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University of British Columbia Pulmonary Research Laboratory, St Paul's Hospital, Vancouver, British Columbia, Canada, V6Z 1Y6
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Baile, Elisabeth M., Lu Wang, Lorraine Verburgt, and Peter
D. Paré. Bronchial vasodilatory response to ionic and
nonionic contrast media. J. Appl.
Physiol. 82(3): 841-845, 1997.
It has recently
been shown that bronchial arterial injection of conventional contrast
medium causes a significant increase in bronchial blood flow
(
br) and that this response is partially attenuated
after infusion of
N
-nitro-L-arginine
(L-NNA). However, the precise
mechanism for this increase in br is unknown. In
this study we examined the effect of bronchial arterial injection of
conventional ionic as well as nonionic contrast media. We measured
br in nine anesthetized, ventilated, open-chest
sheep. br was recorded before (baseline) and at the
peak response to injection of 0.5 ml of either 0.9% saline (control;
isosmolar with plasma), Omnipaque 300 (iohexol; nonionic), Conray 66 (sodium iothalamate; ionic), or 50% dextrose (viscous
control).
sheep; ultrasonic flow probe; N INTRODUCTION OUR LABORATORY has recently shown that conventional
ionic contrast medium (66% diatrizoate meglumine and 10% diatrizoate
sodium; MD-76) causes vasodilation of the bronchial vasculature in
sheep and that this response was significantly attenuated after
infusion of N In this study we have examined the effect of bronchial arterial
injection of an ionic (Conray 66) and a nonionic contrast agent
(Omnipaque 300) and a solution of intermediate viscosity but higher
osmolality (50% dextrose). The contrast agents were selected on the
basis of their different ionic properties, osmolality, and viscosities.
(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 are not related. Density reflects the concentration
and atomic number of the solute.) The contrast agents used in this
study are in widespread use throughout North America. We measured
bronchial blood flow at baseline and after a bolus injection of these
agents, and we repeated this protocol after bronchial arterial infusion
of L-NNA to examine whether the
changes in bronchial blood flow were mediated by NO.
MATERIALS AND METHODS 
-nitro-L-arginine; nitric oxide; osmolality
-nitro-L-arginine
(L-NNA), a competitive inhibitor
of nitric oxide (NO) synthase, suggesting that endothelium-derived NO
partially mediates the contrast-induced bronchial vascular dilation
(1).
1 · h1).
A catheter was inserted in the left carotid artery for measurement of
systemic arterial blood pressure and to obtain blood samples to measure
arterial blood-gas tensions. With use of fluoroscopy, a
thermistor-tipped triple-lumen catheter was inserted into the right
jugular vein and advanced to the pulmonary artery for measurement of
pulmonary arterial and wedge pressures and of cardiac output by using
the thermodilution technique; a double-lumen catheter was placed in the
superior vena cava for continuous infusion of the anesthetic (proximal
port) and administration of intravenous fluids and drugs (distal port),
as necessary. All vascular pressures were referenced to the level of
the left atrium.
Sheep were paralyzed by intravenous injection of 2 mg pancuronium
bromide. The chest was then opened by a left thoracotomy incision
between the fifth and sixth ribs, and 3 cmH2O of positive end-expiratory
pressure were applied. To measure bronchial arterial blood flow, the
bronchial artery was carefully exposed and a 2-mm flow probe (Transonic
Systems, Ithaca, NY) was placed around the bronchial esophageal artery.
The probe was then connected to the flowmeter, and bronchial blood flow
was recorded by using a low-pass filter setting of 10 Hz. A 5-Fr cobra
catheter was introduced into the right femoral artery. With use of
fluoroscopy and injection of small amounts of radiocontrast material,
the catheter was advanced so that the tip was in the orifice of the
bronchial esophageal artery. Bronchial blood flow was recorded
continuously during placement of the cobra catheter to ensure that it
was situated so that it did not alter the blood flow. To prevent
clotting in the cobra catheter and the bronchial artery, heparin (4,000 U) was given intravenously, and this was supplemented by the
administration of 1,000 U every 2 h. All pressure and flow tracings
were displayed continuously on a video display unit and were recorded
as necessary by using a digital recording system (Raytech, Vancouver,
BC).
As soon as an intravenous line was in place, ibuprofen (15 mg/kg) was
administered to block any vasodilatory effects of prostaglandins; after
completion of surgery, an intravenous bolus of the 
-adrenergic blocker propranolol (2 mg/kg) was administered, followed by a continuous infusion of 20 µg · kg1 · min1.
To avert vagally mediated reflexes from affecting the bronchial vascular response to the injected agents, a bilateral vagotomy was
carried out.
Experimental protocol.
After the surgery and when the sheep were stable, we recorded baseline
measurements of arterial blood-gas tensions, cardiac output, systemic
arterial blood pressure, and pulmonary arterial pressure. Bronchial
blood flow was recorded during three different experimental conditions:
1) control,
2) bronchial arterial infusion of
the 
-agonist phenylephrine, and
3) bronchial arterial infusion of
the NO synthase inhibitor L-NNA.
The reason that phenylephrine was given in six of the nine sheep was
because we knew from results of a previous study (4) that infusion of
L-NNA produces a consistent
decrease in baseline bronchial blood flow. Therefore, to test whether
simple vasoconstriction with a contractile agonist would attenuate the
vasodilatory response to contrast agents, we gave sufficient
phenylephrine to decrease bronchial blood flow by the same amount as we
anticipated would occur on infusion of
L-NNA. It usually took 5-10
min of infusion of phenylephrine to reduce bronchial blood flow to this
anticipated level (~50% of the baseline value). As previously
described (1), L-NNA was infused
for 20 min via the cobra catheter into the bronchial artery. The
infusion rate was set at one-tenth of the bronchial blood flow and
adjusted at 5-min intervals as bronchial blood flow decreased. Contrast
agents were injected after 20 min of infusion of
L-NNA.
During each of these periods we recorded changes in bronchial blood
flow in response to bronchial arterial injection of four different
agents: saline (0.5 mol/l); Omnipaque 300, a nonionic contrast agent
(Sterling-Winthrop, Markham, ON); Conray 66, an ionic contrast agent
(Mallinckrodt Medical, Pointe Claire, PQ); and 50% dextrose, a viscous
nonionic agent.
These agents were administered in random order, and duplicate
measurements of the response were made. The protocol was as follows.
The cobra catheter was loaded with 0.5 ml of one of the agents (the
dead space of the catheter was 0.7 ml), which was then infused into the
bronchial artery by using a pump set at a rate of 2 ml/min. Between
bolus injections, the bronchial artery was infused with one of three
solutions: for period 1, the infusate was 0.5 mol/l saline; for period 2, it
was phenylephrine (5 × 106 to 5 × 107 M); and for
period 3, it was
L-NNA
(102 M). Recording of
bronchial blood flow was started 15 s before injection of each bolus
(baseline) and continued until bronchial blood flow had returned
to its baseline value (usually <1 min). At the end of the
experiment, the sheep were deeply anesthetized and killed by
intravascular injection of saturated potassium chloride.
The relative physicochemical properties of saline, Omnipaque,
Conray, and 50% dextrose 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 by using a blood-gas
analyzer (model ABL 30 acid-base analyzer, Radiometer, Copenhagen,
Denmark). The viscosity was measured against water at 37°C by using
an Ostwald viscosimeter, where the viscosity of water = 1. The
osmolality was measured by freezing-point depression by using a
microosmometer (model 3MO, Advanced Instruments, Norwood, MA).
Data analysis.
To test whether a bolus injection increased blood flow, baseline and
peak bronchial blood flow (ml/min) were analyzed by using a one-tailed
paired t-test. A two-way analysis of
variance was used to compare changes in baseline bronchial blood flow
caused by infusion of L-NNA and
phenylephrine. After application of a square-root transformation of the
data, the absolute and percent increases in blood flow produced by the
four injectates during the three experimental periods were analyzed by
using a repeated-measures analysis of variance with one repeating
factor and one grouping factor while blocking on sheep.
RESULTS
There were no differences in baseline values of bron- chial blood flow before the injection of saline, Omnipaque, Conray, or 50% dextrose for each of the three experimental periods. Infusion of phenylephrine and L-NNA resulted in a reduction in baseline bronchial blood flow of 53 ± 0.2 (P < 0.001) and 37 ± 0.3% (P < 0.001), respectively (Table 1).
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Bronchial arterial injection of saline, Omnipaque, Conray, and 50% dextrose produced an increase in bronchial blood flow (ml/min) irrespective of the experimental period (P < 0.01 for all comparisons). There were, however, considerable differences in the magnitude of the increase depending on which of the four agents was injected and on the experimental period. The absolute increase in bronchial blood flow was significantly less during the L-NNA period relative to the control period for all four agents. The absolute increase during the L-NNA period was less than during the phenylephrine period.
The percent increases in bronchial arterial blood flow for individual sheep are shown in Table 2, and the mean values (± SD) for the percent increases are shown in Table 3.
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The percent increase in bronchial blood flow induced by injection of each of the four agents was always in the same order, irrespective of the experimental period. Fifty percent dextrose induced the greatest increase in bronchial blood flow, followed by Conray and then Omnipaqe, and lastly 0.9% saline (P < 0.05; Tables 2 and 3).
Arterial blood-gas tensions and hemodynamics were within normal physiological limits throughout the study. Values (means ± SE) are shown in Table 4.
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Results of the physico-chemical analyses for saline, Omnipaque, Conray, and 50% dextrose are shown in Table 5 (normal serum osmolality is 285-295 mosmol/kg).
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DISCUSSION
The results from this study show that bronchial arterial injection of any one of the four agents produced a transient increase in bronchial blood flow. The absolute magnitude of this increase, however, differed considerably between agents: saline and Omnipaque elicited somewhat less than a doubling of bronchial blood flow, whereas injection of Conray elicited a three- to fivefold increase; the greatest increase (4.5- to 9-fold) was produced by 50% dextrose.
Infusion of L-NNA partially
attenuated the increase in bronchial blood flow produced by injection
of each one of the four agents, suggesting that vasodilation was caused
in part by endothelial release of NO. The attenuation of the
vasodilatory response was not attributable to an increase in baseline
bronchial vascular tone because infusion of the
1-agonist phenylephrine, which
lowered the baseline bronchial blood flow by an equivalent amount as
did infusion of L-NNA, resulted
in a greater percent increase in bronchial blood flow. It is difficult
to compare the magnitude of vascular dilation in response to a stimulus
before and after an intervention that changes baseline vascular
caliber. A constricted vessel has a greater capability of dilating yet
may resist the smooth muscle-relaxant effect of a mediator. At constant
perfusion pressure, as was the case in our study (aortic pressure was
not effected during the bolus injection and was constant during the
three experimental periods), the same degree of smooth muscle
relaxation may produce different degrees of change in flow because of
the alinear relationship between vascular diameter and flow. Therefore,
it was impossible to implicate a role for NO release to explain the
response to contrast and hyperosmolar boluses by merely comparing the
control and post-L-NNA
responses. However, the fact that the response was attenuated, relative
to that during comparable degrees of vasoconstriction produced by
phenylephrine, is strong evidence that NO has a role in this response.
A similar pattern of response has been shown in the bronchial
vasculature for the vasodilation caused by acetylcholine, which is know
to release endothelial NO (17).
Because there is evidence to suggest that NO and prostaglandins are
coreleased (8), and because vasodilatory prostaglandins can be released
in response to surgery (3), we administered a blocking dose of
ibuprofen at the start of the study, making it unlikely that
vasodilatory prostaglandins were participating in the bronchial
vasodilatory response. Similarly, to prevent a confounding effect of
bronchial vasodilation due to -adrenergic stimulation, a continuous
infusion of the nonselective -adrenergic antagonist propranolol was
administered. We can only speculate as to why the bronchial
vasodilatory response was not completely attenuated after
administration of L-NNA,
cyclooxygenase blockers, and a -adrenergic blocker. It could be that
insufficient L-NNA was given or
that other vasodilatory mediators, such as endothelium-derived hyperpolarizing factor, were present (20).
The vasodilatory effect of contrast media on other vascular beds has been well documented (4-6, 10). However, the precise mechanism for this response remains unclear. Although the different effects of ionic and nonionic contrast agents have often been attributed to differences in osmolality (6, 10), results from some studies suggest that other factors such as viscosity, pH, chemotoxicity, and different metabolic effects may contribute to the vasodilatory response (2, 5, 14, 15). It is recognized that endothelial shear stress is an important stimulus for NO release. Because endothelial shear should be directly related to viscosity, we injected agents in which osmolality and viscosity varied independently to test which of the physicochemical characteristics was most important.
A vasodilatory response to osmolar stimuli in the airway vasculature and its attenuation by an NO synthase inhibitor were reported in a recent study by Smith et al. (19). They showed that hypertonic solutions superfused over the tracheal epithelium of anesthetized rats resulted in vasodilation of the underlying mucosal microcirculation; vasodilation increased with each increase in osmolality, and at 300% of control osmolality, leakage of fluorescein isothiocyanate-labeled dextran from microcirculation to interstitium was observed.
In harmony with the findings of Smith et al. (19), our results support the idea that osmolar challenge causes release of NO. We found a linear relationship between osmolality and changes in bronchial blood flow, and no relationship between blood flow and viscosity, suggesting that the vasodilatory response in the bronchial vasculature is mainly induced by the high osmolality.
Although it is not clear how changes in osmolality lead to generation
of NO, a possible explanation for the series of events leading to
release of NO when contrast agent is injected intra-arterially is
illustrated diagramatically in Fig
1. Bronchial vascular
injection of a hyperosmolar bolus could draw fluid into the vessel
lumen by osmosis; the resulting increased flow could increase
endothelial shear, causing release of NO. The increased release of NO
causes vasodilation and a decrease in shear stress. Vasodilatory
mediators are released from the endothelium because of transient
increase in endothelial shear stress in a variety of vascular beds (7, 9, 12, 13). Results from some studies suggest that the dilation in
response to increased shear stress is caused, at least partially, by
endothelial release of NO (8, 16). However, the fact that the change in
blood flow is more closely related to osmolality than to viscosity
suggests that additional mechanisms may be contributing to the
vasodilation. The passage of a hyperosmolar bolus through the
vasculature may cause transient dehydration and consequent deformation
of endothelial cells; the endothelial deformation could result in an
additional stimulus for release of NO. It should be noted that the
mechanism described above cannot explain the results of Smith et al.
(19) because their osmolar stimulus was extravascular.
In summary, results from this study show that conventional ionic and nonionic intravenous contrast media cause vasodilation of the bronchial vasculature and that the magnitude of the response is related to the osmolality of the media. The vasodilation is, in part, due to a local release of NO. Angiographers should be aware of this effect, especially the profound effect of the high-osmolar contrast media. Bronchial angiography is often used to locate the site of hemorrhage in patients who have hemoptysis; one would anticipate that there could be an increase in the rate of hemorrhage at the time of injection. Although this might make a slowly bleeding vessel more visible, it could also aggravate the hemoptysis. The results also raise the intriguing possibility of using intra-arterial infusion of L-NNA as a therapeutic intervention. Besides decreasing blood flow, NO synthase inhibitors have been shown to increase platelet adhesion (11) and could aid in the treatment of hemoptysis by encouraging thrombosis in the bronchial artery.
ACKNOWLEDGEMENTS
We thank Diane Minshall and Lynne Carter for technical assistance.
FOOTNOTES
Address for reprint requests: E. M Baile, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6 (E-mail: lbaile{at}prl.pulmonary.ubc.ca).
Received 13 August 1996; accepted in final form 5 November 1996.
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