vasomotor control at the whole
organ and/or microvascular level (1, 4, 14–17, 20–23,
25, 26). Results from the intact coronary circulation
indicate that reactivity of coronary resistance arteries
to vasodilator stimuli (4, 14, 15, 17, 23) and vasoconstrictor stimuli (4) is increased after exercise training.
DiCarlo et al. (4) reported that the norepinephrineinduced vasoconstrictor responses of coronary resistance arteries in conscious dogs were increased after
exercise training. The cause of the difference between
results of the present study and those of DiCarlo et al.
(4) cannot be established at this time. However, we do
not believe the differing results necessarily indicate
that vascular adaptations to exercise training are
different in the coronary circulation of dogs and pigs.
Rather, in vivo measurements of coronary function
reflect an average response of all sizes of coronary
resistance arteries throughout the coronary arterial
tree. Because vasomotor responsiveness is not uniform
throughout the coronary arterial tree, regional changes
in vasomotor function may be masked by compensatory
responses at other levels in the arterial tree (11). For
example, constriction of large resistance arteries may
produce metabolic vasodilation of small resistance arteries so that total vascular resistance measured across
the entire vascular tree is not different, whereas changes
occurred regionally along the arterial tree (8). It is also
possible that the observations of DiCarlo et al. (4) are
norepinephrine specific, which cannot be tested in
isolated coronary resistance arteries. Other neuralhumoral factors present in vivo could also be responsible for the increased sensitivity to norepinephrine in
trained dogs rather than the sensitivity of vascular
smooth muscle in coronary resistance arteries to vasoconstrictor agents.
Muller et al. (20) reported that myogenic constriction
in response to increased intraluminal pressure was
enhanced in coronary resistance arteries from exercisetrained pigs. Kuo et al. (9, 10) reported that myogenic
responses of porcine coronary resistance arteries are
endothelium independent. Therefore, the enhanced
myogenic reactivity reported by Muller et al. (20) likely
results from a change in the vascular smooth muscle in
these arteries. These results combined with present
observations suggest that this effect of exercise training on coronary resistance arteries is somehow specific
to contractions induced by stretch.
Exercise training has been shown to increase the
reactivity of the coronary microcirculation to vasodilator stimuli (4, 14, 15, 17, 23) and vasoconstrictor
stimuli (4). We selected the resistance artery size used
in the present study because the bulk of vascular
resistance in the coronary circulation lies in arteries in
this size range (8, 11). Present results indicate that
training does not alter responses of coronary resistance
EXERCISE TRAINING AND CORONARY RESISTANCE ARTERIES
14.
15.
16.
17.
18.
19.
20.
Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H1558–H1562,
1988.
Laughlin, M. H. Effects of exercise training on coronary transport capacity. J. Appl. Physiol. 58: 468–476, 1985.
Laughlin, M. H., J. N. Diana, and C. M. Tipton. Effects of
chronic exercise training on coronary reactive hyperemia and
coronary blood flow in the dog. J. Appl. Physiol. 45: 604–610,
1978.
Laughlin, M. H., and R. M. McAllister. Exercise traininginduced coronary vascular adaptation. J. Appl. Physiol. 73:
2209–2225, 1992.
Laughlin, M. H., K. A. Overholser, and M. J. Bhatte.
Exercise training increases coronary transport reserve in miniature swine. J. Appl. Physiol. 67: 1140–1149, 1989.
Meininger, G. A., and M. J. Davis. Cellular mechanisms
involved in the vascular myogenic response. Am. J. Physiol. 263
(Heart Circ. Physiol. 32): H647–H659, 1992.
Muller, J. M., M. H. Laughlin, and P. R. Myers. Vasoactivity
of isolated coronary microvessels: influence of albumin. Microvasc. Res. 46: 107–115, 1993.
Muller, J. M., P. R. Myers, and M. H. Laughlin. Exercise
training alters myogenic responses in porcine coronary resistance arteries. J. Appl. Physiol. 75: 2677–2682, 1993.
889
21. Muller, J. M., P. R. Myers, and M. H. Laughlin. Vasodilator
responses of coronary resistance arteries from exercise trained
pigs. Circulation 89: 2308–2314, 1994.
22. Oltman, C. L., J. L. Parker, H. R. Adams, and M. H.
Laughlin. Effects of exercise training on vasomotor reactivity of
porcine coronary arteries. Am. J. Physiol. 263 (Heart Circ.
Physiol. 32): H372–H382, 1992.
23. Overholser, K. A., M. H. Laughlin, and M. J. Bhatte.
Exercise training-induced increase in coronary transport capacity. Med. Sci. Sports Exerc. 26: 1239–1244, 1994.
24. Srere, P. A. Citrate synthase. Methods Enzymol. 13: 3–5, 1969.
25. Stehno-Bittel, L., M. H. Laughlin, and M. Sturek. Exercise
training alters calcium release from coronary smooth muscle
sarcoplasmic reticulum. Am. J. Physiol. 259 (Heart Circ. Physiol.
28): H643–H647, 1990.
26. Stehno-Bittel, L., M. H. Laughlin, and M. Sturek. Exercise
training depletes sarcoplasmic reticulum calcium in coronary
smooth muscle. J. Appl. Physiol. 71: 1764–1773, 1991.
27. Tipton, C. M., R. A. Carey, W. C. Eastin, and H. H. Erickson.
A submaximal test for dogs: evaluation of the effects of exercise
training, detraining, and cage confinement. J. Appl. Physiol. 37:
271–275, 1974.
Downloaded from http://jap.physiology.org/ by 10.220.33.1 on August 2, 2017