(Chest. 1999;116:1039-1045.)
© 1999
American College of Chest Physicians
Effect of Contrast Media on Coronary Vascular Resistance*
Contrast-Induced Coronary Vasodilation
Elisabeth M. Baile, MSc;
Peter D. Paré, MD;
Yulia D'yachkova, MSc and
Ronald G. Carere, MD
*
From the UBC Pulmonary Research Laboratory (Mss. Baile, D'yachkova, and Dr. Pa
e) and the Division of Cardiology (Dr. Carere), St. Paul's Hospital, 1081 Burrard St, Vancouver, BC.
Correspondence to: Elisabeth Baile, MSc, UBC Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard St, Vancouver, BC, V6Z 1Y6 Canada; e-mail: lbaile{at}MRL.ubc.ca
 |
Abstract
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Study objectives: To determine if the vasodilatory
response to the intracoronary injection of ionic and nonionic contrast
media in intact pigs is dependent on nitric oxide (NO). The mechanisms
responsible for inducing the increase in coronary blood flow in
response to the intracoronary injection of contrast media during
angiography are still not entirely understood. There is evidence to
suggest that the response could be partially mediated by NO.
Participants: We studied 14 anesthetized, open-chested pigs
receiving ventilation.
Measurements and results:
Changes in coronary blood flow and coronary vascular resistance were
measured in response to the coronary artery injection of saline
solution (0.5 mol/L, isosmolar with plasma) and three different
contrast agents: meglumine sodium ioxaglate (Hexabrix; Mallinckrodt
Medical; Point-Claire, Quebec, Canada), a low osmolar ionic contrast
agent; iohexol (Omnipaque 300; Sanofi Winthrop; Markham, Ontario,
Canada), a nonionic contrast agent; and diatrizoate meglumine 66%,
diatrizoate sodium 10% (MD-76; Mallinckrodt Medical), an ionic
contrast agent. Measurements were made during three experimental
conditions: the coronary artery infusion of (1) saline solution,
control; (2) L-nitro-arginine (LNNA; 10-3 mol/L and
10-2 mol/L), a competitive inhibitor of NO synthase; and
(3)L-arginine 10-1 mol/L, a substrate for NO synthase. The
infusion of LNNA produced an increase in baseline coronary vascular
resistance (p < 0.001), but it did not attenuate the vasodilatory
response to the infusion of the contrast agents. Both the high and low
osmolar ionic and nonionic contrast media caused a decrease in baseline
coronary vascular resistance. For all three conditions, MD-76, which
has the highest osmolality, produced the greatest decrease in coronary
vascular resistance.
Conclusion: The vasodilatory
response of the coronary vasculature to contrast agents is directly
related to osmolality and is not mediated by NO.
Key Words: coronary blood flow • nitric oxide • pigs
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Introduction
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The
injection of contrast media during coronary angiography produces a
variety of hemodynamic and electrophysiologic effects; these include
hypotension, a reduction in myocardial contractility, ECG changes, and
increased coronary arterial blood flow.1
2
Although the
mechanisms responsible for inducing the increase in coronary blood flow
are not entirely understood,3
they have variously been
attributed to the osmolality, cationic content,4
viscosity,5
and/or pH6
of the injected
contrast agent. These physicochemical properties could mediate their
effect indirectly through coronary endothelial cells and/or directly on
vascular smooth muscle cells.
The role of endothelial nitric oxide (NO) in mediating the vasodilation
caused by hyperosmolar solutions has been investigated. However, the
results are inconclusive. Ishizaka and Kuo7
showed that
although the response was endothelium dependent, it was independent of
NO. These investigators perfused the abluminal aspect of small coronary
arteries in vitro with hyperosmolar glucose or sucrose
solutions. The resultant vasodilation was abolished after removal of
the endothelium; however, it was not dependent on the release of NO and
arachidonic metabolites, or on the activation of adenosine
triphosphate-sensitive potassium (K[ATP]) or calcium-sensitive
potassium channels in the vascular smooth muscle. The response
was attenuated by the intraluminal administration of the K(ATP)-channel
inhibitor, glibenclamide, suggesting that it is mediated, at least in
part, by opening of endothelial K(ATP) channels. Vacca et
al8
have also examined the effect of hyperosmolar
solutions on coronary blood flow. They infused hyperosmolar saline
solution into porcine coronary arteries and showed that the resultant
increase in coronary blood flow was not affected by blockade of
adrenergic or cholinergic receptors. However, in contrast to the
results of Ishizaka and Kuo,7
the increase in coronary
blood flow was abolished by administration of the NO-synthase
inhibitor, N
-nitro-L-arginine methyl ester
(L-NAME). Recent studies from our laboratory also indicate that
increased osmolality is the likely trigger for the contrast-induced
vasodilation in the bronchial vasculature (Sasaki et al,9
and Baile et al10
) These investigators showed that
bronchial arterial injection of ionic and nonionic contrast medium
increased bronchial blood flow and the response was partly mediated by
NO.
The purpose of this study was to measure changes in coronary blood flow
and coronary vascular resistance in response to intracoronary injection
of ionic and nonionic contrast media in intact pigs, and to determine
whether or not the response was dependent on, or independent of, NO.
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Materials and Methods
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All studies were conducted using Canadian guidelines for the use
and care of animals. We studied 14 Landrace-cross pigs, weighing from
25 to 35 kg, in the supine position. The pigs were sedated by IM
injection of medazolam, 0.5 mg/kg, premedicated with IM ketamine, 500
mg, and anesthetized by IV injection of sodium thiopental, 10 mg/kg. A
tracheotomy tube was used for ventilation with 50% oxygen and air,
using a tidal volume of 12 to 15 mL/kg and a rate of 12 to 14
breaths/min. Ventilation was adjusted to keep the
PaCO2 between 35 mm Hg and 40 mm Hg,
and arterial PaO2 > 100 mm Hg.
Anesthesia was maintained by using a continuous infusion of ketamine,
15 mg/mL at 0.16 mL/min; and pancuronium bromide, 0.074 mg/min. A
catheter was inserted into the left carotid artery for the measurement
of systemic arterial BP and to obtain blood samples to measure arterial
blood gas tensions. A thermistor-tipped, triple lumen catheter was
inserted into the right jugular vein and advanced to the pulmonary
artery for the determination of pulmonary arterial pressure and cardiac
output using the thermodilution technique. A second catheter (double
lumen) was placed in the superior vena cava for the continuous infusion
of the anesthetic, and for the administration of IV fluids and drugs as
necessary. All vascular pressures were referenced to the level of the
left atrium. After ensuring that the pigs were deeply anesthetized, the
chest was opened using a left thoracotomy incision between the fifth
and sixth ribs, and 3 to 5 cm H2O positive
end-expiratory pressure was applied. Heparin, 3,000 U, was administered
IV, and another 1,000 U was given every 2 h. The left anterior
descending coronary artery was carefully exposed, a 2-mm ultrasonic
flow probe (Transonic; Ithaca, NY) was placed around it, and mean
coronary blood flow was measured continuously. Using fluoroscopy, a 5F
cobra catheter was guided into the left main coronary artery via
the carotid artery.
Experimental Protocol:
Vascular pressures (systemic arterial
BP, central venous pressure, and pulmonary arterial pressure), coronary
blood flow, cardiac output, heart rate, and arterial blood gas tensions
were obtained after completion of the surgery, and they were monitored
until the pigs were physiologically stable; control measurements were
then obtained.
The study consisted of three experimental conditions: (1) control,
coronary artery infusion of saline solution; (2) coronary artery
infusion of L-nitro-arginine (LNNA), a competitive inhibitor of NO
synthase, and (3) coronary artery infusion of L-arginine
10-1 mol/L, a substrate for NO synthase. These
solutions were infused directly into the left main coronary artery via
the cobra catheter at a rate ~1/10 of the coronary flow; during the
infusion of each solution, the vasodilatory effect of bolus injections
of saline solution and the radiocontrast agents were measured. The
first eight pigs that were studied received LNNA
10-2 mol/L, and the next six pigs received LNNA
10-3 mol/L. The concentration was reduced
because the higher concentration caused hemodynamic instability and,
consequently, three pigs (not included in the study) died before
complete measurements could be made after the infusion of LNNA. The
hemodynamic instability was characterized by a sudden, profound fall in
cardiac output, a reduction in heart rate, an increase in systemic
arterial BP, and a profound decrease in coronary blood flow. Another
two pigs that received the high dose of LNNA died after the infusion of
L-arginine, but before measurements could be made in response to
injection of the four agents (the control and LNNA results from these
two pigs were included in the analysis). Complete measurements were
obtained for the remaining three pigs in this group and for all six
pigs that received the low dose of LNNA.
During the infusion of these solutions, changes in coronary blood flow
were measured in response to coronary artery injection of saline
solution (0.5 mol/L, isosmolar with plasma), and three different,
commonly used contrast agents that were selected to provide a range of
ionic properties, osmolalities, and viscosities. The contrast agents
were meglumine sodium ioxaglate (Hexabrix; Mallinckrodt Medical;
Point-Clarke, Quebec, Canada), a low osmolar ionic contrast agent;
iohexol (Omnipaque 300; Sanofi Winthrop; Markham, Ontario, Canada), a
nonionic contrast agent; and diatrizoate meglumine 66% diatrizoate
sodium 10% (MD-76; Mallinckrodt Medical), an ionic contrast
agent.
The protocol for injection of the different agents was as follows: the
cobra catheter (dead space, 0.7 mL) was loaded with 0.6 mL of one of
the agents. The bolus was injected into the left main coronary artery
at a rate of 2 mL/min using an infusion pump (time for the infusion of
the bolus was ~8 s). Coronary blood flow was recorded 10 s
before (baseline), during, and at the peak response to injection of the
bolus (from 25 to 30 s). Recording continued until flow had
returned to baseline values (~90 s), and the next contrast agent was
injected ~3 to 5 min after the previous injection. It took from 45
min to 1 h to complete each experimental condition. Duplicate
measurements of the response of coronary blood flow were made for each
agent. Agents were injected in random order.
After the responses to the bolus injections were made during the
infusion of saline solution, LNNA was infused into the left main
coronary artery for 20 min at a rate 1/10 of the coronary blood flow
(~2 mL/min). When the pigs were physiologically stable, hemodynamics
and arterial blood gas tensions were recorded, and measurements of
coronary artery blood flow were made again in response to a bolus
injection of the different agents, as described above. Finally,
L-arginine was infused into the left main coronary artery at a rate
~2 mL/min for 20 min. Measurements of hemodynamics and arterial blood
gas tensions were repeated, and coronary artery blood flow was recorded
in response to the injection of the different agents, as described for
control. At the end of the experiment, the pigs were deeply
anesthetized and killed by intravascular injection of saturated
potassium chloride.
The relative physicochemical properties of saline solution, Hexabrix,
Omnipaque 300, and MD-76 were measured. Specifically, we measured
density, pH, relative viscosity, and osmolality. Density was measured
by weighing, in duplicate, 1 mL of each of the substances. The pH of
each agent was measured using a blood gas analyzer (ABL 30 Acid Base
Analyzer; Radiometer; Copenhagen, Denmark). The viscosity was measured
against water at 37°C using a viscosimeter (model VWR 66044-007;
Ostwald; Vancouver, British Columbia, Canada), where the
viscosity of water was = 1. The osmolality was measured by freezing
point depression, using a micro-osmometer (Model 3MO; Advanced
Instruments; Norwood, MA). It is possible for a contrast medium to have
a high osmolality and low ionic content if the solute does not
dissociate. Similarly, ionic content and density, a determinate of
viscosity, are not related. Density reflects the concentration and
atomic number of the solute.
Data Analysis:
To test if a bolus injection of either saline
solution, Hexabrix, Omnipaque 300, or MD-76 increased blood flow,
baseline and peak coronary blood flow (mL/min) were analyzed using a
1-tailed, paired t test. A two-way analysis of variance
(S-PLUS 4; MathSoft; Cambridge, MA) was used to compare changes
in baseline coronary blood flow and coronary vascular resistance caused
by the infusion of LNNA and L-arginine; coronary vascular resistance
was calculated as mean systemic arterial pressure/coronary blood flow.
After applying a square root transformation of the data, the absolute
and percentage change in coronary vascular resistance were analyzed
using a repeated measures analysis of variance (SPSS 7.5; SPSS;
Chicago, IL) in which there was one repeating factor and one
grouping factor while blocking on pigs. Using a nonparametric Wilcoxon
signed-rank test (S-PLUS 4; MathSoft), pairwise comparisons were used
to test if there were differences in the magnitude of change in
coronary vascular resistance in response to saline solution, Hexabrix,
Omnipaque 300, and MD-76. The sequential rejective Bonferroni procedure
was used to correct for multiple comparisons and multiple
t tests. The correlation between the viscosity and the
osmolality, pH, and density of the injectate, and the resultant
percentage increase in coronary blood flow were examined using a
Pearson correlation. A corrected p value < 0.05 was considered to be
significant.
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Results
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Coronary Blood Flow:
For each experimental condition, there were no differences between
baseline values of coronary blood flow (mL/min) measured just before
the injection of saline solution, Omnipaque 300, Hexabrix, or MD-76,
respectively (Table 1
). Baseline coronary blood flow before the injection of MD-76 was higher
during control than after the infusion of LNNA and L-arginine, but was
not different before injection of saline solution, Hexabrix, or
Omnipaque 300. Baseline coronary blood flow was not affected by the
infusion of LNNA or L-arginine (Table 1)
.
Coronary Vascular Resistance:
Baseline coronary vascular resistance increased on the infusion of
LNNA (p < 0.001). After the infusion of L-arginine, baseline
coronary vascular resistance was less than it was during the infusion
of LNNA (p < 0.02; Table 2
), but it remained greater than the control value (p < 0.01). For
each experimental condition, there were no differences between baseline
values of coronary vascular resistance measured just before the
injection of saline solution, Omnipaque 300, Hexabrix, or MD-76,
respectively.
Changes in coronary vascular resistance (mean ± SE) are shown
in Figure 1
. The values shown were obtained before and after the injection of each
of the four agents for control, LNNA, and L-arginine periods. In
comparison to control, the change in resistance was greater after LNNA
for all four agents (p < 0.01). The change in coronary vascular
resistance (Fig 1) was variable in response to injection of each of the
four agents: the greatest change was observed after injection of MD-76
for all three experimental conditions, and this decrease was greater
than that caused by each of the other three agents (p < 0.01).
Injection of saline solution caused less of a decrease in resistance
than did the other three agents (p < 0.01). During control, the
decrease in resistance after Hexabrix was greater than after Omnipaque
300; however, during LNNA infusion, there was no difference in the
decrease in resistance between Omnipaque 300 and Hexabrix. There was no
difference in coronary artery blood flow or coronary vascular
resistance between the pigs that received the high or low dose of LNNA
(Table 3
). Although L-arginine did not restore coronary vascular resistance to
control values, the absolute values of coronary vascular resistance
were less (p < 0.01) than during LNNA. However, the change in
coronary vascular resistance remained higher than during the control
period.
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Figure 1. Coronary vascular resistance before (B, baseline)
and after the injection of each of the four agents (Sal, saline
solution; Hex, Hexabrix; Omni, Omnipaque 300; MD-76) for the following
experimental conditions: Control (closed circles), LNNA (closed
squares), and L-arginine (L-arg; triangles). *p < 0.01, LNNA
greater than control;  p < 0.01, Hexabrix greater than Omnipaque
300;  p < 0.01, MD-76 greater than saline solution, Omnipaque 300,
and Hexabrix; §p < 0.01 saline solution less than Omnipaque 300,
Hexabrix, and MD-76. L-arginine statistics not noted.
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Hemodynamics and Blood Gas Tensions:
There was no difference in values for heart rate or pulmonary arterial
pressure for any of the three experimental conditions (Table 4
). Arterial BP increased after the infusion of LNNA
(p < 0.001) and remained higher than control after the
infusion of L-Arginine (p < 0.02). Cardiac output was less
than control after the infusion of LNNA and L-arginine (p < 0.01).
There was a twofold increase in mean systemic vascular resistance after
the infusion of LNNA (p < 0.0); this did not return to the control
value after the infusion of L-arginine. Hemodynamic parameters were
affected more by the higher dose of LNNA (10-2
mol/L vs 10-3 mol/L; Table 4
). When compared to
their control value, cardiac output was lower and pulmonary arterial
and systemic arterial BP were greater (p < 0.001) in the pigs that
received the high dose of LNNA compared to those that received the low
dose. Similarly, when compared to their control value, mean systemic
vascular resistance was higher in the pigs that received the high dose
of LNNA (p < 0.05). Arterial blood gas tensions remained constant
throughout the experiment.
Physicochemical Properties:
The physicochemical properties of each injectate are shown in Table 5
. There was a significant correlation between the percentage decrease in
coronary vascular resistance and osmolality (r = 0.99). There was
also a significant correlation between osmolality and pH; however, the
range was very small and the correlation was not as close (r = 0.95).
|
Discussion
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Results from this study show that both high and low osmolar ionic
and nonionic contrast media cause an decrease in coronary vascular
resistance and increase in coronary artery blood flow (not shown in
results; Fig 1
; Table 3
). The magnitude of the response appears to be
related to the osmolality of the contrast agent: the greater the
osmolality, the greater the decrease in coronary vascular resistance
(Table 5)
. Although the infusion of the NO synthase inhibitor LNNA
caused an increase in baseline coronary vascular resistance (Table 2)
,
it did not attenuate the vasodilatory response to the infusion of the
contrast agents, suggesting that unlike the bronchial vasculature, the
dilatory response of the coronary vasculature to hyperosmolar stimuli
is not mediated by NO. We combined the data for the high- and
low-dose LNNA because there was no suggestion of a dose-response
relationship between the concentration of LNNA and the magnitude of the
radiocontrast-induced vasodilatation. The mean increases in coronary
blood flow in response to saline solution, Hexabrix, Omnipaque 300, and
MD-76 during the infusion of high-dose LNNA were 4.4, 4,8, 7.6, and
14.9 mL/min, respectively; the increases in response to the same agents
during the infusion of the low-dose of LNNA were 1.7, 3.0 5.0 and 14.2
mL/min, respectively. There was no significant difference for any
agent; in fact, the change in blood flow tended to be greater during
the infusion of high-dose LNNA.
Our results confirm and extend those reported recently by Ishizaka and
Kuo,7
but are in contrast to those of Vacca et
al.8
Ishizaka and Kuo used an in vitro approach
to examine the mechanism of the vasodilatory response of the coronary
vasculature to hyperosmolar stimuli. They perfused isolated porcine
coronary arteries that were between 60 and 100 µm in diameter, and
measured the vasodilatory response to changes in the osmolality of the
solution applied to the ablumenal surface of the vessels. Although the
addition of hyperosmolar solutions of sucrose and glucose caused
vascular dilation that was dependent on the presence of an intact
vascular endothelium, inhibitors of NO synthase and arachidonic acid
metabolism failed to attenuate the response. However, intralumenal (but
not ablumenal) administration of potassium chloride or the
K(ATP)-channel inhibitor, glibenclamide, significantly attenuated the
vasodilation induced by osmolar solutions. Ishizaka and
Kuo7
concluded that the vasodilation was related in some
way to the opening of K(ATP) channels in the vascular endothelium, but
they could not determine how this happened. Vacca et al8
studied the effect of intracoronary infusion of hyperosmolar solutions
on left circumflex coronary blood flow in adult anesthetized pigs.
Arterial BP and heart rate were kept constant by aortic constriction
and pacing the heart. The infusion of 2 mL of the highest concentration
of hyperosmolar saline solution (7%) caused an increase in coronary
blood flow that remained elevated for 11 to 23 min after stopping the
infusion. The increase in coronary blood flow was not affected by
blockade of adrenergic or cholinergic receptors. However, in contrast
to the results of our present study and those of Ishizaka and
Kuo,7
the coronary vasodilation was abolished by the
intracoronary administration of the NO-synthase inhibitor, L-NAME.
In our study, we administered two concentrations of the NO synthase
inhibitor, LNNA, directly into the coronary artery; neither
concentration produced significant alterations in coronary blood flow,
but both resulted in an increase in coronary vascular resistance,
systemic arterial BP, and systemic vascular resistance (Table 4)
.
Although the higher dose of LNNA had a greater effect on these
variables than the lower dose, the data were combined for comparison
with the control values. We attempted to reverse the increase in
coronary vascular resistance produced by LNNA by the administration of
L-arginine. However, two of the pigs who received the high dose of LNNA
developed hemodynamic instability, and it was not possible to stabilize
them after the infusion of L-arginine. In addition, three pigs whose
data are not included in any of the results died after receiving the
high dose of LNNA. It is possible that this hemodynamic instability was
due to the formation of platelet thrombi and subsequent coronary
vascular occlusion as a result of the inhibition of NO synthase and
enhanced platelet adhesiveness (in the pigs that died, coronary blood
flow decreased to < 2 mL/min despite a measurable, although reduced,
systemic arterial BP).
The discrepancies in results between our study and that of Vacca et
al8
may be related to one or a number of differences
between the experimental protocols. These include the age of the pigs,
the hyperosmolar agents that were used, and the NO-synthase inhibitors
that were used. In our study, the pigs were 25 kg juveniles (~3
months old), whereas in the study of Vacca et al,8
the
pigs were 70 kg adults; it is possible that the response of coronary
vessels to hyperosmolar stimuli may be different between adult and
juvenile pigs. In our study, we infused hypertonic radiocontrast
agents, whereas Vacca et al8
infused hypertonic saline
solution. However, we do not think that this is a likely explanation
for the observed differences because in a previous study10
there was a direct correlation between the osmolality of the injectate
and changes in bronchial arterial blood flow when hyperosmolar dextrose
or contrast agents were injected. Although the percentage increase in
coronary blood flow in response to the hyperosmolar injectate was
similar in magnitude in both studies, the duration of the response
differed. Vacca et al8
observed that the greater the
osmolality, the more prolonged the vascular response. However, we
observed that coronary blood flow returned to baseline within ~5 min.
Another possible explanation for the different results is the
difference in the concentration of the NO-synthase inhibitors (LNNA and
L-NAME) that were used. Again, this is an unlikely explanation because
we gave two different concentrations of LNNA (one higher and one lower
than that given by Vacca et al8
), and we found no
difference in the response to hyperosmolar stimuli with either dose.
Vacca et al8
administered 0.005 mmol/kg of L-NAME, and we
gave 0.02 mmol/kg of LNNA to five pigs and 0.002 mmol/kg of LNNA to six
pigs. Finally, because we did not test whether acetylcholine-induced
vasodilatation was completely inhibited by LNNA
10-3 and LNNA 10-2, we
cannot completely rule out that the release of NO did not partially
contribute to the contrast-induced coronary vasodilatation.
|
Conclusion
|
|---|
Although NO is a major determinant of basal coronary vascular
tone, the substantial vasodilation, observed in response to the
injection of contrast media into the coronary vasculature, appears to
be unrelated to the NO-synthase pathway in juvenile pigs. A more likely
mechanism is that the vasodilation is related to the opening of K(ATP)
channels in the vascular endothelium, as suggested by Ishizaka and
Kuo.7
The opening of these channels could be mediated by
the bolus of hyperosmolar solution or by a transient change in the
shear stress on the endothelial cells. In a previous
study10
involving the vasodilatory response to
radiocontrast agents in the bronchial circulation, we showed that
bronchial arterial vasodilatation was most closely related to the
osmolarity and not to the density of the bolus injectate. Since shear
is directly related to density, we concluded that the pertinent
stimulus in the bronchial circulation was osmolarity; however, in that
study, NO-synthase inhibitors attenuated the response considerably,
indicating that endothelial release of NO was a mechanism of
vasodilatation. If the response in the coronary vessels is due to
opening of K(ATP) channels in the vascular endothelium, the
vasodilatory response would persist, even in the presence of a
dysfunctional endothelial NO-synthase pathway. Whether this would be
true in the presence of generalized endothelial dysfunction awaits the
determination of the role of other endothelial mechanisms, such as
K(ATP) channels.
|
Footnotes
|
|---|
Abbreviations: K(ATP) = adenosine
triphosphate-sensitive potassium;
L-NAME = N-nitro-L-arginine methyl ester;
LNNA = L-nitro-arginine; NO = nitric oxide
Supported by the British Columbia and Yukon Heart and Stroke Foundation
and the Medical Research Council of Canada.
Received for publication January 25, 1999.
Accepted for publication May 14, 1999.
|
References
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Ishizaka, H, Kuo, L (1997) Endothelial ATP-sensitive potassium channels mediate coronary microvascular dilation to hyperosmolarity. Am J Physiol 273,H104-H112[Abstract/Free Full Text]
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Vacca, G, Papillo, B, Battaglia, A, et al (1996) The effects of hypertonic saline solution on coronary blood flow in anaesthetized pigs. J Physiol 491,843-851[ISI][Medline]
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Sasaki, F, Paré, PD, Ernest, D, et al (1995) Endogenous nitric oxide influences acetylcholine-induced bronchovascular dilation in pig. J Appl Phsyiol 78,539-545[Abstract/Free Full Text]
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Abstract
Introduction
