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Effects of ionic and nonionic contrast media on coronary diameter and blood flow in chronically instrumented dogs
Effects of ionic and nonionic contrast media on coronary diameter and blood flow in chronically instrumented dogs The effects of intracoronary administration of ionic and nonionic contrast media on coronary circulation were studied in 14 chronically instrumented dogs. A pair of 10 MHz piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery, under sterile conditions, to measure the epicardial coronary diameter and coronary blood flow, respectively. A polyethylene tube for drug infusion was inserted into the circumflex coronary artery proximal to the sonomicrometers. In the conscious dogs (n = 8) iopamidol, 2 ml and 5 ml, increased the coronary diameter by 64 f 19 pm and 66 f 19 pm and coronary blood flow by 35 f 10% and 61 L 18%, respectively (p < 0.01 vs control level). Meglumine diatrizoate, 2 ml and 5 ml, increased coronary diameter by 102 k 20 Am and 114 -t- 18 Am and coronary blood flow by 87 k 32% and 107 + 26%, respectively (p < 0.01 vs control level). In the anesthetized dogs (n = 6), a bolus intracoronary injection of 5 ml iopamidol and meglumine diatrizoate within a few seconds increased the coronary diameter by 103 + 23 Am and 164 + 39 pm (p < 0.05) and increased the coronary blood flow by 126 k 33% and 180 f 40% (p < 0.05), respectively. Balloon denudation of the endothelium was performed in six anesthetized dogs. The increases in coronary diameter and coronary blood flow after a bolus injection of contrast medium remained the same after the denudation. Thus application of iopamidol seems to be more suitable than meglumine diatriroate for quantitative coronary angiography because of the milder and more transient effects on coronary circulation. (AM HEART J 1989;118:39.)
Shogo Egashira, MD, Hitonobu Tomoike, MD, Hiromitsu Nishijima, MD, Hideyuki Adachi, BS, and Motoomi Nakamura, MD. Fukuoka, Japan
Coronary angiography is commonly used for clinical examinations and provides pertinent data on vascular anatomy, responsiveness of the coronary artery to vasoactive stimuli, and the severity of coronary artery disease. The contrast media used for this angiography have several side effects such as reduction of myocardial contractility,1-6 systemic hypotension,2-11 increases in coronary blood flow l-8> 12-15and ECG changes.4-6, g-11Mechanisms of increases in coronary blood flow have been attributed to vasodilation resulting from hyperosmolarity of the contrast medium.‘3 5-7,13-15 These side effects often distort quantitative evaluations of coronary angiograms. Repeated angiographies are necessary for
three-dimensional documentation of the anatomy of the coronary artery lesions within a short period of time, to minimize invasive and thrombogenic procedures.16 Despite such clinical importance of the behavior of the large epicardial vessel, the effects of contrast medium on large coronary diameter have not been thoroughly examined. We investigated the effects of meglumine diatrizoate, an ionic highosmolarity contrast medium, and iopamidol, a nonionic low-osmolarity contrast medium, on large epicardial coronary diameter and small resistance vessels in both conscious and anesthetized dogs. The role of the intact endothelium on modulation of coronary diameter by the contrast medium was also examined in anesthetized dogs.
From Clinic,
METHODS
the Research Institute Faculty of Medicine.
of Angiocardiology Kyushu University.
and
the
Cardiovascnlar
Supported in part by Grants-in-Aid for Scientific Research (63440037, 63870039,63113007,63624005,63480231, and 63624511) from the Ministry of Education, Science, and Culture and by a Research Grant for Cardiovascular Disease (1-l) from the Ministry of Health and Welfare, Japan. Received
for publication
Reprint requests: Hitonobu diology and Cardiovascular 3-1-l. Maidashi, Higashi-ku,
Nov.
18, 1988;
accepted
March
Tomoike. MD, Research Clinic, Faculty of Medicine, Fukuoka 812. Japan.
1, 1989.
Institute Kyushu
of AngiocarLJniversity.
Animal preparation. Fourteen adult mongrel dogs, weighing 16 to 23 kg, were anesthetized with intravenous sodium pentobarbital (25 mg/kg); their lungs were ventilated with room air by means of a positive-pressure respirator. Under sterile surgical conditions a left thoracotomy was performed through the fourth intercostal space. A polyvinyl chloride catheter was inserted into the aortic arch via the left internal thoracic artery to measure aortic pres-
39
40
Egashira
et al
American
July 1989 Heart Journat
COD (mm> CoD (mm> CBF (mI/min)
CBF (ml/min)
AoP M-+k) AoP mJ+k) HR @Pm) 1 min Fig. 1. Effects of intracoronary infusion of contrast media into left circumflex coronary artery in conscious dogs. COD, phasic coronary diameter; COD, mean COD; CBF, phasic coronary blood flow; CBF, mean CBF; AoP, phasic aortic pressure; AoP, mean AoP; HR, heart rate. COD and CBF are unchanged by injection of saline solution. After iopamidol and meglumine diatrizoate, COD and CBF are increased and those changes are greater in the latter.
150-
contrast 2ml/min
medium is.
o iopamidol l meglumine
diatrizoate
4 O-
P
0
1
3
5
10
Time (min) Fig. 2. Effects of intracoronary injection of contrast media in conscious dogs. ACoD, increase in mean 0, meglumine diatrizoate. coronary diameter; ACBF, increase in coronary blood flow; 0, iopamidol; *p < 0.05; tp < 0.01 significant vs control; jp < 0.05; §p < 0.01 significant vs iopamidol. After intracoronary injection COD and CBF were significantly increased from control levels, and degree was significantly greater with meglumine diatrizoate. Shaded area represents duration of constant-speed infusion of contrast medium.
Volume Number
110 1
Contrast
media effects on coronary circulation
4I
I. Maximum changesin mean value of coronary circulation and hemodynamicsby contrast media in conscious dogs (n = 8)
Table
Meglumine
Iopamidol Control
COD(mm) ACoD(rm) CBF (mUmin) ACBF (%) AoP (mmHg) HR (beats/min) Results
are expressed
*p < 0.05. tp < 0.01; lp < 0.05;
significantly significantly
2.74
+ 0.11
2.80
35 f 5 97 + 5 107f 7
as mean
+ standard
different different
from from
ml
2
?I O.ll*
+ 19* + 5t 35 + lot 97 2 5 105 + 7 64 45
error.
COD = coronary
5 ml 2.81
Control
+ 0.11t
k 19t ? 5t 61 + 18t 99 k 5 110-t 8 66 52
diameter;
CBF
= coronary
2.74
k
2.84
t
O.lli
2.851
* 20t,t. lr 6t,% 87 k 32t,f 98 k 5 107 2 7
5
flow; AoP
= aortic
ml
5
102 60
96 + 5 107 k 6 blood
ml
2
+ 0.1.1
36
diatrizoate
pressure;
k O.llt
114 k 18t,$ 67 k 6t,$ 107
+- 26t,t:
96 k 104 f HR
= heart
4 7
rate.
control. iopamidol.
II. Maximum changesin mean value of coronary circulation and hemodynamicsby contrast media in anesthetized dogs (n = 6) Table
Iopamidol
Control COD(mm) ACoD(Km) CBF (mUmin) ACBF (%) AoP (mmHg) HR (beats/min) Results
are expressed
as mean
3.06 37
2
k 0.19 25
3.13 63 62
Meglumine
ml k 0.197 + 13t
5 3.17 103
+ lO*
+ standard
121 error.
-t 0.21* k 23*
k 33t 97 + 6
126
+ 12
COD = coronary
Control
82 + 147
+ 16* 98 t 6 61
97 f 6 123?Z11
ml
124 diameter;
iz 11 CBF
= coronary
3.08
k
diatrizoate
ml
2
3.19t
-
0.20
104
0.21* YT 25*
ix 4 99 + 7
81
L 12t,$
121
36
127
+ 11
blood
flow;
3.24 164
= aortic
pressure;
2 0.23* + 39*
99 *
* 21T,f 98 iz 7 125 + 11 AoP
ml
5
15t
180
+ 40t 99 k 6 126 k 11 HR
= heart
rate.
‘p < 0.05. tp < 0.01; significantly ip < 0.05; significantly
different different
from from
control. iopamidol.
sure. The pericardium wasopened,the left circumflex coronary artery was dissected,and a pair of 10 MHz piezoelectric crystals were fixed on the opposite surface of the artery with an adhesive agent (Alon Alpha, Konishi Co., Ltd., Tokyo, Japan). An electromagnetic flow probe and hydraulic cuff occluder were placed on the left circumflex coronary artery distal to the piezoelectric crystals. A fine polyethylene tube was inserted into a branch of the left circumflex coronary artery proximal to the sonomicrometers for intracoronary injection of drug solution. Experimental protocol Protocol 1. The experiments were performed on instru-
mented dogs 7 to 10 days after surgery. All dogs were healthy and had recovered from the effects of surgery. In the consciousdogs(n = 8), 2 ml and 5 ml of salinesolution, iopamidol (370 mg iodine/ml iopamidol), and meglumine diatrizoate (76% iodine megluminediatrizoate) were administered into the left circumflex artery through the intracoronary catheter by constant-rate (2 ml/min) hand injection. One to 5 days later, the samedogs(n = 6) were anesthetized with intravenous sodium pentobarbital (25 mg/kg). A Kifa catheter (7F) (Kifa, Stockholm, Sweden) wasinserted into the orifice of the left main coronary artery via the carotid artery, under fluoroscopic guidance. Two and 5 ml of salinesolution, iopamidol, and meglumine
diatrizoate weregiven randomly asa bolusinjection within a few secondsinto the left main coronary artery through the catheter, and fluoroscopy was used for confirmation. An adequate interval between dye injections was maintained for 15 to 40 minutes, the criteria being that the epicardial coronary diameter and coronary blood flow had reverted to predrug levels. Protocol 2. To elucidate the role of the endothelium on dye-induced coronary dilation, responsesof the coronary artery were compared (n = 6) before and after mechanical denudation of the endothelium, after anesthesiawas induced with sodium pentobarbital (25 mg/kg). A balloontipped catheter (2F Fogarty embolectomy catheter) was advanced from the carotid artery to the left circumflex artery under fluoroscopy. The balloon catheter was pulled from the distal to the proximal sites of the sonomicrometers as previously described.17-lgEffects of intracoronary administration of contrast media as a bolus injection, intravenous nitroglycerin (20 pg/kg), intravenous acetylcholine (1 fig/kg), and a transient coronary occlusionfor 20 secondson coronary diameter and coronary blood flow were studied before and immediately after balloon denudation of the endothelium. After the study the dogswere given a lethal doseof potassiumchloride, and the isolated hearts were fixed by perfusion with 2% glutaraldehyde. The left
42
Egashira
July
et al.
American
Table III. Physical properties meglumine diatrizoate --
of iopamidol
0 370
Ion Sodium content (mEq/L) Iodine content (mg/ml) Viscosity (cp, 37.5’ C) Osmolarity (mosm/L)
B 200
-
100
/
(From Hanky permission.)
-loo.c
1*
F 6
1,
0
pi
1,
/
a
0
50-
A/
Dose (ml)
P+
5
Dose (ml)
Fig. 3. Dose-responserelationship of contrast media. A, In consciousstate. B, In anesthetized state. ACoD, increase in mean coronary diameter; A CBF, increasein mean coronary blood flow; 0, iopamidol; 0, meglumine diatrizoate. *p < 0.05; tp < 0.01 significant vs control; $p < 0.05 significant vs iopamidol. Iopamidol and meglumine diatrizoate increasedCODand CBF in dose-dependentmanner. Degree was significantly greater with meglumine diatrizoate.
circumflex coronary artery, including the denuded portion, wasremoved and processedfor silver staining or scanning electron microscopicexamination. Data analysis. Epicardial coronary diameter, coronary blood
flow, aortic pressure,
and heart rate were recorded
simultaneously on a multichannel pen recorder, and the data were stored on an FM data recorder. Mean coronary diameter, coronary blood flow, and aortic pressure were obtained with an electronic resistance-capacitance filter with a 2-second time constant. Heart rate was monitored with a cardiotachometer triggered on the pressure pulse. All results were expressed as mean + standard error. Time sequence data were analyzed by two-way analysis of variance with repeated measures.20 When the results was statistically significant (p < 0.05), Dunnett’s method was used to identify differences for any variable within the group. A probability of less than 5% was considered statistically significant. RESULTS Effects
of contrast
media
on coronary
with
diameter and of contrast medium
Iopamidol
O-
2
Dis 1986;28:435. Reproduced
Table IV. Time course of coronary coronary blood flow after injection
a
O-
+ 135-14.5 0 1.4-1.8 7.4 275-295
in anesthetized dogs (n = 6)
/
yt
+
796
PC et al. Prog Cardiovasc
Blood
190 570 8.4 6.0-7.0 1,600-2,400
9.5 6.5-7.5
PH
1989
Journal
and
Megluminf~ diatrizvatc
lopamidol
Heart
circulation.
Representative effects of the intracoronary administration of contrast media (5 ml) on coronary diameter, coronary blood flow, aortic pressure, and heart rate in a conscious dog are shown in Fig. 1. Injection
Meglumine diatrizoate
Coronary diameter T
0.8 k 0.2
peak bin)
T5o
2.9
bin)
Coronary blood flow T peak bd
-+ 0.5
18 ZIz 1 31 k 4
TSO (set)
0.8 t 0.2 4.3 I 0.4* 18 i 1 32 i- 3
Results are expressed as mean + standard error. Tpeak = time from intracoronary injection of contrast medium to maximum response; Trio = time reverted to 50% response of Tpesk. *p < 0.05; significantly different from iopamidol.
of saline solution (5 ml) into the coronary artery did not immediately alter the coronary and hemodynamic variables, and a transient coronary dilation of the epicardial coronary artery occurred at the end of saline infusion. After intracoronary infusions of contrast media, coronary diameter and coronary blood
flow were transiently increased without significant changes in aortic pressure and heart rate. Changes in coronary diameter and coronary blood flow were gradual, and maximum
dilation
of the coronary
diameter occurred 2.2 k 0.8 minutes and 2.2 L 1.5 minutes after the intracoronary administration of meglumine diatrizoate
and iopamidol, respectively
(Fig. 2). Increases in coronary diameter and blood flow after iopamidol were less than those seen with meglumine diatrizoate in conscious and anesthetized dogs.
The dose-related changes in coronary diameter, coronary blood flow, aortic pressure, and heart rate, attributed to iopamidol and meglumine diatrizoate in the conscious and anesthetized states are summarized in Tables I and II. In conscious dogs, iopamidol increased the coronary diameter in a dose-dependent manner (2 ml = 64 f 19 pm; 5 ml = 66 -+ 19p.m);this was also the case for coronary blood flow (2
Volume Number
118 1
Contrast media effects on
0
iopamidol
q
meglumine
COFOTUIFY
circulation
43
diatrizoate
CBF
COD
Tpeak
I
0
1
1
I
3
5
Time
1 0
1
30
10
Time
(min)
(set)
4. Time courseof increasesin coronary diameter and coronary blood flow after coronary injection of contrast media in anesthetized dogs.COD, coronary diameter; CBF, coronary blood flow; q , iopamidol; 0, megluminediatrizoate; Tpeak,time from intracoronary injection of contrast mediumto maximum response of CODand CBF; TSO time from intracoronary injection to 50% responseof Tpeak.Tpeakand Tssof CBF were not significant with either medium. However, Tsc of CODwas significantly longer with megluminediatrizoate, although Tpeakwas not significant.
Fig.
ml = 35 + 10% ; 5 ml = 61 + 18% ). Meglumine diatrizoate increased the coronary diameter and coronary blood flow in a dose-dependent manner (2 ml = 102 +- 20 pm and 87 f 32% ; 5 ml = 114 + 18 pm and 107 + 26% in diameter and flow, respectively). Responses of the coronary circulation to iopamidol were significantly smaller (p < 0.01) than those seen with meglumine diatrizoate (Fig. 3, A). In anesthetized dogs, increases in coronary diameter and coronary blood flow after a bolus injection of either iopamidol or meglumine diatrizoate were dose dependent as was the case in conscious dogs (Fig. 3, B). Duration of arterial dilation of the epicardial vessel is shown in Fig. 4. The time from the intracoronary administration of iopamidol and meglumine diatrizoate to the maximum response (Tpeak) was 0.8 + 0.2 and 0.8 f 0.2 minutes (not statistically significant), respectively. The time to 50% of the maximum response was 2.9 f 0.5 and 4.3 f 0.4 minutes (p < 0.01) with iopamidol and meglumine diatrizoate, respectively. Late hyperemic constriction after intracoronary administration of contrast medium was observed in three of eight conscious dogs.21 The constriction induced by iopamidol and meglumine diatrizoate was 22 + 1 and 23 f 1 pm, respectively (not statistically significant between dyes). Effects of endothelial denudation on dye-induced coronary dilation. Representative tracings of coronary
diameter before and after denudation are shown in Fig. 5. Before denudation, reactive hyperemia after 20 seconds of coronary occlusion accompanied coro-
V. Effect of denudation on coronary diameter and coronary blood flow (n = 6) Tgble
Before denudation
20-minuteocclusion
km)
(ml/min) Acetylcholine,
1 pg/kg
Nitroglycerin,
20 fig/kg
Iopamidol,
5 ml ic
Meglumine 5 ml ic
diatrizonte,
Results are expressed *p < 0.01; significantly
iv iv
(pm) (ml/min) (pm) (ml/min) (w4 (mUmin) km) (ml/min)
129 71 126 11 239 16 88 30 139 46
k * k * * * + + * ?
After denudation 33 5 9 2 47 3 24 7 21 8
-2 59 6 11 254 15 73 32 113 50
It * _t + f f + k ? *
1* 4t 5* 2 51 2 16 4 24 7
as mean + standard error. different from before denudation.
tp < 0.05.
nary dilation (reactive dilation). The extent of reactive dilation before denudation was 129 + 33 pm, and after denudation it was -2 + 1 I.crn (p < 0.01). Intravenous acetylcholine (1 pg/kg) dilated the coronary artery by 126 + 9 pm, which was also abolished after denudation (p < 0.01). Effects of iopamidol, meglumine diatrizoate, and nitroglycerin on the coronary diameter were not altered by endothelial denudation (Fig. 6). Results of histologic examination showed that the left circumflex artery was well covered with endothelium in cases of no denudation. Absence of endothelial cells was confirmed by scanning electron microscopy or by silver staining after balloon denudation of the endothelium.
44
Egashiraet al.
A. Before
American
Denudation 20”
occlusion
TNG =?&/kg
iopamidol 5ml i.c
megiumme 5ml i.c.
diatrizoate
1”
TNG 2O&kg
i.v.
iopamidol 5ml i.c
meglumine 5ml ix.
diatrizoate
July 1989 Heart Journai
COD (mm) CoD
4.” J----s”
(mm)
6. After
-i--1
---_ +
Denudation 20”
occlusion
T ~_.-’ 1 f- .a.
~.. 7
COD (mm)
CoD m-4
4.0
38
CBF (ml/min)
mF (mI/min)
‘:
100 0I 1 min
Fig. 5. Effects of vasoactive stimuli on coronary blood flow and coronary diameter before and after balCOD,phasic coronary diameter; COD,mean COD; CBF, phasic coronary loon denudation of endothelium. blood flow; CBF, mean CBF; TNG, nitroglycerin. A, Before denudation, transient coronary occlusion of 20 seconds, TNG (20 pg/kg iv), iopamidol (5 ml ic), and meglumine diatrizoate (5 ml ic) increased coronary diameter. B, After denudation, increases in coronary diameter after intravenous TNG and intracoronary iopamidol and meglumine diatrizoate were not attenuated. although dilation of 20 seconds coronary occlusion was abolished. DISCUSSION
We examined the effects of intracoronary administration of contrast media on the coronary circulation of dogs. Relaxation of the large epicardial coronary artery and resistance vessels was noted in both conscious and anesthetized dogs after intracoronary injection of contrast media. Meglumine diatrizoate, an ionic high-osmolarity contrast medium, evoked larger changes in coronary diameter and coronary blood flow than did iopamidol, a nonionic low-osmolarity contrast medium. We also found that balloon denudation of the endothelium did not modify the extent of contrast-induced epicardial coronary artery dilation. Vasodilating effects of contrast medium have been documented with regard to changes in coronary blood flo~.‘-~* i2-i5 Decrease in coronary vascular re-
sistance may depend on (1) direct coronary relaxation as a result of hyperosmolar property of the medium,‘, 5-7.13-15 (2) in d irect relaxation as a result of increases in myocardial oxygen consumptioql or (3) relaxation caused by myocardial ischemia resulting from injection of hypoxemic contrast medium. Because the pressure-rate product was unchanged after intracoronary infusions of contrast medium, the second mechanism can be ruled out. In the present study increases in coronary blood flow were significantly larger after meglumine diatrizoate than after iopamidol. Wolf et al.’ reported that 5% sodium chloride, a compound similar in osmolarity to meglumine diatrizoate, exerted a similar increase in coronary blood fl0w.l Characteristics of both contrast media were similar but the osmolarity differed (Table III). Therefore it was believed that the vasodilation probably
Volume Number
118 1
Contrast
q q
300
z-
200
before after
circulation
45
denudation denudation
jn
:B :.:. ., .j T
2
3
media effects on coronary
100
i
0 20”
occlusion
acetylcholine l&kg i.v.
TNG 20/lg/kg I.“.
iopamidol 5ml 1%.
meglumm diatrizoate 5ml I.C.
Fig. 6. Summary of endothelial denudation on coronary vasomotion. ACoD, increasein mean coronary diameter; TNG, nitroglycerin. *p < 0.05 significant vs before denudation. Reactive dilation of coronary artery after transient occlusionof 20 secondsand dilation after intravenous acetylcholine (1 pg/kg) are abolishedafter balloon denudation, but coronary dilation of intravenous TNG (20 pg/kg) and intracoronary iopamidol (5 ml) and meglumine diatrizoate (5 ml) were not attenuated by denudation.
depended on the direct effects of the high osmolarity on endothelial cells and vascular smooth muscle. Coronary arteriography has been used to define vascular anatomy more than 500 km in diameter. Lardani et al.22 showed that contrast medium relaxed the canine epicardial coronary artery in vitro and dose dependently 22; however, little is known of the effects of contrast medium on the large epicardial coronary artery. In the present study the external diameter of the epicardial coronary artery was continuously measured with sonomicrometers.23 Alterations of coronary diameter after coronary occlusion or administration of contrast medium persisted for a longer period than changes in the coronary blood flow. Persistent coronary dilation was more evident after meglumine diatrizoate than after iopamidol (Table IV). These results suggest that the higher the osmolarity of the contrast medium, the greater the response of the epicardial coronary artery and resistance vessels. Furchgott and Zawadzki24p 25 reported that the endothelium plays an important role in relaxation of vascular smooth muscle. Endothelium-dependent relaxation has been confirmed not only in cases of physical stimulus such as an increase in flow velocity or a shear stressi 26-28but also in cases of vasoactive agents such as histamine and serotonin. Whether coronary dilation after an injection of contrast medium depended on the presence of endothelium has heretofore not been elucidated. In the present study both reactive dilation and acetylcholine-induced di-
lation of the coronary artery were abolished after endothelial balloon denudation (Table V). However, this denudation did not alter dilation of the coronary artery by contrast medium. Thus the coronary dilation by contrast medium may depend mainly on an action on vascular smooth muscle cells. Inasmuch as the contrast dye is hyperosmotic, derangement of endothelial function is plausible despite the anatomic presence of endothelial cells through repeated coronary angiography. In the present study endothelial function was evaluated by the degree of flow-related coronary dilation.18, lgr 21 Reactive dilation was repeatedly noted before and after coronary angiography in either the conscious or anesthetized state. These events proved that contrast dye did not alter endothelial function. Contrast medium is an important agent for assessment of coronary arterial lesions with its inevitable perturbation of the basal arterial tonus. In case of vasospasm or organic coronary stenosis produced by atherosclerosis, slight changes in arterial tone alter to a great extent the luminal diameter as a result of a geometric effect. 2gp3o Accordingly, in quantitative analysis of not only the degree of coronary artery lesion but also alterations of arterial tone after drug administration, selection of contrast media and an interval between consecutive coronary angiograms should be given attention. Nonionic contrast medium such as iopamidol seems to be more suitable than an ionic compound for repeated angiography performed within an interval of 1 minute.
46
Egashira et al.
We thank T. Kuga, MD, J. Kurita, BS, and I. Takahashi, BS, for discussion, T. An-noura and Y. Hisano for technical assistance. and M. Ohara for critical comments. REFERENCES
1. Wolf GL, Gerlings ED, Wilson WJ. Depression of myocardial contractility induced by hypertonic coronary injections in the isolated perfused dog heart. Radiology 1973;107:655-8. 2. Gerber KH, Higgins CB. Comparative effects of ionic and nonionic contrast materials on coronary and peripheral blood flow. Invest Radio1 1982;17:292-8. 3. Higgins CB, Gerber KH, Mattrey RF, Slutsky RA. Evaluation of the hemodynamic effects of intravenous administration of ionic and nonionic contrast materials. Radiology 1982;142: 681-6. 4. Guzman SV, West JW. Cardiac effects of intracoronary arterial injections of various roentgenographic contrast media. AM HEART J 1959;58:597-607. 5. Fischer HW, Thomson KR. Contrast media in coronary arteriography: a review. Invest Radio1 1978;13:450-9. 6. Hanley PC, Holmes Jr DR, Julsrud PR, Smith HC. Use of conventional and newer radiographic contrast agents in cardiac angiography. Prog Cardiovasc Dis 1986;28:435-47. 7. Talbert JL, Joyce EE, Sabiston Jr DC. The effect of intra-arterial injection of radiopaque contrast media on coronary blood flow. Surgery 1959;46:400-6. 8. Yamazaki H, Aya S, Hirokawa M, Matsumura N, Nakamura Y. Effects of radiopaque material on coronary vascular reserve. Jpn Heart J 1975;16:57-64. 9. Krovetz LJ, Mitchell BM, Neumaster T. Hemodynamic effects of rapidly injected hypertonic solutions into the heart and great vessels. AM HEART J 1967;74:453-62. 10. Thomson KR, Evil1 CA, Fritzsche J, Benness GT. Comparison of iopamidol, ioxaglate, and diatrizoate during coronary arteriography in dogs. Invest Radio1 1980;15:234-41. 11. Gertz EW, Wineski JA, Chiu D, Akin JR, Hu C. Clinical superiority of new nonionic contrast agent (iopamidol) for cardisc angiography. J Am Co11 Cardiol 1985;5:250-8. 12. Bassan M. Ganz W. Marcus HS. Swan HJC. The effect of intracoronary injection of contrast’medium upon coronary blood flow. Circulation 1975;51:442-5. 13. Kloster FE, Friesen WG, Green GS, Judkins MP. Effects of coronary arteriography on myocardial blood flow. Circulation 1972;46:438-44. 14. Trlgardh B, Lynch P, Trlgirdh M. Coronary angiography with diatrizoate and metrizamide. Comparison of ionic and non-ionic contrast medium effect on coronary blood flow in dogs. Acta Radio1 1976;17:69-80.
Amencan
July 1989 Heart Journa!
15. Lanzer P, Dean PB, Lipton MJ, Sievers R, Botvinick E, Higgins CB. Effects of intravenous administration of’ a new nonionic dimeric contrast medium on the coronary circulation. Invest Radio1 1985;20:746-50. 16. Grossman W. Complications of cardiac catheterization: incidence. causes, and nrevention. In: Grossman W. ed. Cardiac catheterization and-angiography. 3rd ed. Philadelphia: Lea & Febiger, Publishers, 1987:30-40. 17. Kawachi Y, Tomoike H, Maruoka Y, et al. Selective hypercontraction caused by ergonovine in the canine coronary artery under conditions of induced atherosclerosis. Circulation 1984;69:441-50. 18. Hayashi Y, Tomoike H, Nagasawa K, et al. Functional and anatomical recovery of endothelium after denudation of coronary artery. Am J Physiol 1988;254:H1081-90. 19. Inoue T, Tomoike H, Hisano K, Nakamura M. Endothelium determines flow-dependent dilation of the epicardial coronary artery in dogs. .J Am Co11 Cardiol 1988;11:187-91. 20. Winer BJ. Statistical principles in experimental design, 2nd ed. New York: McGraw-Hill. 1971:201-4. 21. Yamamoto H, Tomoike H, Hisano K, Inoue T, Mohri M, Nakamura M. Reactive dilation and late-hyperemic constriction of epicardial coronary artery after short coronary occlusion. Am J Physiol 1986;251:H554-61. 22. Lardani H, Rinaldi G, Cingolani H. Effects of angiographic contrast medium on isolated canine coronary arteries. Am ,J Cardiol 1982;50:869-73. 23. Tomoike H, Ootsubo H, Sakai K, Kikuchi Y, Nakamura M. Continuous measurement of coronary artery diameter in situ. Am J Physiol 1981;240:H73-9. 24. Furchgott RF, Zawadzki cJV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-6. 25. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res 1983;53:557-73. 26. Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986;250:H1145-9. 27. Pohl U. Holtz J. Busse R. Bassenee E. Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 1986;8:37-44. 28. Hintze TH, Vatner SF. Reactive dilation of large coronary ar teries in conscious dogs. Circ Res 1984;54:50-7. 29. MacAlpin RN. Contribution of dynamic vascular wall thickening to luminal narrowing during coronary arterial constriction. Circulation 1980;61:296-301. 30. Freedman B. Richmond DR, Kelly DT. Pathophysiology of coronary artery spasm. Circulation 1982;66:705-9.
Shogo Egashira, MD, Hitonobu Tomoike, MD, Hiromitsu Nishijima, MD, Hideyuki Adachi, BS, and Motoomi Nakamura, MD. Fukuoka, Japan
Coronary angiography is commonly used for clinical examinations and provides pertinent data on vascular anatomy, responsiveness of the coronary artery to vasoactive stimuli, and the severity of coronary artery disease. The contrast media used for this angiography have several side effects such as reduction of myocardial contractility,1-6 systemic hypotension,2-11 increases in coronary blood flow l-8> 12-15and ECG changes.4-6, g-11Mechanisms of increases in coronary blood flow have been attributed to vasodilation resulting from hyperosmolarity of the contrast medium.‘3 5-7,13-15 These side effects often distort quantitative evaluations of coronary angiograms. Repeated angiographies are necessary for
three-dimensional documentation of the anatomy of the coronary artery lesions within a short period of time, to minimize invasive and thrombogenic procedures.16 Despite such clinical importance of the behavior of the large epicardial vessel, the effects of contrast medium on large coronary diameter have not been thoroughly examined. We investigated the effects of meglumine diatrizoate, an ionic highosmolarity contrast medium, and iopamidol, a nonionic low-osmolarity contrast medium, on large epicardial coronary diameter and small resistance vessels in both conscious and anesthetized dogs. The role of the intact endothelium on modulation of coronary diameter by the contrast medium was also examined in anesthetized dogs.
From Clinic,
METHODS
the Research Institute Faculty of Medicine.
of Angiocardiology Kyushu University.
and
the
Cardiovascnlar
Supported in part by Grants-in-Aid for Scientific Research (63440037, 63870039,63113007,63624005,63480231, and 63624511) from the Ministry of Education, Science, and Culture and by a Research Grant for Cardiovascular Disease (1-l) from the Ministry of Health and Welfare, Japan. Received
for publication
Reprint requests: Hitonobu diology and Cardiovascular 3-1-l. Maidashi, Higashi-ku,
Nov.
18, 1988;
accepted
March
Tomoike. MD, Research Clinic, Faculty of Medicine, Fukuoka 812. Japan.
1, 1989.
Institute Kyushu
of AngiocarLJniversity.
Animal preparation. Fourteen adult mongrel dogs, weighing 16 to 23 kg, were anesthetized with intravenous sodium pentobarbital (25 mg/kg); their lungs were ventilated with room air by means of a positive-pressure respirator. Under sterile surgical conditions a left thoracotomy was performed through the fourth intercostal space. A polyvinyl chloride catheter was inserted into the aortic arch via the left internal thoracic artery to measure aortic pres-
39
40
Egashira
et al
American
July 1989 Heart Journat
COD (mm> CoD (mm> CBF (mI/min)
CBF (ml/min)
AoP M-+k) AoP mJ+k) HR @Pm) 1 min Fig. 1. Effects of intracoronary infusion of contrast media into left circumflex coronary artery in conscious dogs. COD, phasic coronary diameter; COD, mean COD; CBF, phasic coronary blood flow; CBF, mean CBF; AoP, phasic aortic pressure; AoP, mean AoP; HR, heart rate. COD and CBF are unchanged by injection of saline solution. After iopamidol and meglumine diatrizoate, COD and CBF are increased and those changes are greater in the latter.
150-
contrast 2ml/min
medium is.
o iopamidol l meglumine
diatrizoate
4 O-
P
0
1
3
5
10
Time (min) Fig. 2. Effects of intracoronary injection of contrast media in conscious dogs. ACoD, increase in mean 0, meglumine diatrizoate. coronary diameter; ACBF, increase in coronary blood flow; 0, iopamidol; *p < 0.05; tp < 0.01 significant vs control; jp < 0.05; §p < 0.01 significant vs iopamidol. After intracoronary injection COD and CBF were significantly increased from control levels, and degree was significantly greater with meglumine diatrizoate. Shaded area represents duration of constant-speed infusion of contrast medium.
Volume Number
110 1
Contrast
media effects on coronary circulation
4I
I. Maximum changesin mean value of coronary circulation and hemodynamicsby contrast media in conscious dogs (n = 8)
Table
Meglumine
Iopamidol Control
COD(mm) ACoD(rm) CBF (mUmin) ACBF (%) AoP (mmHg) HR (beats/min) Results
are expressed
*p < 0.05. tp < 0.01; lp < 0.05;
significantly significantly
2.74
+ 0.11
2.80
35 f 5 97 + 5 107f 7
as mean
+ standard
different different
from from
ml
2
?I O.ll*
+ 19* + 5t 35 + lot 97 2 5 105 + 7 64 45
error.
COD = coronary
5 ml 2.81
Control
+ 0.11t
k 19t ? 5t 61 + 18t 99 k 5 110-t 8 66 52
diameter;
CBF
= coronary
2.74
k
2.84
t
O.lli
2.851
* 20t,t. lr 6t,% 87 k 32t,f 98 k 5 107 2 7
5
flow; AoP
= aortic
ml
5
102 60
96 + 5 107 k 6 blood
ml
2
+ 0.1.1
36
diatrizoate
pressure;
k O.llt
114 k 18t,$ 67 k 6t,$ 107
+- 26t,t:
96 k 104 f HR
= heart
4 7
rate.
control. iopamidol.
II. Maximum changesin mean value of coronary circulation and hemodynamicsby contrast media in anesthetized dogs (n = 6) Table
Iopamidol
Control COD(mm) ACoD(Km) CBF (mUmin) ACBF (%) AoP (mmHg) HR (beats/min) Results
are expressed
as mean
3.06 37
2
k 0.19 25
3.13 63 62
Meglumine
ml k 0.197 + 13t
5 3.17 103
+ lO*
+ standard
121 error.
-t 0.21* k 23*
k 33t 97 + 6
126
+ 12
COD = coronary
Control
82 + 147
+ 16* 98 t 6 61
97 f 6 123?Z11
ml
124 diameter;
iz 11 CBF
= coronary
3.08
k
diatrizoate
ml
2
3.19t
-
0.20
104
0.21* YT 25*
ix 4 99 + 7
81
L 12t,$
121
36
127
+ 11
blood
flow;
3.24 164
= aortic
pressure;
2 0.23* + 39*
99 *
* 21T,f 98 iz 7 125 + 11 AoP
ml
5
15t
180
+ 40t 99 k 6 126 k 11 HR
= heart
rate.
‘p < 0.05. tp < 0.01; significantly ip < 0.05; significantly
different different
from from
control. iopamidol.
sure. The pericardium wasopened,the left circumflex coronary artery was dissected,and a pair of 10 MHz piezoelectric crystals were fixed on the opposite surface of the artery with an adhesive agent (Alon Alpha, Konishi Co., Ltd., Tokyo, Japan). An electromagnetic flow probe and hydraulic cuff occluder were placed on the left circumflex coronary artery distal to the piezoelectric crystals. A fine polyethylene tube was inserted into a branch of the left circumflex coronary artery proximal to the sonomicrometers for intracoronary injection of drug solution. Experimental protocol Protocol 1. The experiments were performed on instru-
mented dogs 7 to 10 days after surgery. All dogs were healthy and had recovered from the effects of surgery. In the consciousdogs(n = 8), 2 ml and 5 ml of salinesolution, iopamidol (370 mg iodine/ml iopamidol), and meglumine diatrizoate (76% iodine megluminediatrizoate) were administered into the left circumflex artery through the intracoronary catheter by constant-rate (2 ml/min) hand injection. One to 5 days later, the samedogs(n = 6) were anesthetized with intravenous sodium pentobarbital (25 mg/kg). A Kifa catheter (7F) (Kifa, Stockholm, Sweden) wasinserted into the orifice of the left main coronary artery via the carotid artery, under fluoroscopic guidance. Two and 5 ml of salinesolution, iopamidol, and meglumine
diatrizoate weregiven randomly asa bolusinjection within a few secondsinto the left main coronary artery through the catheter, and fluoroscopy was used for confirmation. An adequate interval between dye injections was maintained for 15 to 40 minutes, the criteria being that the epicardial coronary diameter and coronary blood flow had reverted to predrug levels. Protocol 2. To elucidate the role of the endothelium on dye-induced coronary dilation, responsesof the coronary artery were compared (n = 6) before and after mechanical denudation of the endothelium, after anesthesiawas induced with sodium pentobarbital (25 mg/kg). A balloontipped catheter (2F Fogarty embolectomy catheter) was advanced from the carotid artery to the left circumflex artery under fluoroscopy. The balloon catheter was pulled from the distal to the proximal sites of the sonomicrometers as previously described.17-lgEffects of intracoronary administration of contrast media as a bolus injection, intravenous nitroglycerin (20 pg/kg), intravenous acetylcholine (1 fig/kg), and a transient coronary occlusionfor 20 secondson coronary diameter and coronary blood flow were studied before and immediately after balloon denudation of the endothelium. After the study the dogswere given a lethal doseof potassiumchloride, and the isolated hearts were fixed by perfusion with 2% glutaraldehyde. The left
42
Egashira
July
et al.
American
Table III. Physical properties meglumine diatrizoate --
of iopamidol
0 370
Ion Sodium content (mEq/L) Iodine content (mg/ml) Viscosity (cp, 37.5’ C) Osmolarity (mosm/L)
B 200
-
100
/
(From Hanky permission.)
-loo.c
1*
F 6
1,
0
pi
1,
/
a
0
50-
A/
Dose (ml)
P+
5
Dose (ml)
Fig. 3. Dose-responserelationship of contrast media. A, In consciousstate. B, In anesthetized state. ACoD, increase in mean coronary diameter; A CBF, increasein mean coronary blood flow; 0, iopamidol; 0, meglumine diatrizoate. *p < 0.05; tp < 0.01 significant vs control; $p < 0.05 significant vs iopamidol. Iopamidol and meglumine diatrizoate increasedCODand CBF in dose-dependentmanner. Degree was significantly greater with meglumine diatrizoate.
circumflex coronary artery, including the denuded portion, wasremoved and processedfor silver staining or scanning electron microscopicexamination. Data analysis. Epicardial coronary diameter, coronary blood
flow, aortic pressure,
and heart rate were recorded
simultaneously on a multichannel pen recorder, and the data were stored on an FM data recorder. Mean coronary diameter, coronary blood flow, and aortic pressure were obtained with an electronic resistance-capacitance filter with a 2-second time constant. Heart rate was monitored with a cardiotachometer triggered on the pressure pulse. All results were expressed as mean + standard error. Time sequence data were analyzed by two-way analysis of variance with repeated measures.20 When the results was statistically significant (p < 0.05), Dunnett’s method was used to identify differences for any variable within the group. A probability of less than 5% was considered statistically significant. RESULTS Effects
of contrast
media
on coronary
with
diameter and of contrast medium
Iopamidol
O-
2
Dis 1986;28:435. Reproduced
Table IV. Time course of coronary coronary blood flow after injection
a
O-
+ 135-14.5 0 1.4-1.8 7.4 275-295
in anesthetized dogs (n = 6)
/
yt
+
796
PC et al. Prog Cardiovasc
Blood
190 570 8.4 6.0-7.0 1,600-2,400
9.5 6.5-7.5
PH
1989
Journal
and
Megluminf~ diatrizvatc
lopamidol
Heart
circulation.
Representative effects of the intracoronary administration of contrast media (5 ml) on coronary diameter, coronary blood flow, aortic pressure, and heart rate in a conscious dog are shown in Fig. 1. Injection
Meglumine diatrizoate
Coronary diameter T
0.8 k 0.2
peak bin)
T5o
2.9
bin)
Coronary blood flow T peak bd
-+ 0.5
18 ZIz 1 31 k 4
TSO (set)
0.8 t 0.2 4.3 I 0.4* 18 i 1 32 i- 3
Results are expressed as mean + standard error. Tpeak = time from intracoronary injection of contrast medium to maximum response; Trio = time reverted to 50% response of Tpesk. *p < 0.05; significantly different from iopamidol.
of saline solution (5 ml) into the coronary artery did not immediately alter the coronary and hemodynamic variables, and a transient coronary dilation of the epicardial coronary artery occurred at the end of saline infusion. After intracoronary infusions of contrast media, coronary diameter and coronary blood
flow were transiently increased without significant changes in aortic pressure and heart rate. Changes in coronary diameter and coronary blood flow were gradual, and maximum
dilation
of the coronary
diameter occurred 2.2 k 0.8 minutes and 2.2 L 1.5 minutes after the intracoronary administration of meglumine diatrizoate
and iopamidol, respectively
(Fig. 2). Increases in coronary diameter and blood flow after iopamidol were less than those seen with meglumine diatrizoate in conscious and anesthetized dogs.
The dose-related changes in coronary diameter, coronary blood flow, aortic pressure, and heart rate, attributed to iopamidol and meglumine diatrizoate in the conscious and anesthetized states are summarized in Tables I and II. In conscious dogs, iopamidol increased the coronary diameter in a dose-dependent manner (2 ml = 64 f 19 pm; 5 ml = 66 -+ 19p.m);this was also the case for coronary blood flow (2
Volume Number
118 1
Contrast media effects on
0
iopamidol
q
meglumine
COFOTUIFY
circulation
43
diatrizoate
CBF
COD
Tpeak
I
0
1
1
I
3
5
Time
1 0
1
30
10
Time
(min)
(set)
4. Time courseof increasesin coronary diameter and coronary blood flow after coronary injection of contrast media in anesthetized dogs.COD, coronary diameter; CBF, coronary blood flow; q , iopamidol; 0, megluminediatrizoate; Tpeak,time from intracoronary injection of contrast mediumto maximum response of CODand CBF; TSO time from intracoronary injection to 50% responseof Tpeak.Tpeakand Tssof CBF were not significant with either medium. However, Tsc of CODwas significantly longer with megluminediatrizoate, although Tpeakwas not significant.
Fig.
ml = 35 + 10% ; 5 ml = 61 + 18% ). Meglumine diatrizoate increased the coronary diameter and coronary blood flow in a dose-dependent manner (2 ml = 102 +- 20 pm and 87 f 32% ; 5 ml = 114 + 18 pm and 107 + 26% in diameter and flow, respectively). Responses of the coronary circulation to iopamidol were significantly smaller (p < 0.01) than those seen with meglumine diatrizoate (Fig. 3, A). In anesthetized dogs, increases in coronary diameter and coronary blood flow after a bolus injection of either iopamidol or meglumine diatrizoate were dose dependent as was the case in conscious dogs (Fig. 3, B). Duration of arterial dilation of the epicardial vessel is shown in Fig. 4. The time from the intracoronary administration of iopamidol and meglumine diatrizoate to the maximum response (Tpeak) was 0.8 + 0.2 and 0.8 f 0.2 minutes (not statistically significant), respectively. The time to 50% of the maximum response was 2.9 f 0.5 and 4.3 f 0.4 minutes (p < 0.01) with iopamidol and meglumine diatrizoate, respectively. Late hyperemic constriction after intracoronary administration of contrast medium was observed in three of eight conscious dogs.21 The constriction induced by iopamidol and meglumine diatrizoate was 22 + 1 and 23 f 1 pm, respectively (not statistically significant between dyes). Effects of endothelial denudation on dye-induced coronary dilation. Representative tracings of coronary
diameter before and after denudation are shown in Fig. 5. Before denudation, reactive hyperemia after 20 seconds of coronary occlusion accompanied coro-
V. Effect of denudation on coronary diameter and coronary blood flow (n = 6) Tgble
Before denudation
20-minuteocclusion
km)
(ml/min) Acetylcholine,
1 pg/kg
Nitroglycerin,
20 fig/kg
Iopamidol,
5 ml ic
Meglumine 5 ml ic
diatrizonte,
Results are expressed *p < 0.01; significantly
iv iv
(pm) (ml/min) (pm) (ml/min) (w4 (mUmin) km) (ml/min)
129 71 126 11 239 16 88 30 139 46
k * k * * * + + * ?
After denudation 33 5 9 2 47 3 24 7 21 8
-2 59 6 11 254 15 73 32 113 50
It * _t + f f + k ? *
1* 4t 5* 2 51 2 16 4 24 7
as mean + standard error. different from before denudation.
tp < 0.05.
nary dilation (reactive dilation). The extent of reactive dilation before denudation was 129 + 33 pm, and after denudation it was -2 + 1 I.crn (p < 0.01). Intravenous acetylcholine (1 pg/kg) dilated the coronary artery by 126 + 9 pm, which was also abolished after denudation (p < 0.01). Effects of iopamidol, meglumine diatrizoate, and nitroglycerin on the coronary diameter were not altered by endothelial denudation (Fig. 6). Results of histologic examination showed that the left circumflex artery was well covered with endothelium in cases of no denudation. Absence of endothelial cells was confirmed by scanning electron microscopy or by silver staining after balloon denudation of the endothelium.
44
Egashiraet al.
A. Before
American
Denudation 20”
occlusion
TNG =?&/kg
iopamidol 5ml i.c
megiumme 5ml i.c.
diatrizoate
1”
TNG 2O&kg
i.v.
iopamidol 5ml i.c
meglumine 5ml ix.
diatrizoate
July 1989 Heart Journai
COD (mm) CoD
4.” J----s”
(mm)
6. After
-i--1
---_ +
Denudation 20”
occlusion
T ~_.-’ 1 f- .a.
~.. 7
COD (mm)
CoD m-4
4.0
38
CBF (ml/min)
mF (mI/min)
‘:
100 0I 1 min
Fig. 5. Effects of vasoactive stimuli on coronary blood flow and coronary diameter before and after balCOD,phasic coronary diameter; COD,mean COD; CBF, phasic coronary loon denudation of endothelium. blood flow; CBF, mean CBF; TNG, nitroglycerin. A, Before denudation, transient coronary occlusion of 20 seconds, TNG (20 pg/kg iv), iopamidol (5 ml ic), and meglumine diatrizoate (5 ml ic) increased coronary diameter. B, After denudation, increases in coronary diameter after intravenous TNG and intracoronary iopamidol and meglumine diatrizoate were not attenuated. although dilation of 20 seconds coronary occlusion was abolished. DISCUSSION
We examined the effects of intracoronary administration of contrast media on the coronary circulation of dogs. Relaxation of the large epicardial coronary artery and resistance vessels was noted in both conscious and anesthetized dogs after intracoronary injection of contrast media. Meglumine diatrizoate, an ionic high-osmolarity contrast medium, evoked larger changes in coronary diameter and coronary blood flow than did iopamidol, a nonionic low-osmolarity contrast medium. We also found that balloon denudation of the endothelium did not modify the extent of contrast-induced epicardial coronary artery dilation. Vasodilating effects of contrast medium have been documented with regard to changes in coronary blood flo~.‘-~* i2-i5 Decrease in coronary vascular re-
sistance may depend on (1) direct coronary relaxation as a result of hyperosmolar property of the medium,‘, 5-7.13-15 (2) in d irect relaxation as a result of increases in myocardial oxygen consumptioql or (3) relaxation caused by myocardial ischemia resulting from injection of hypoxemic contrast medium. Because the pressure-rate product was unchanged after intracoronary infusions of contrast medium, the second mechanism can be ruled out. In the present study increases in coronary blood flow were significantly larger after meglumine diatrizoate than after iopamidol. Wolf et al.’ reported that 5% sodium chloride, a compound similar in osmolarity to meglumine diatrizoate, exerted a similar increase in coronary blood fl0w.l Characteristics of both contrast media were similar but the osmolarity differed (Table III). Therefore it was believed that the vasodilation probably
Volume Number
118 1
Contrast
q q
300
z-
200
before after
circulation
45
denudation denudation
jn
:B :.:. ., .j T
2
3
media effects on coronary
100
i
0 20”
occlusion
acetylcholine l&kg i.v.
TNG 20/lg/kg I.“.
iopamidol 5ml 1%.
meglumm diatrizoate 5ml I.C.
Fig. 6. Summary of endothelial denudation on coronary vasomotion. ACoD, increasein mean coronary diameter; TNG, nitroglycerin. *p < 0.05 significant vs before denudation. Reactive dilation of coronary artery after transient occlusionof 20 secondsand dilation after intravenous acetylcholine (1 pg/kg) are abolishedafter balloon denudation, but coronary dilation of intravenous TNG (20 pg/kg) and intracoronary iopamidol (5 ml) and meglumine diatrizoate (5 ml) were not attenuated by denudation.
depended on the direct effects of the high osmolarity on endothelial cells and vascular smooth muscle. Coronary arteriography has been used to define vascular anatomy more than 500 km in diameter. Lardani et al.22 showed that contrast medium relaxed the canine epicardial coronary artery in vitro and dose dependently 22; however, little is known of the effects of contrast medium on the large epicardial coronary artery. In the present study the external diameter of the epicardial coronary artery was continuously measured with sonomicrometers.23 Alterations of coronary diameter after coronary occlusion or administration of contrast medium persisted for a longer period than changes in the coronary blood flow. Persistent coronary dilation was more evident after meglumine diatrizoate than after iopamidol (Table IV). These results suggest that the higher the osmolarity of the contrast medium, the greater the response of the epicardial coronary artery and resistance vessels. Furchgott and Zawadzki24p 25 reported that the endothelium plays an important role in relaxation of vascular smooth muscle. Endothelium-dependent relaxation has been confirmed not only in cases of physical stimulus such as an increase in flow velocity or a shear stressi 26-28but also in cases of vasoactive agents such as histamine and serotonin. Whether coronary dilation after an injection of contrast medium depended on the presence of endothelium has heretofore not been elucidated. In the present study both reactive dilation and acetylcholine-induced di-
lation of the coronary artery were abolished after endothelial balloon denudation (Table V). However, this denudation did not alter dilation of the coronary artery by contrast medium. Thus the coronary dilation by contrast medium may depend mainly on an action on vascular smooth muscle cells. Inasmuch as the contrast dye is hyperosmotic, derangement of endothelial function is plausible despite the anatomic presence of endothelial cells through repeated coronary angiography. In the present study endothelial function was evaluated by the degree of flow-related coronary dilation.18, lgr 21 Reactive dilation was repeatedly noted before and after coronary angiography in either the conscious or anesthetized state. These events proved that contrast dye did not alter endothelial function. Contrast medium is an important agent for assessment of coronary arterial lesions with its inevitable perturbation of the basal arterial tonus. In case of vasospasm or organic coronary stenosis produced by atherosclerosis, slight changes in arterial tone alter to a great extent the luminal diameter as a result of a geometric effect. 2gp3o Accordingly, in quantitative analysis of not only the degree of coronary artery lesion but also alterations of arterial tone after drug administration, selection of contrast media and an interval between consecutive coronary angiograms should be given attention. Nonionic contrast medium such as iopamidol seems to be more suitable than an ionic compound for repeated angiography performed within an interval of 1 minute.
46
Egashira et al.
We thank T. Kuga, MD, J. Kurita, BS, and I. Takahashi, BS, for discussion, T. An-noura and Y. Hisano for technical assistance. and M. Ohara for critical comments. REFERENCES
1. Wolf GL, Gerlings ED, Wilson WJ. Depression of myocardial contractility induced by hypertonic coronary injections in the isolated perfused dog heart. Radiology 1973;107:655-8. 2. Gerber KH, Higgins CB. Comparative effects of ionic and nonionic contrast materials on coronary and peripheral blood flow. Invest Radio1 1982;17:292-8. 3. Higgins CB, Gerber KH, Mattrey RF, Slutsky RA. Evaluation of the hemodynamic effects of intravenous administration of ionic and nonionic contrast materials. Radiology 1982;142: 681-6. 4. Guzman SV, West JW. Cardiac effects of intracoronary arterial injections of various roentgenographic contrast media. AM HEART J 1959;58:597-607. 5. Fischer HW, Thomson KR. Contrast media in coronary arteriography: a review. Invest Radio1 1978;13:450-9. 6. Hanley PC, Holmes Jr DR, Julsrud PR, Smith HC. Use of conventional and newer radiographic contrast agents in cardiac angiography. Prog Cardiovasc Dis 1986;28:435-47. 7. Talbert JL, Joyce EE, Sabiston Jr DC. The effect of intra-arterial injection of radiopaque contrast media on coronary blood flow. Surgery 1959;46:400-6. 8. Yamazaki H, Aya S, Hirokawa M, Matsumura N, Nakamura Y. Effects of radiopaque material on coronary vascular reserve. Jpn Heart J 1975;16:57-64. 9. Krovetz LJ, Mitchell BM, Neumaster T. Hemodynamic effects of rapidly injected hypertonic solutions into the heart and great vessels. AM HEART J 1967;74:453-62. 10. Thomson KR, Evil1 CA, Fritzsche J, Benness GT. Comparison of iopamidol, ioxaglate, and diatrizoate during coronary arteriography in dogs. Invest Radio1 1980;15:234-41. 11. Gertz EW, Wineski JA, Chiu D, Akin JR, Hu C. Clinical superiority of new nonionic contrast agent (iopamidol) for cardisc angiography. J Am Co11 Cardiol 1985;5:250-8. 12. Bassan M. Ganz W. Marcus HS. Swan HJC. The effect of intracoronary injection of contrast’medium upon coronary blood flow. Circulation 1975;51:442-5. 13. Kloster FE, Friesen WG, Green GS, Judkins MP. Effects of coronary arteriography on myocardial blood flow. Circulation 1972;46:438-44. 14. Trlgardh B, Lynch P, Trlgirdh M. Coronary angiography with diatrizoate and metrizamide. Comparison of ionic and non-ionic contrast medium effect on coronary blood flow in dogs. Acta Radio1 1976;17:69-80.
Amencan
July 1989 Heart Journa!
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