(Circulation. 1999;100:1432-1437.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Endothelial Vasodilator Function Is Preserved at the Spastic/Inflammatory Coronary Lesions in Pigs
From the Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
Correspondence to Hiroaki Shimokawa, MD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail shimo{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Background—The question of whether or not endothelial vasodilator function in the spastic coronary artery is preserved is still controversial. We recently developed a porcine model in which long-term and local treatment with interleukin-1ß (IL-1ß) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses to autacoids. The aim of this study was to examine the endothelial vasodilator function in our new porcine model of the spasm both in vivo and in vitro.
Methods and Results—A segment of the porcine coronary artery was aseptically wrapped with cotton mesh that held absorbed IL-1ß–bound microbeads. Two weeks after the procedure, intracoronary administration of serotonin caused coronary vasospasm at the IL-1ß–treated site (n=10). Coronary vasodilatation to bradykinin, substance P, or an increase in coronary blood flow was preserved at the spastic site. Vasodilator responses to 3-morpholinosydnonimine (an NO donor) and nitroglycerin also were comparable between the 2 sites. The vasoconstricting response to NG-monomethyl-L-arginine and the extent of the augmentation of the serotonin-induced vasoconstriction were comparable between the 2 sites. Organ chamber experiments showed that endothelium-dependent relaxations to bradykinin, the calcium ionophore A23187, and even the vasospastic agonist serotonin were preserved at the spastic site, whereas contractions to serotonin were augmented at the spastic site regardless of the presence or absence of the endothelium (n=6). Endothelium-independent relaxations to sodium nitroprusside were also preserved at the spastic site.
Conclusions—These results indicate that endothelial vasodilator function is preserved at the spastic site and that the spasm is caused primarily by smooth muscle hypercontraction in our porcine model.
Key Words: vasospasm • endothelium • serotonin • muscle, smooth • interleukins
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Introduction |
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Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart disease.1 2 3 4 However, the pathogenesis of the spasm is still unknown, and the elucidation of its mechanism remains an important clinical issue. Indeed, it is still controversial whether or not endothelial vasodilator function in the spastic coronary artery is preserved in humans.5 6 7 8 We previously developed a porcine model of coronary spasm in which atherosclerotic coronary lesions were induced by a combination of balloon removal of the endothelium and high-cholesterol feeding.9 10 11 In this model, endothelial dysfunction is inevitable because of endothelial regeneration per se.12 13 Although this finding may explain the coronary hyperconstriction to serotonin in the human coronary artery after PTCA,14 most patients with vasospastic angina do not undergo such coronary intervention with massive removal of the endothelium before the appearance of the coronary vasospastic activity. We recently developed a porcine model in which long-term and local treatment with interleukin-1ß (IL-1ß) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses.15 16 17 18 19 These findings in our new porcine model confirmed the importance of the adventitial inflammation in the pathogenesis of coronary spasm in humans.20 21 Because this model does not require removal of the endothelium and thus the endothelial lining is preserved,18 it is a more suitable model, from a clinical point of view, to examine the endothelial vasodilator function at the spastic site. Thus, the aim of this study was to examine whether or not endothelial vasodilator function is altered at the spastic site in our new porcine model both in vivo and in vitro.
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Methods |
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Animal Preparation
Ten male domestic pigs (2 to 3 months old and weighing 25 to 30 kg, Nihon Crea Inc, Tokyo) were used. The animals were housed individually under a controlled room temperature. They were sedated with ketamine hydrochloride 12.5 mg/kg IM and anesthetized with sodium pentobarbital 20 mg/kg IV. They were then intubated and mechanically ventilated with a respirator. Under aseptic conditions, a left thoracotomy was performed, and the proximal segments of the left anterior descending and circumflex coronary arteries were carefully dissected. The dissected segments of the coronary arteries were aseptically wrapped with cotton mesh that held absorbed IL-1ß 2.5 µg.15 16 17 18 19
This experiment was reviewed by the Ethics Committee on Animal Experiment at the Kyushu University School of Medicine and was carried out in accordance with the Guidelines for Animal Experiment at the Kyushu University School of Medicine and the Law (No. 105) and Notification (No. 6) of the Japanese Government.
Preparation of IL-1ß Beads
IL-1ß beads were prepared as previously
reported.15 16 17 18 19 Briefly, 1 g sepharose microbeads
(CNBr-activated sepharose 4B, 45 to 165 µm in diameter,
Pharmacia), which bind to the amino-residues of proteins, including
cytokines, was added to 50 mL of 1 mmol/L HCl solution and
centrifuged 4 times at 1200 rpm for 5 minutes each time. The
beads were then resuspended in 20 mL of
NaHCO3/NaCl solution with 1 mg of
cytokines. The beads were allowed to bind with the
cytokines at room temperature for 1 hour and then at 4°C
overnight. After centrifugation at 1200 rpm for 5
minutes, the supernatant was measured by an ELISA. The
cytokine-bound beads in the pellet were resuspended with
Tris/HCl buffer solution for 1 hour to block any remaining active
sites. The cytokine-bound beads were finally washed and
resuspended so that the final concentration of cytokine was 50
µg/mL. The number of cytokines or control beads in the
suspension was 
70/µL. All of the above procedures were performed
under sterile conditions.15 16 17 18 19
Because in our bead preparation most of the IL-1ß molecules are bound
inside the beads by a covalent bond at the amino-residues of the
protein, 
1.2% of the IL-1ß molecules are actually bound to surface
of the beads and biologically active.15 Thus, when 2.5
µg of IL-1ß that is bound to the beads is applied to the
coronary artery, 30 ng of IL-1ß is biologically
active.14 In addition, we previously confirmed that the
treatment with control beads alone causes minimal intimal thickening
and no hyperconstrictive responses.15
In Vivo Experiment
Two weeks after the operation, animals were anesthetized
and ventilated as described above, and selective coronary
arteriography was performed. A preshaped Judkins catheter was inserted
into the right carotid artery, and then coronary arteriography
in a left anterior oblique view was performed. Heparin 3000 U IV bolus
was administered every 60 minutes. ECGs in leads I, II, III,
V1, and V6 were
recorded. The arterial pressure was measured with a
pressure transducer (Gould Inc) connected to the Kifa catheter. The
arterial pressure, heart rate, and ECGs were continuously
monitored and recorded on a pen recorder (NEC San-Ei Polygraph
System).15 16 17 18 19
Coronary arteriography was performed with the Toshiba cineangiography system (DG-15GB/CAS-CA, Toshiba Medical Inc). The angiograms were recorded on 35-mm cine film (Varicath I; VARI·X) at 48 frames per second. The angle of the projection, the posture of the animal, and the distance from the x-ray focus to the animal and that from the animal to the image intensifier were all carefully kept constant during each experiment.15 16 17 18 19
The cineangiograms were projected on a screen with a cine projector (ELK-35CB, Nishimoto Sangyo Inc), and an end-diastolic frame was selected. The coronary luminal diameters were measured with a caliper.15 16 17 18 19 With this technique, excellent correlations between repeated measurements (r=0.99) and between different observers (r=0.98) were confirmed in the range of the coronary diameter from 0.98 to 5.58 mm.15 16 17 18 19 The degree of the vasoconstricting response was expressed as the percent decrease in the luminal diameter from the control level.
The following protocols were examined in the coronary angiographic study in vivo. First, coronary arteriography was performed under control conditions (n=10). Second, coronary vasoconstricting responses to intracoronary serotonin 10 µg/kg were examined (n=10). Coronary arteriography was performed 2 minutes after intracoronary administration of serotonin.15 16 17 18 19 Third, coronary vasodilating responses were examined in response to intracoronary administration of bradykinin 0.1 µg/kg, substance P 10 µg/kg, 3-morpholinosydnonimine (SIN-1, an NO donor) 10 µg/kg,22 and nitroglycerin 10 µg/kg (n=6). Fourth, coronary vasodilating responses to an increase in coronary blood flow caused by intracoronary infusion of adenosine 60 µg · kg-1 · min-1 for 2 minutes were examined (n=4). A slightly higher dose of adenosine was required to obtain flow-dependent dilation of the coronary artery compared with that used in the previous clinical study in patients with variant angina (40 µg · kg-1 · min-1 for 2 minutes).8 This is probably because in the present study, the porcine coronary artery tended to be dilated under basal conditions because of the effect of general anesthesia. In this protocol, a small catheter for intracoronary infusion of adenosine was advanced into the coronary artery beyond the IL-1ß–treated site, and the coronary vasodilating responses to the increase in flow (but not to adenosine) were examined. Fifth, changes in basal coronary diameter and vasoconstricting responses to intracoronary serotonin 10 µg/kg before and after intracoronary infusion of NG-monomethyl-L-arginine (L-NMMA) 1 mg/kg over 10 minutes23 were examined (n=4).
Coronary arteriography was performed 2 minutes after intracoronary administration of these agents, when the vasodilator or vasoconstrictor effect of each agent peaked. Each dose of drugs was diluted with 1 mL of physiological saline and was injected into the left coronary artery.
In Vitro Experiment
One day after the in vivo experiment, the animals were sedated
with ketamine hydrochloride 12.5 mg/kg IM, euthanized with a
lethal dose of sodium pentobarbital, and exsanguinated, and then the
heart was excised. The coronary arteries at the
IL-1ß–treated and control sites were carefully dissected, cleaned of
any perivascular tissue, and cut into rings 4 mm long. In some
of the rings, the endothelium was removed by gentle
rubbing of the luminal surface with a cotton swab.12 13
The rings were fixed vertically between hooks in an organ bath of 20-mL
capacity containing Krebs-Henseleit solution, which was maintained at
37°C and aerated with a mixture of 95% O2–5%
CO2. The hook anchoring the upper end of the
strip was connected to the lever of a force transducer (Nihon-Kohden
Kogyo). The resting tension was adjusted to 5 g.19
KCl solution (62 mmol/L) was applied every 15 to 20 minutes until
the amplitude of the contraction reached a constant value. The
developed tension was expressed as a percentage of the tension attained
in the last precontraction with 62 mmol/L KCl. The presence or
absence of the endothelium was confirmed by the
presence or absence of the relaxation to bradykinin
10-7 mol/L during a contraction evoked by
prostaglandin F2
(PGF2). Endothelium-dependent
relaxations to serotonin, bradykinin, and the calcium
ionophore were examined in rings from the spastic and control sites in
parallel during a contraction evoked by PGF2
2x10-6 mol/L.12 13 The
endothelium-dependent relaxations to
serotonin were examined in the presence of ketanserin
10-6 mol/L, a
5HT2A-serotonergic receptor
antagonist, to inhibit the direct vasocontracting effect of
the monoamine on the vascular smooth muscle.12 13
Drugs
The following drugs were used: recombinant human IL-1ß (Otsuka
Pharmaceutical Co), adenosine,
5-hydroxytryptamine (serotonin), histamine,
bradykinin, substance P, the calcium ionophore A23187, SIN-1, L-NMMA
(Sigma Chemical Co), nitroglycerin (Nihon-Kayaku
Pharmaceutical Co), and PGF2 (Ono
Pharmaceutical Co).
Data Analysis
All results are expressed as the mean±SEM. Statistical
analysis was performed by ANOVA followed by Fisher's test for
multiple comparisons. Paired data were analyzed by Student's
t test. A probability of <0.05 was considered to be
statistically significant.
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Results |
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In Vivo Experiment
Figure 1
shows coronary
arteriograms taken 2 weeks after the application of IL-1ß. After
intracoronary administration of nitroglycerin,
mild organic stenosis was noted at the IL-1ß–treated site
(Figure 1A). Intracoronary administration of
serotonin (Figure 1B) repeatedly induced
coronary hyperconstriction at the IL-1ß–treated site,
whereas it caused only mild vasoconstriction at the control (untreated)
site. The difference in the extent of the coronary
vasoconstriction to serotonin was highly significant
between the control (13±3%) and the IL-1ß–treated (43±3%) sites
(n=10, P<0.01).
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Endothelium-dependent vasodilatation to
intracoronary bradykinin, substance P, or an increase in
coronary blood flow was comparable between the IL-1ß–treated
and the control sites (Figure 2).
Endothelium-independent vasodilatation to
intracoronary nitroglycerin or SIN-1 was also
comparable between the 2 sites, although the vasodilatation tended to
be greater at the IL-1ß–treated sites than at the control sites
(Figure 2). When the coronary vasodilating responses to
bradykinin, substance P, or an increase in coronary blood flow
were corrected by the increased coronary tone (ratio of the
endothelium-dependent relaxation to each stimulus to
the endothelium-independent relaxation to SIN-1 or
nitroglycerin), the vasodilating responses to
bradykinin, substance P, or an increase in coronary blood flow
were still comparable between the 2 sites (data not shown). The extent
of the L-NMMA–induced coronary vasoconstriction under basal
conditions was comparable between the IL-1ß–treated (14±5%) and
the control (13±6%) sites, and the extent of the L-NMMA–induced
augmentation of the serotonin-induced coronary
vasoconstriction was also comparable between the 2 sites (Figure 3).
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In Vitro Experiment
In organ-chamber experiments, serotonin-induced
contractions were significantly greater in the IL-1ß–treated
coronary segments than in the control segments regardless of
the presence or absence of the endothelium (Figure 4). The serotonin-induced
contractions tended to be inhibited by the presence of the
endothelium to the same extent at both sites (Figure 4).
Endothelium-dependent relaxations to
serotonin, bradykinin, and the calcium ionophore A23187
were all comparable between the control and the IL-1ß–treated
coronary segments (Figure 5).
Furthermore, endothelium-independent relaxations to
sodium nitroprusside were also comparable between the 2 sites (Figure 6).
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Discussion |
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The major findings of the present study were that (1) endothelium-dependent coronary vasodilatations to pharmacological agents (bradykinin, substance P, the calcium ionophore A23187, and even the vasospastic agent serotonin) as well as to physiological stimulus (increase in flow) were all preserved at the spastic site and (2) vascular smooth muscle hypercontraction appears to play a central role in our porcine model of coronary spasm.
Animal Model of Coronary Spasm Without Removal of the
Endothelium
It has been controversial in clinical studies whether or not
endothelial vasodilator functions in the spastic
coronary artery are preserved.5 6 7 8 Clinical
studies with coronary angiography may have fundamental
limitations, because it is difficult in practice with this in vivo
methodology alone to clearly dissect the reduced
endothelial vasodilator function and the enhanced
vasoconstrictor response of the smooth muscle. Thus, this point needed
to be addressed in animal models from which isolated spastic blood
vessels are available. Because our previous porcine model of
coronary spasm required a combination of balloon
endothelium removal and high-cholesterol
feeding to induce atherosclerotic coronary
lesions,9 10 11 endothelial dysfunction due
to endothelial regeneration after the balloon
injury12 13 was inevitable. In contrast, our present
porcine model with an inflammatory cytokine is unique and
important because the spasm can be induced by the adventitial
inflammation without removal of the
endothelium.15 16 17 18 19 The preserved
endothelium-dependent coronary vasodilatation
to bradykinin 1 day after the IL-1ß application18
further supports the preserved integrity of the
endothelium after the procedure. Thus, the present
porcine model enables us to examine the endothelial
vasodilator function of the spastic coronary artery without the
effect of removal/regeneration of the endothelium.
In Vivo Evaluation of Endothelial Vasodilator
Function
To evaluate endothelium-dependent coronary
vasodilatation in vivo, we examined the
endothelium-dependent vasodilatation to bradykinin,
substance P, or an increase in coronary blood flow and the
endothelium-independent vasodilatation to SIN-1 or
nitroglycerin in vivo. The present results showed
that coronary vasodilatations to all these stimuli were
preserved at the spastic site in vivo. Vasodilating responses to SIN-1
and nitroglycerin tended to be increased at the
IL-1ß–treated sites, suggesting the increased basal tone of the
coronary artery at the spastic site. However, even after the
correction of the increased basal tone, the vasodilator responses to
bradykinin, substance P, or an increase in coronary blood flow
were preserved at the spastic site. Thus, the present in vivo
findings are consistent with the previous clinical reports that
endothelium-dependent coronary vasodilatations
are fairly preserved at the spastic site in patients with vasospastic
angina in response to substance P,5 24
histamine,25 or bradykinin.26 Furthermore,
the present study demonstrated that the basal release of NO is also
preserved at the spastic site, which is consistent with our
previous in vivo findings.6 23
In Vitro Evaluation of Endothelial Vasodilator
Function
Organ chamber experiments further demonstrated that
endothelium-dependent relaxations to
serotonin, bradykinin, or A23187 were comparable between
the control and the IL-1ß–treated sites. Moreover, the contractions
to serotonin were significantly inhibited by the presence
of the endothelium to a similar degree at both the
control and the IL-1ß–treated sites.
Endothelium-independent relaxations to sodium
nitroprusside were unaltered at the spastic site. These results further
indicate that endothelial vasodilator function is
preserved in the spastic porcine coronary artery. The
present study further demonstrated that
endothelium-dependent relaxations even to the
vasospastic agonist serotonin are preserved not only at
lower concentrations but also in a wide range of concentrations if the
direct vasocontracting effect of the monoamine is inhibited. A
contribution of endothelium-derived contracting
factors (eg, endothelin)27 to the occurrence of
coronary spasm is unlikely, because there was no component of
endothelium-dependent contractions in the
serotonin-induced coronary vasoconstrictions in the
present study.
However, we do not deny the possible importance of endothelial dysfunction for the development of coronary arteriosclerotic lesions27 in which coronary spasm due to smooth muscle hypercontractions occurs. We have also confirmed in the present model that NO derived from inducible NO synthase shortly after the IL-1ß application indeed plays an important role in inhibiting the development of coronary lesions and associated vasospastic responses.18
Smooth Muscle Hypercontraction and Coronary Spasm
The present study confirmed our previous findings in our
original porcine model that the enhanced smooth muscle
contractility plays an important role in the
pathogenesis of the spasm.28 We recently demonstrated that
the enhanced myosin light chain phosphorylation plays a
central role in the occurrence of the spasm in the present porcine
model.19 The increased contractility of
the spastic coronary artery is not due to the increased muscle
mass, because there is no significant increase in the mass in our
present model.15 Although the molecular mechanism for
the smooth muscle hypercontraction remains to be clarified, we recently
demonstrated that the rho A/rho-kinase–mediated signaling pathway for
vascular smooth muscle contraction plays an important role in the
pathogenesis of coronary spasm.29 30
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Acknowledgments |
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This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports, and Culture and the Japanese Ministry of Health and Welfare, Tokyo, Japan. The authors wish to thank S. Tomita and E. Gunshima for their excellent technical assistance.
Received February 3, 1999; revision received May 21, 1999; accepted May 26, 1999.
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  T. Hizume, K. Morikawa, A. Takaki, K. Abe, K. Sunagawa, M. Amano, K. Kaibuchi, C. Kubo, and H. Shimokawa Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo: A Possible Link Between Stress and Coronary Vasospasm Circ. Res., September 29, 2006; 99(7): 767 - 775. [Abstract] [Full Text] [PDF]
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 T. Kandabashi, H. Shimokawa, K. Miyata, I. Kunihiro, Y. Eto, K. Morishige, Y. Matsumoto, K. Obara, K. Nakayama, S. Takahashi, et al. Evidence for Protein Kinase C-Mediated Activation of Rho- Kinase in a Porcine Model of Coronary Artery Spasm Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2209 - 2214. [Abstract] [Full Text] [PDF]
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K. Morishige, H. Shimokawa, Y. Eto, T. Kandabashi, K. Miyata, Y. Matsumoto, M. Hoshijima, K. Kaibuchi, and A. Takeshita Adenovirus-Mediated Transfer of Dominant-Negative Rho-Kinase Induces a Regression of Coronary Arteriosclerosis in Pigs In Vivo Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 548 - 554. [Abstract] [Full Text] [PDF]
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K. Miyata, H. Shimokawa, T. Kandabashi, T. Higo, K. Morishige, Y. Eto, K. Egashira, K. Kaibuchi, and A. Takeshita Rho-Kinase Is Involved in Macrophage-Mediated Formation of Coronary Vascular Lesions in Pigs In Vivo Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2351 - 2358. [Abstract] [Full Text] [PDF]
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