Vol. 277, Issue 4, H1447-H1452, October 1999
Enhanced 
-receptor-mediated vasorelaxation in hypoxic
porcine coronary artery
Satoru
Fukuda,
Takashi
Toriumi,
Hui
Xu,
Hidenori
Kinoshita,
Hironobu
Nishimaki,
Seiichiro
Kokubun,
Naoshi
Fujiwara,
Hideyoshi
Fujihara, and
Koki
Shimoji
Department of Anesthesiology, Niigata University School of Medicine,
Niigata 951-8510, Japan
 |
ABSTRACT |
To investigate the 
-adrenoceptor-mediated
responses in hypoxic coronary arteries, we studied the effect of
isoproterenol (Iso) on isolated porcine coronary arteries contracted
with endothelin-1 in media aerated with 0, 5, 7.5, and 95%
O2. The concentration-response curve of Iso was significantly shifted to the left by hypoxia (0 and
5% O2). In oxygenated and
hypoxic arteries, 3 × 10
8,
106, and
105 M Iso significantly
increased the contents of cAMP. However, there was no difference in the
increases of cAMP content induced by 3 × 108 M Iso between
oxygenated and hypoxic arteries. The content of cAMP induced by high
concentrations of Iso (106
and 105 M) was
significantly larger in hypoxic than in oxygenated arteries. Furthermore, the potentiation by hypoxia of the Iso-induced
vasorelaxation was inhibited by glibenclamide and depolarization by
KCl, but not by removal of endothelium and indomethacin. The
vasodilatory response to forskolin and dibutyryl cAMP was unaffected by
hypoxia. We conclude that activation of the ATP-sensitive
K+ channel may account for the
potentiation of the response to Iso in hypoxic coronary arteries.
isoproterenol; cyclic nucleotides; ATP-sensitive potassium channel; glibenclamide
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INTRODUCTION |
-RECEPTOR AGONISTS such as isoproterenol
(Iso), dobutamine, and dopamine have been used for inotropic support
for patients with congestive heart failure due to myocardial
ischemia or myocardial infarction. Arterial
O2 desaturation has sometimes been
seen in these patients, and episodic and constant hypoxemia are common during the 1st wk after acute myocardial infarction (9, 22). However,
the mechanism by which these -inotropics influence coronary vascular
tone in a hypoxic environment has not been reported. In our previous
study we found that low PO2 greatly
enhanced the prostaglandin E1
(PGE1)-induced coronary
relaxation in porcine coronary arteries (8). Iso, like
PGE1, has been reported to induce
vasodilatation mainly through formation of cAMP via -adrenoceptors (10). Besides this mechanism, Iso has been reported to have other
vasodilatory actions: nitric oxide (NO) formation (3, 27, 29) and
activation of ATP-sensitive K+
(KATP) channels (13, 23, 25,
28). In addition, it has been reported that changes in
PO2 may produce prostaglandins, which
reduce the -adrenergic responsiveness in bovine and porcine coronary
arteries (31). In this study we examined the vasodilatory action of Iso
at various O2 concentrations and
explored the vasodilatory mechanism of Iso in a hypoxic condition. We
used endothelin-1 (ET-1) as a constrictor agent for observation of the
vasodilatory response to Iso, because hypoxia induces ET-1 production
in blood vessels (5, 8, 17).
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METHODS |
Experimental Protocol
Tension measurement.
Porcine hearts, obtained immediately after slaughter, were immersed in
cold modified Krebs solution. Ring segments of the middle portion of
the left anterior descending coronary arteries (2.0-3.0 mm in
diameter, 3 mm long) were isolated. The methods used in this study were
similar to those we have reported previously (7). Briefly, the
preparations were fixed vertically between hooks, at a resting tone of
2.0 g, in 20-ml siliconized glass tissue baths containing modified
Krebs solution. In some preparations, the endothelium was mechanically
rubbed off by using wooden sticks. The composition of the modified
Krebs solution (mM) was 143.0 Na+,
5.9 K+, 2.5 Ca2+, 1.2 Mg2+, 153.9 Cl, 25.0 HCO3, 1.2 SO24, 1.2 H2PO4, and 10.0 dextrose. The
solution was maintained at 37.0 ± 0.2°C and aerated with 95%
O2-5%
CO2 (pH 7.37-7.43). Arterial
segments were connected to a transducer (model TB-612T, Nihon Kohden),
and changes in their isometric force were measured. After 1 h of
equilibration, 5 × 102 M KCl was administered
repeatedly until a stable contraction was obtained (usually 2 or 3 times). After the preparations were washed several times and the basal
tone was adjusted, we administered 107 M bradykinin to the
stabilized 2 × 102 M
KCl contraction to determine the presence or absence of functioning endothelial cells. Bradykinin
(107 M) induced maximal
relaxation in rings with endothelium, whereas it caused no relaxation
in rings without endothelium. After they were washed with Krebs
solution, the coronary arteries were exposed to 0, 5, or 7.5%
O2-N2
with 5% CO2 or 95%
O2-5%
CO2 for 30 min before titration
with
109-108
M ET-1 to induce a contraction equivalent to 40-60% of the
high-K+ contraction. After the
tone of the coronary arteries contracted with ET-1 had been stabilized,
we administered Iso
(109-105
M) in a cumulative fashion to endothelium-intact preparations. The
relaxation was expressed as a percentage of the ET-1-induced contraction. The responses to Iso in medium aerated with 0, 5, and
7.5% O2 were compared with those
in medium aerated with 95% O2.
In the second set of experiments we tested the vasorelaxing effects of
Iso
(109-105
M) in endothelium-denuded preparations treated with indomethacin (5 × 106 M) and
glibenclamide (106 M)
constricted with ET-1 under oxygenated (95%
O2-5%
CO2) or hypoxic conditions (95%
N2-5%
CO2). The protocol was similar
to that outlined above. Indomethacin was administered 40 min before hypoxic gas introduction or 70 min before ET-1 administration in the
oxygenated condition. Glibenclamide was administered 10 min before
hypoxic gas exposure.
In the third set of experiments, relaxation by Iso in preparations
contracted with KCl was investigated under oxygenated (95% O2-5%
CO2) or hypoxic conditions (95%
N2-5%
CO2). The KCl contraction was
adjusted to induce a contraction of ~50% of the magnitude produced
by 5 × 102 M KCl
obtained previously.
In the last set of experiments we examined the responses to forskolin
(109-105
M) in untreated and glibenclamide-treated preparations under oxygenated
(95% O2-5% CO2) or hypoxic conditions (95%
N2-5%
CO2). The response to dibutyryl
cAMP
(108-104
M) was also examined in preparations contracted with ET-1 under oxygenated (95% O2-5%
CO2) or hypoxic conditions (95%
N2-5%
CO2).
Measurement of cyclic nucleotides.
For measurement of cAMP in responses to Iso, endothelium-intact porcine
coronary arteries were at a resting tone of 2 g. The arteries were
divided into five groups: 2 × 109 M ET-1 (control), ET-1 + 109 M Iso, ET-1 + 3 × 108 M Iso, ET-1 + 106 M Iso, and ET-1 + 105 M Iso in oxygenated
(95% O2-5%
CO2) and hypoxic (95%
N2-5%
CO2) conditions. For the
measurement of cGMP in response to Iso, the arteries were divided into
two groups: ET-1 (control) and ET-1 + 105 M Iso in oxygenated and
hypoxic conditions. In all the groups, hypoxic gas was administered 30 min before 2 × 109 M
ET-1 administration. Inasmuch as the contraction by ET-1 was stabilized
within 10 min and the relaxation by Iso after ET-1 was stabilized
within 10 min, we obtained frozen preparations with liquid
N2 20 min after ET-1
administration. Frozen tissues were homogenized in ice-cold 6% TCA,
and the extracts were assayed for cAMP and cGMP by RIA with use of cAMP
and cGMP kits (New England Nuclear). Protein levels in the tissues were
assayed by the method of Lowry et al. (18). The cAMP and cGMP levels
were expressed as picomoles per milligram of protein. Throughout the
experiments, PO2 in the bath solution
was measured with an O2 monitor (model POG-5500, MT-Gikken).
Drugs
Iso was obtained from Nikken Chemical Pharmaceutical, dibutyryl cAMP,
forskolin, glibenclamide, and indomethacin from Sigma Chemical (St.
Louis, MO), and ET-1 from the Peptide Institute (Osaka, Japan).
Statistics
Values are means ± SE. Statistical analysis for
concentration-response curves of Iso was performed using two-way ANOVA.
The half-maximal effective doses and maximum responses in Table
1 and the cyclic nucleotide contents among
groups were compared using one-way ANOVA followed by the least
significant difference test for multiple comparisons. Before one-way
ANOVA was used, the Bartlett test was used for homogeneity of variance
of the data. If homogeneity of variance among groups was not obtained, we used the Kruskal-Wallis test for comparison among groups. For comparison between two groups, we used the Mann-Whitney
U test. Differences were considered
significant at P < 0.05.
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Table 1.
ED50 values and maximum responses to isoproterenol in
untreated, endothelium-denuded, indomethacin-treated, and
glibenclamide-treated preparations
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RESULTS |
The PO2 values of the solutions
aerated with 95, 7.5, 5, and 0%
O2 were 615 ± 15 (n = 129), 61 ± 2 (n = 8), 50 ± 1 (n = 13), and 24 ± 1 mmHg
(n = 112), respectively.
The basal tone was slightly decreased by 5 × 106 M indomethacin by 0.06 ± 0.01 g (1.2 ± 0.3% of 50 mM KCl contraction,
n = 11). Glibenclamide
(106 M) did not alter the
basal tone in 11 of 16 preparations, but in the other 5 preparations it
increased the basal tone by 0.09 ± 0.01 g (2.3 ± 0.3% of 50 mM
KCl contraction, n = 5). Hypoxia (0%
O2) induced a contraction
followed by a decrease in its tone. The tone of the vessels returned to
basal value within 15 min. The transient contractions by hypoxia in
untreated, glibenclamide-treated, and endothelium-denuded preparations
were 0.21 ± 0.03 g (4.6 ± 0.6% of the 50 mM KCl contraction,
n = 34), 0.17 ± 0.03 g
(4.2 ± 0.7% of the 50 mM KCl contraction,
n = 20), and 0.18 ± 0.04 g (4.8 ± 1.0% of the 50 mM KCl contraction,
n = 5), respectively. In
indomethacin-treated preparations the hypoxia-induced transient contraction was not observed. Hypoxia (5%
O2) induced a transient contraction (0.02 ± 0.01 g; 0.5 ± 0.2% of the 50 mM KCl
contraction, n = 13) that was less
than that induced by 0% O2
hypoxia. Hypoxia (7.5% O2) did
not alter the basal tone.
Iso (>3 × 109 M)
relaxed the endothelium-intact arteries in solution aerated with 95%
O2. The relaxant response curve of
Iso was significantly shifted to the left by aeration with 0 and 5% O2, but not by aeration with 7.5%
O2 (Fig.
1). There was no significant difference in
the response to Iso between the groups aerated with 0 and 5%
O2 and between the groups aerated
with 7.5 and 95% O2.
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Fig. 1.
Influence of O2 concentration on
response of porcine coronary arteries to isoproterenol (Iso).
* Significantly different from preparations in medium aerated
with 95% O2
(P < 0.01). Mean absolute values of
contractions produced with endothelin-1 (ET-1) were 2.2 ± 0.1 g
(n = 32) in 95%
O2 group, 1.7 ± 0.1 g
(n = 13) in 0%
O2 group, 1.8 ± 0.2 g (n = 13) in 5%
O2 group, and 2.1 ± 0.2 g
(n = 8) in 7.5%
O2 group. Values in parentheses
represent number of experiments. Responses to Iso were potentiated by
aeration with 0 and 5% O2.
However, there was no difference between 0 and 5%
O2 groups.
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In oxygenated (95% O2) and
hypoxic (0% O2) conditions,
glibenclamide significantly decreased the maximum response to Iso
(Table 1), and in the hypoxic condition (0%
O2), glibenclamide significantly restored the response of hypoxic coronary arteries to Iso to that observed in oxygenated untreated preparations (Fig.
2A, Table 1). The relaxations of coronary arteries contracted with KCl to Iso
were not different between oxygenated and hypoxic conditions (Fig.
2B). Removal of the endothelium and
treatment with indomethacin did not prevent the potentiation of
Iso-induced relaxation under the hypoxic (0%
O2) condition (Table 1).
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Fig. 2.
Responses to Iso in preparations treated with
106 M glibenclamide
(Gliben, A) and contracted with KCl
(B). Mean absolute values of
contractions produced with ET-1 were 2.3 ± 0.1 g
(n = 8) in glibenclamide-treated
oxygenated preparations and 2.2 ± 0.2 g
(n = 8) in glibenclamide-treated
hypoxic preparations. Mean absolute values of contractions with KCl
were 2.2 ± 0.2 g (n = 4) in
oxygenated preparations and 2.0 ± 0.1 g
(n = 4) in hypoxic preparations.
Values in parentheses represent number of experiments. Glibenclamide
restored response to Iso to that observed in untreated oxygenated
preparations. Hypoxia did not influence response to Iso in preparations
contracted with KCl. NS, not significant.
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Forskolin (>108 M)
relaxed the porcine coronary arteries in oxygenated and hypoxic
conditions. Glibenclamide did not alter the response to forskolin, and
hypoxia did not influence the response to forskolin in untreated and
glibenclamide-treated preparations (Fig.
3A).
Dibutyryl cAMP (>107 M)
relaxed the porcine coronary arteries in oxygenated and hypoxic conditions. Hypoxia did not potentiate the relaxant response to dibutyryl cAMP (Fig. 3B).
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Fig. 3.
Responses to forskolin (A) and
dibutyryl cAMP (B) in oxygenated and
hypoxic conditions. Mean absolute values of contractions produced with
ET-1 were 2.1 ± 0.3 g (n = 9) in
oxygenated preparations, 1.8 ± 0.3 g
(n = 9) in hypoxic untreated
preparations, 2.0 ± 0.2 g (n = 12)
in oxygenated glibenclamide-treated preparations, 2.2 ± 0.3 g
(n = 12) in hypoxic
glibenclamide-treated preparations in response to forskolin, and 1.9 ± 0.1 g (n = 7) in oxygenated
untreated preparations and 1.9 ± 0.1 g
(n = 8) in hypoxic untreated
preparations in response to dibutyryl cAMP. Hypoxia influenced response
to neither forskolin nor dibutyryl cAMP. Values in parentheses
represent number of experiments.
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Iso (3 × 108,
106, and
105 M) significantly
increased the cAMP content in oxygenated and hypoxic conditions. There
was no difference in the increase in the cAMP content induced by 3 × 108 M Iso between
the hypoxic and the oxygenated condition. However, the content of cAMP
in response to 106 and
105 M Iso was significantly
larger in the hypoxic than in the oxygenated condition (Fig.
4A).
Hypoxia significantly reduced the cGMP content in control and
105 M Iso-treated
preparations. However, Iso did not influence the content of cGMP in
oxygenated and hypoxic conditions (Fig.
4B).
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Fig. 4.
Contents of cAMP (A) and cGMP
(B) in response to Iso.
A: >3 × 108 M Iso increased cAMP in
oxygenated and hypoxic conditions. Hypoxia did not influence increase
in cAMP induced by 3 × 108 M Iso, whereas it
enhanced increase in cAMP by
106 and
105 M Iso. Kruskal-Wallis
test was used for comparison among groups, because homogeneity of
variance among groups was not obtained with Bartlett test. For
comparison between 2 groups, Mann-Whitney U test was used.
B: hypoxia significantly decreased cGMP content in response
to 105 M Iso. Iso did not
influence cGMP content in oxygenated or hypoxic condition. Values in
parentheses represent number of experiments.
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DISCUSSION |
The present study demonstrated that the
KATP channels may be involved in
the potentiation of the response to Iso by hypoxia independently of the
increase in the production of cAMP. It has been reported that
Iso-induced relaxation is through an agonist, trimeric G protein
(Gs) stimulation of adenylate
cyclase (10), leading to an increase of cAMP and activation of A
kinase, the phosphorylated substrates of which induce relaxation by
decreasing intracellular Ca2+.
Shaul et al. (33) reported that chronic hypoxia for 3 and 7 days in
rats resulted in increased Gs
activity in systemic arteries. However, they did not show the
relationship between the receptor (G protein) and the
KATP channel. In the present study
the potentiation of the response to Iso in the hypoxic condition was
abolished in preparations treated with glibenclamide, a selective
KATP channel blocker (26), or with
KCl, suggesting that the KATP
channel may be involved in the potentiation of the response to Iso. In addition, there was no difference in the contents of cAMP between oxygenated and hypoxic arteries in responses to 3 × 108 M Iso, which induced a
greater relaxation in the hypoxic than in the oxygenated arteries.
Furthermore, the dilatation by forskolin, which directly activates
adenylate cyclase (32), was not influenced by hypoxia. These findings
suggest that direct coupling between the -receptor and the
KATP channel independently of
intracellular cAMP may play an important role in the vasodilatation of
hypoxic coronary arteries. The direct coupling between
receptor-associated G protein and the
KATP channel was originally
speculated in porcine coronary arteries by Dart and Standen (1).
However, it remains to be elucidated whether the activation of G
protein by Iso is receptor mediated, since some substances, such as
substance P, histamine, and bradykinin, exert their effects not only
via a receptor-operated mechanism but also via the direct activation of
G protein (21). It is interesting to note that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle KATP channels through the
activation of pertussis toxin-sensitive G proteins
(Gi) (14). Further study is
necessary to elucidate the relationship between Iso and
Gi protein in porcine coronary smooth muscle under hypoxic conditions.
The KATP channels have been shown
to be regulated by intracellular factors, such as a decrease in
intracellular acidosis (2, 14, 15) or a fall in the submembrane
concentration of ATP (34). It seems that these changes may modify the
activity of the KATP channel. The
possibility of a decrease in intracellular pH may be excluded, since
hypoxia did not alter the intracellular pH of porcine coronary smooth
muscle cells (6). Von Beckerath et al. (34) reported that the
inhibition of ATP generation in coronary arteries caused a
glibenclamide-sensitive dilatation and hyperpolarization. However,
hypoxia has been reported to cause little change in ATP content in
rabbit aorta (24). We do not know whether hypoxia will induce a fall in
intracellular ATP content to the extent that the open probability of
the KATP channel in these porcine
coronary arteries is increased. In this experiment we could not obtain
a clear concentration-dependent effect of hypoxia; effects of 0 and 5%
O2 were the same but different
from effects of 7.5 and 95%
O2. There might be a
critical PO2 for activation of the
KATP channel or a steep
vasodilatory response to Iso between the 0 and 7.5%
O2 groups. It remains to be
resolved how the ATP content in porcine coronary vascular smooth cells may be influenced by the degree of hypoxia.
Using the patch-clamp technique under oxygenated conditions, Miyoshi
and Nakaya (19) reported that a high concentration of Iso
(103 M) increased the open
probability of the KATP channel in
enzyme-dispersed porcine coronary vascular smooth muscle cells. This
finding is consistent with our result that glibenclamide attenuated the
maximum responses to a high concentration of Iso in oxygenated
preparations. In our study the increase in the cAMP content in response
to high concentrations of Iso that induced maximum dilatation in the
hypoxic condition was larger than that in the oxygenated condition. We cannot explain the action and mechanism of the enhanced accumulation of
cAMP in hypoxic arteries in response to high concentrations of Iso.
There is controversy concerning the involvement of NO in
-adrenergic-induced relaxation. In rat and porcine newborn pial arteries, the relaxant response to Iso was inhibited by methylene blue
and by the NO synthase inhibitor
NG-monomethyl-L-arginine
(11, 12, 29). In contrast, removal of the endothelium or use of NO
synthase inhibitors did not influence the relaxation induced by Iso (4,
20). In the present experiment, removal of the endothelium did not
alter the relaxant response to Iso, and cGMP production was not
increased by Iso. Thus, in porcine coronary arteries, NO may not be
involved in the relaxation induced by Iso in the oxygenated condition
or in potentiation of the Iso response in the hypoxic condition.
Rubanyi and Paul (31) reported that anoxia (0%
O2) transiently increased the
tension, which began to fall and reached its lowest level within 20 min
(relaxation). However, 12% O2
hypoxia induced a sustained contraction. They suggested that the
relaxation induced by anoxia may be related to limitation of oxidative
energy metabolism. In our experiment, aeration with 95%
N2-5%
CO2 induced a transient increase
in the tone that returned to basal level within 15 min. The bath
PO2 in our experiment was ~24 mmHg
and scarcely reached 0 mmHg in our system. The difference between their
experiment and ours may be different bath
PO2. In indomethacin-treated
preparations the transient contraction was not observed, suggesting
that the transient contraction induced by hypoxia is mediated by
vascular prostaglandin synthesis.
It has been reported that a decrease of bath
O2 concentration from 95 to 40%
significantly reduced -receptor responsiveness in porcine coronary
preparations precontracted with KCl or histamine (30). Indomethacin
augmented this -adrenergic responsiveness in the presence of 95%
O2 and prevented the inhibitory
effects of the decrease in bath O2
concentration. It appears that changes in
PO2 may modify the relaxant response
to Iso under these O2-rich
conditions through prostaglandin production via cyclooxygenase. In
contrast, it has been reported that hypoxia (9 mmHg) suppressed
prostaglandin production in isolated bovine coronary arteries (16). In
the present study the cyclooxygenase inhibitor indomethacin did not
modify the response to Iso in oxygenated or hypoxic conditions,
suggesting that cyclooxygenase-related prostaglandin may not be
involved in the potentiation of the response to Iso in the hypoxic condition.
Hypoxemia is common in congestive heart failure due to myocardial
ischemia or infarction (9, 22), because the intrapulmonary shunt increases as a result of pulmonary edema derived from left ventricular dysfunction. Our study showed that hypoxia potentiated the
response to a low concentration of Iso through the
KATP channel independently of the
increase in cAMP, and it greatly enhanced the accumulation of cAMP
induced by a high concentration of Iso. In our previous study, hypoxia
also potentiated the relaxation of endothelium-intact arteries induced
by nitroglycerin and PGE1, whereas
it attenuated the hydralazine-induced relaxation (7). From these
findings we conclude that hypoxia may greatly modify the action of
vasoactive agents on porcine coronary arteries. Further study is
necessary to determine how hypoxia modifies the action of these
vasoactive agents in coronary resistance vessels, since this study was
performed in large conduit coronary arteries, which might not mainly
contribute to coronary flow regulation.
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ACKNOWLEDGEMENTS |
We are grateful to Prof. A. V. Somlyo (Dept. of Molecular
Physiology and Biological Physics, University of Virginia Health Sciences Center) for valuable comments and suggestions.
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FOOTNOTES |
This work was supported in part by Japanese Ministry of Education,
Science, and Culture Grant-in-Aid 08407051.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. Fukuda,
Department of Anesthesiology, Niigata University School of Medicine,
1-757 Asahi-machi, Niigata 951-8122, Japan (E-mail:
fukuda{at}med.niigata-u.ac.jp).
Received 23 February 1998; accepted in final form 17 May 1999.
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