(Circulation. 1995;92:1590-1596.)
© 1995 American Heart Association, Inc.
Articles |
Myogenic Reactivity of Coronary Resistance Arteries After Cardiopulmonary Bypass and Hyperkalemic Cardioplegia
From the Division of Cardiothoracic Surgery, Department of Surgery, and Harvard-Thorndike Research Laboratory of Beth Israel Hospital and Harvard Medical School, Boston, Mass.
Correspondence to Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Cardiopulmonary bypass (CPB) and cardioplegia are associated with systemic hypotension and altered vascular responses, suggesting a defect in the smooth muscle control of vascular tone. Previous studies demonstrated alteration in neurohumoral control of the systemic and coronary circulation after CPB and cardioplegia; however, effects of CPB and cardioplegia on the intrinsic control of the vascular smooth muscle, especially in the coronary microcirculation, remain to be determined.
Methods and Results Pigs were placed on CPB. Selected hearts were arrested with a cold, hyperkalemic ([K+]=25 mmol/L) crystalloid cardioplegic solution for 1 hour. In another group, hearts were arrested and then reperfused with warm blood for 1 hour. Coronary arterioles (70 to 149 µm) were studied in a pressurized, no-flow state with video microscopy. Myogenic reactivity was examined to stepwise increases in intraluminal pressure from 10 to 100 mm Hg. The vessel diameter was normalized to the diameter at 50 mm Hg after application of papaverine (10-4 mol/L). Myogenic reactivity of vessels from noninstrumented control pigs was not altered after mechanical denudation of the endothelium or pretreatment with NG-nitro-L-arginine or indomethacin. In vessels from control pigs and vessels from the CPB group, myogenic contraction was observed with pressures >40 mm Hg. However, CPB significantly decreased intrinsic tone as the pressure-diameter relation shifted upward (P<.05 versus control). This decreased intrinsic tone was markedly attenuated by NG-nitro-L-arginine, suggesting an increased basal release of nitric oxide. Cardioplegic arrest, with or without reperfusion, decreased myogenic contraction to pressures >40 mm Hg (P<.05 versus control). Pretreatment of vessels with glybenclamide normalized the cardioplegia-induced decrease in myogenic contraction (P<.05), suggesting that the reduced myogenic contraction is due to activation of ATP-sensitive potassium channels.
Conclusions The result of the present study suggests that coronary microvascular myogenic reactivity and the intrinsic tone are reduced after hyperkalemic cardioplegia and that CPB preserves myogenic reactivity but reduces the intrinsic tone of the vascular smooth muscle.
Key Words: extracorporeal circulation • muscle, smooth • arteries • cardiopulmonary bypass • microcirculation
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Myogenic reactivity is a property of the vascular smooth muscle manifested by an increase in wall tension and a decrease in vessel diameter in response to increases in vascular transmural pressure. Myogenic reactivity has been demonstrated in a variety of vessels, including coronary1 and cerebral vessels,2 skeletal muscle,3 renal arteries,4 and coronary venules.5 Previous studies indicated an important role of the myogenic mechanism in the regulation of blood flow and maintenance of the basal vascular tone. Chilian and Layne6 and Kuo et al1 showed that coronary arterioles <150 µm in diameter exhibit myogenic reactivity over a wide range of intraluminal pressure. Arterioles are the primary site of resistance to coronary blood flow; therefore, the myogenic mechanism may contribute importantly to the control of myocardial perfusion.
After extracorporeal circulation (cardiopulmonary bypass [CPB]), patients frequently manifest systemic hypotension, necessitating the use of phenylephrine or other vasoconstrictive agents to increase systemic vascular resistance. This implies that CPB may be associated with a generalized defect in the intrinsic control of the vascular smooth muscle. However, little is known of the cause of this clinical insult. Previous studies provided no information on changes in the intrinsic property of coronary or systemic vascular beds during CPB. In addition, it is well recognized that the release of the aortic cross clamp after cardioplegic arrest is associated with a marked coronary hyperemic response.7 Although the metabolic effect is thought to play an important role, a number of in vivo studies also suggested a contribution of myogenic mechanisms to reactive hyperemia.8 9 The accuracy of assessments of myogenic reactivity may be limited by metabolic influences associated with the in vivo preparation. Furthermore, prior studies did not examine the effects of cardioplegic arrest and CPB on myogenic reactivity in the coronary microcirculation. Thus, alterations in the intrinsic smooth muscle control of the coronary microcirculation after cardioplegia and CPB remain to be determined. The primary objective of the present study was to examine whether extracorporeal circulation or cardioplegic arrest alters myogenic reactivity and the intrinsic tone in the coronary resistance arteries. Using a video electronic system in an in vitro preparation, we examined myogenic responses in isolated coronary arterioles (<150 µm in diameter) from a clinically applicable model of extracorporeal circulation and cardioplegia.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Animal Preparation
Yorkshire pigs (19 to 23 kg) of either sex were premedicated with ketamine (10 mg/kg IM) and anesthetized with
-chloralose and urethane (60 and 300 mg/kg IV initially and 15 and
60 mg/kg every 60 minutes as needed, respectively). Pigs were
tracheally intubated and mechanically ventilated. In the control group
(n=16), a sternotomy was performed and the pig was heparinized (500
U/kg). The heart was rapidly excised and immediately placed in cold
(5°C to 10°C) MOPS buffer solution of the following composition (in
mmol/L): NaCl 145.0, KCl 4.7, CaCl2 2.0, MgSO4
2.0, glucose 5.0, pyruvate 2.0, EDTA 0.02,
NaH2PO4 1.2, and MOPS 3.0.
CPB Group
In 14 pigs, after induction of anesthesia and
tracheal intubation, a fluid-filled catheter was introduced from the
femoral artery for the measurement of aortic pressure. A femoral vein
was cannulated for a vascular access. After a sternotomy was performed,
pigs were heparinized (500 U/kg) and cannulated through the distal
ascending aorta and the right atrium. A left ventricular
vent was placed through the left ventricular apex for
decompression. CPB was instituted and maintained for 75 minutes by use
of a bubble oxygenator (Bentley Bio-2, Baxter Healthcare Corp) and a
standard roller pump. An arterial filter (Bentley Bio-1025,
Baxter Healthcare Corp) was inserted into the circuit distal to the
roller pump. Blood flow was maintained at 2.0 to 3.0 L/min (2.6 to 4.2
L · min-1 · m-2) to maintain a
mean
perfusion pressure between 50 and 70 mm Hg. Systemic blood temperature
was maintained at 37°C. Ventilation was discontinued during the CPB
period. Arterial blood gases were obtained before CPB was
begun and at approximately 20-minute intervals thereafter. Before and
after CPB, arterial blood gases were adjusted by
ventilatory rate, tidal volume, and FiO2 to
maintain PO2 >100 mm Hg, pH between 7.35
and 7.45, and PCO2 >30 and <45 mm Hg.
During the CPB period, arterial blood gases were frequently
monitored, and the above parameters were maintained in all
cases without additional intervention. After 75 minutes of CPB, the
heart was rapidly excised and immediately placed in cold (1°C to
5°C) MOPS buffer solution.
Cardioplegia Group
In 12 pigs, after 10 to 15 minutes of CPB,
an aortic cross clamp
was placed, and 300 mL of cold (4°C) crystalloid, hyperkalemic
([K+]=25 mmol/L) cardioplegic solution was
infused into
the aortic root at a pressure of 60 mm Hg through a catheter inserted
into the proximal ascending aorta. The composition of the crystalloid
cardioplegic solution was (in mmol/L) NaCl 121, KCl 25,
NaHCO3 12, and glucose 11.1 (pH 7.6;
PO2 range, 160 to 260 mm Hg). Saline slush
was placed on the surface of the heart to provide topical hypothermia
during the cross-clamp period. At no time did the heart appear to
fibrillate during the cardioplegic period. Myocardial temperature of
the anterior left ventricular wall was measured with a
probe and ranged from 8°C to 14°C during the period of
cardioplegia. Infusion of the cardioplegic solution (150 mL) was
repeated at 20-minute intervals for 60 minutes (two additional doses),
during which time CPB was maintained. After 60 minutes of cardioplegic
arrest, the heart was rapidly excised and immediately placed in cold
MOPS buffer solution.
Cardioplegia-Reperfusion Group
In 6 pigs, the same procedure
was performed as in the
cardioplegia group. However, after 60 minutes of cardioplegic arrest,
the aortic cross clamp was removed, and the heart was reperfused for 60
minutes with normothermic blood in the bypass circuit
(cardioplegia-reperfusion group). The heart was kept decompressed with
a left ventricular vent placed through the left
ventricular apex until a stable rhythm was obtained. During
reperfusion, arterial pressure was maintained between 50
and 70 mm Hg. In the case of ventricular fibrillation,
lidocaine (10 mg) was infused intravenously, and the heart
was defibrillated with 10 J after the myocardial temperature rose to
>30°C. Ventilation was reestablished, and pigs were weaned from CPB
approximately 5 to 10 minutes after release of the aortic cross clamp,
when arterial pressure became stable. Pigs were then
decannulated with maintenance of adequate systemic
hemodynamics. After 60 minutes of reperfusion, the
heart was rapidly excised and immediately placed in cold MOPS buffer
solution.
In Vitro Coronary Microvessel Studies
Vessel
Preparation
Subepicardial coronary arterioles were dissected from
the left ventricular myocardium perfused by the
left circumflex coronary artery with a x10 to x60 dissecting
microscope (Olympus Optical Co, Ltd). Microvessels were placed in an
isolated Plexiglas organ chamber, cannulated with dual glass
micropipettes 30 to 80 µm in diameter, and secured with 10-0 nylon
monofilament suture (Ethicon). Both ends of micropipettes filled with
MOPS-albumin buffer solution (human albumin, 1 g/100
mL) were connected to a pressure reservoir, so that intraluminal
pressure could be varied by adjustment of the height of the reservoir.
Pressure was measured by use of a burette manometer connected to the
micropipettes. MOPS-albumin buffer solution (pH 7.4)
equilibrated with room air was continuously circulated through the
organ chamber and a reservoir (total volume, 100 mL). The solution was
warmed to 37°C by an external heat exchanger. With an inverted
microscope (x40 to x200, Olympus Optical Co, Ltd) connected to a
video camera, the vessel image was projected onto a black and white
television monitor (Hitachi Denshi Ltd). An electronic dimension
analyzer (Living System Instrumentation) was used to measure
internal lumen diameter. Measurements were recorded with a
strip-chart recorder (Graphtec).
Experimental Protocol
After the vessels were equilibrated for at least 30 minutes at
50 mm Hg, the active pressure-diameter relation was studied.
Initially, the pressure was reduced to 10 mm Hg, and the vessel was
allowed to stabilize for 5 to 10 minutes. Then, the pressure was
increased in increments of 10 mm Hg up to 100 mm Hg. At each pressure
increment, changes in ID were measured when the vessel response was
stabilized (2 to 3 minutes). On completion of determination of the
active pressure-diameter relation, the pressure was returned to 50
mm Hg. Papaverine (10-4 mol/L) was then applied, and the
passive pressure-diameter relation was examined according to the
protocol described above. On completion of the protocol, vessels were
washed three times with MOPS buffer solution, and the luminal pressure
was set at 50 mm Hg. Potassium chloride (100 mmol/L) was applied to
test viability and responsiveness of the vessel.
In 2 vessels from separate pigs, a stepwise increase in pressure followed by a stepwise decrease over a pressure range of 10 to 100 mm Hg was performed. Consistent with previous findings,1 pressure-diameter relations obtained in the different manners were superimposed. Thus, in the present study, the pressure-diameter relation was determined with each pressure increment.
In vessels from control pigs, myogenic reactivity was examined after denudation of the endothelium (n=8) and after pretreatment of vessels with the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (10-4 mol/L, n=8) or the cyclooxygenase inhibitor indomethacin (10-5 mol/L, n=8), respectively. Each agent was applied once in each vessel. Endothelial cells were removed selectively by advancement of a human hair (approximately 60 µm in diameter) into the lumen to abrade the luminal surface, followed by the intraluminal injection of air bubbles. All vessels denuded of endothelium showed normal relaxation to sodium nitroprusside (91±5%, 10-4 mol/L) but failed to relax in response to ADP (5±2%, 10-4 mol/L).
To examine the role of endothelium- or smooth muscle–derived vasoactive substances in alterations of the myogenic tone after CPB, additional experiments were performed in 6 pigs. The pressure-diameter relation of vessels from these additional experiments was determined after pretreatment of vessels with NG-nitro-L-arginine (10-4 mol/L), indomethacin (10-5 mol/L), or glybenclamide (10-5 mol/L) for 15 minutes. To evaluate the possible role of ATP-sensitive potassium (K+ATP) channels in cardioplegia-induced changes in myogenic reactivity, additional experiments were performed in six pigs. The pressure-diameter relation from these pigs was studied 15 minutes after pretreatment of vessels with the K+ATP channel blocker glybenclamide (10-5 mol/L). All antagonists were applied after an initial equilibration period of at least 30 minutes.
In three additional noninstrumented pigs, the experiment was performed to determine whether lidocaine and electric defibrillation could alter intrinsic properties of coronary vessels. After induction of anesthesia and intubation, ventricular fibrillation was induced by application of direct current (8 V). Lidocaine (10 mg) was infused intravenously, and the heart was defibrillated with 10 J. The heart was excised and placed in cold MOPS buffer solution. The pressure-diameter relation of coronary arterioles was determined in each pig. In another three pigs, the time control study was performed to examine whether an additional 60 minutes of normal perfusion after termination of CPB could affect intrinsic properties of coronary vessels. Briefly, CPB was instituted and was maintained for 75 minutes. Thereafter, pigs were separated from CPB and maintained for 60 minutes. At the end of the study, the heart was excised, and the pressure-diameter relation was examined as described above.
Drugs
Papaverine was obtained from Eli Lilly & Co.
NG-nitro-L-arginine,
indomethacin, sodium nitroprusside, ADP, and
glybenclamide were obtained from Sigma Chemical Co. Glybenclamide was
dissolved in dimethyl sulfoxide. Other drugs were dissolved in
ultrapure distilled water. All solutions were prepared on the day of
the study.
Data Analysis
Each pig served as one sample. The active and
passive
pressure-diameter relations were performed only once in each vessel.
The diameter of each vessel was normalized to the diameter at the
pressure of 50 mm Hg in the presence of papaverine. Normalized
diameters were pooled at each pressure step in the same experimental
group, and an average was calculated. Values were expressed as
mean±SEM. Because significant myogenic contraction was observed with
pressures >40 mm Hg, changes in myogenic reactivity were compared at
the pressure range of 40 and 100 mm Hg. Significance of the upward
shift of the pressure-diameter relation was compared at the pressure
range of 10 to 100 mm Hg. Differences were compared among groups and
within groups before and after the application of papaverine.
Significance of the shift in the pressure-diameter relation (ie, change
in the intrinsic tone) and the change in myogenic reactivity (ie,
myogenic contraction during elevations of the intraluminal pressure)
were determined by two-factor (treatment and transmural pressure) ANOVA
for repeated-measures design.10 Fisher's
least-significant-difference multiple-range test was used to compare
myogenic contraction between groups when appropriate. The slope of the
pressure-diameter relation of vessels obtained after application of
papaverine was calculated by linear regression analysis.
Significance of the slope of the pressure-diameter relation, changes in
ID, and contractile response to potassium chloride among experimental
groups was examined by use of a nonpaired Student's t test.
A value of P<.05 was considered significant. A value of
P>.05 but <.1 was considered borderline significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
At the intraluminal pressure of 50 mm Hg in the absence of papaverine, coronary microvessels ranged from 70 to 149 µm in ID, averaging 122±9, 132±10, 125±8, 109±7, and 121±8 µm in control, CPB, cardioplegia, reperfusion, and time control groups, respectively. Percent contraction after application of potassium chloride (100 mmol/L) was 33±6%, 32±5%, 38±7%, 36±6%, 31±8%, and 33±7 in control, CPB, cardioplegia, reperfusion, time control, and lidocaine/defibrillation groups, respectively. There was no significant difference in the ID or contractile response to potassium chloride between different groups. We observed that 70% of vessels developed spontaneous tone at 50 mm Hg before determination of the active pressure-diameter relation. There were no differences in the frequency or magnitude of spontaneous tone development in vessels before application of an antagonist compared with vessels in the same group without pretreatment with the antagonist.
In control and CPB vessels, similar myogenic contractions were observed
to a stepwise increase in the pressure >40 mm Hg (Fig 1
).
However, CPB caused an upward shift in the active
pressure-diameter relation (P<.05 versus control; Fig
1),
indicating a decrease in the intrinsic tone of the vascular smooth
muscle. The CPB-induced upward shift of the pressure-diameter relation
was not significantly altered by pretreatment of vessels with
indomethacin (P=.11 CPB with
indomethacin versus CPB without pretreatment;
P=.02 CPB with indomethacin versus control)
or glybenclamide (P=.44 CPB with glybenclamide versus CPB
without pretreatment; P=.09 CPB with glybenclamide versus
control) but was markedly attenuated by
NG-nitro-L-arginine
(P=.06 CPB with
NG-nitro-L-arginine versus
CPB without pretreatment; P=.83 CPB with
NG-nitro-L-arginine versus
control; Fig 2). Cardioplegia, with or without
reperfusion, was associated with a decrease in myogenic contraction of
vessels in response to elevations in the pressure (both
P<.001 versus control and CPB; Fig 1) and an upward
displacement of the active pressure-diameter relation (both
P<.05 versus control; Fig 1). In vessels from the
cardioplegia group, pretreatment with glybenclamide attenuated the
cardioplegia-induced decrease in myogenic reactivity
(P<.001 versus cardioplegia without glybenclamide) but
failed to prevent the cardioplegia-induced upward shift in the
pressure-diameter relation (Fig 3). The slopes (ie,
vessel compliance) of the pressure-diameter relations were 0.86±0.2,
0.84±0.2, 0.87±0.3, 0.87±0.2, 0.87±0.1, and
0.85±0.02 (normalized
diameter divided by millimeters of mercury) in control, CPB,
cardioplegia, reperfusion, time control, and lidocaine/defibrillation
groups, respectively. There was no significant difference in the slope
of the pressure-diameter relation among different experimental groups,
suggesting a similar vascular compliance in all experimental
groups.
|
|
|
After pretreatment of vessels with papaverine, vessels behaved
passively in response to the stepwise elevation of the pressure (Fig
4). In control and CPB groups, passive pressure-diameter
relations obtained after application of papaverine were significantly
different from active pressure-diameter relations (both
P<.05). However, in cardioplegia and
cardioplegia-reperfusion groups, there were no statistical differences
between active and passive pressure-diameter relations. The passive
pressure-diameter relation obtained after the application of papaverine
was similar in all experimental groups (Fig 4).
|
In control vessels, the role of the endothelium and the
release of NO or prostaglandin substances in modulating
myogenic properties of coronary vessels were examined. Results
showed that mechanical denudation of the endothelium
(P=.43 versus control) or pretreatment with
NG-nitro-L-arginine
(P=.32 versus control) or indomethacin
(P=.47 versus control) did not significantly alter myogenic
contraction or affect the position of the pressure-diameter relation in
comparison to control vessels (Fig 5).
|
The pressure-diameter relation obtained in vessels from pigs receiving
lidocaine and electric defibrillation was similar to that obtained from
control pigs (Fig 6). In pigs exposed to an additional
60 minutes of normal perfusion after CPB, myogenic contraction in
response to the stepwise elevation of the pressure was preserved,
whereas the upward shift of the pressure-diameter relation observed
immediately after CPB was maintained (P=.23 versus control),
suggesting that the CPB-induced decrease in the intrinsic tone
persisted up to 1 hour after termination of CPB (Fig 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
The primary findings of the present study are that (1) coronary microvascular myogenic reactivity is preserved after extracorporeal circulation but the pressure-diameter relation was shifted upward, suggesting a decrease in the intrinsic tone; (2) the CPB-induced upward shift in the pressure-diameter relation was normalized by NG-nitro-L-arginine, suggesting a CPB-associated increase in the basal release of NO; (3) cardioplegic arrest decreases myogenic reactivity and the intrinsic tone of coronary arterioles; and (4) blockade of K+ATP channels with glybenclamide significantly improved the decreased myogenic reactivity associated with cardioplegic arrest. Thus, our results demonstrate that CPB and hyperkalemic crystalloid cardioplegia are associated with impairment of the intrinsic smooth muscle control of the coronary microcirculation.
The regulation of coronary blood flow is determined primarily by metabolic and myogenic mechanisms, in addition to endothelium-derived and neurohumoral factors. The metabolic control is mediated by the local release of vasoactive substances, whereas the myogenic mechanism is based on the intrinsic property of the vascular smooth muscle to regulate vascular resistance in response to alterations in transmural pressure. It is generally accepted that metabolic mechanisms play an important role in the coronary hyperemic response.11 12 Although this hypothesis has been challenged by several in vivo studies,8 9 the contribution of myogenic alterations to coronary hyperemia is poorly understood primarily because of the difficulty in distinguishing between metabolic and myogenic responses associated with in vivo preparations. In addition, the effect of CPB or hyperkalemic crystalloid cardioplegia on coronary microvascular myogenic reactivity has not previously been examined. Thus, the present study provides evidence that coronary arteriolar myogenic reactivity is blunted after hyperkalemic cardioplegia. This decreased myogenic reactivity may play in part a role in the cardioplegia-associated coronary hyperemic response.
Previous studies suggested that myogenic reactivity and the intrinsic tone may be dependent on the intact endothelium.13 14 Thus, the decreased coronary myogenic reactivity after cardioplegic arrest could be caused by endothelial injury because it is known that hyperkalemic cardioplegia is associated with endothelial injury in coronary microvessels.15 Consistent with the finding of Kuo et al,16 however, our results did not support a role of the endothelium in modulating myogenic reactivity in that mechanical denudation of the endothelium and inhibition of cyclooxygenase or NO synthase failed to abolish or attenuate myogenic reactivity of control vessels, despite the finding that the upward shift of the pressure-diameter relation of vessels in the CPB group was markedly attenuated by NG-nitro-L-arginine. It is noteworthy to indicate that previous reports showing a positive relation between the endothelium and myogenic responses were based on observations in cerebral arteries of the cat13 14 and canine carotid artery.17 Different myogenic mechanisms may exist between different vascular beds and species because previous studies in pulmonary18 and ear19 arteries of rabbits showed that myogenic reactivity is not altered by endothelial denudation. Accordingly, the result of the present study suggests that, in porcine coronary arterioles under the control condition, myogenic reactivity is independent of the endothelium or the release of the endothelium-derived relaxing factor (EDRF, ie, NO) or prostaglandin substances.
The decreased myogenic reactivity after cardioplegia and cardioplegia-reperfusion might be caused by dysfunction of the vascular smooth muscle. However, we observed that the contractile response to potassium chloride was not affected after cardioplegia and cardioplegia-reperfusion. Furthermore, our previous studies showed that the relaxation response to sodium nitroprusside was not altered20 or was slightly enhanced21 after cardioplegia. Thus, it appears that the agonist-induced change in activity of the vascular smooth muscle is preserved, whereas the intrinsic control of the vascular smooth muscle is impaired. It was shown that mechanical perturbation can elicit contraction of isolated coronary smooth muscle cells22 and that stretch can activate cationic channels in the vascular smooth muscle.23 Recently, the contribution of K+ATP channels to myogenic reactivity was implicated in renal afferent arterioles.24 The present study observed that the K+ATP channel blocker glybenclamide significantly attenuated the cardioplegia-induced decrease in myogenic reactivity, suggesting an involvement of K+ATP channels in the altered myogenic mechanism. This result is supportive of previous findings that showed that glybenclamide prevented ischemia-induced reactive hyperemia in the isolated diaphragm.25 It is possible that ischemic cardioplegic arrest may activate K+ATP channels in the vascular smooth muscle of coronary arterioles because of a reduction in the intracellular ATP concentration.26
CPB alone or with cardioplegic arrest resulted in an upward shift of the active pressure-diameter relation, suggesting a decrease in the intrinsic tone in the coronary microcirculation. It was unlikely that a reduction in the intrinsic tone was caused by a decrease in myogenic reactivity because myogenic contraction was not altered after CPB alone. This indicates that myogenic reactivity and the intrinsic tone appear to be distinct physiological entities. Myogenic reactivity is usually defined as myogenic contraction elicited by elevations of intraluminal pressure, whereas the intrinsic tone is used to describe a maintained state of vascular smooth muscle activation and is referred to as the position of the pressure-diameter relation.27 Although myogenic reactivity and intrinsic tone are interrelated, the mechanisms responsible for both entities may not necessarily be identical. In isolated vascular smooth muscle, Sparks28 observed the development of spontaneous tone but failed to elicit a contractile response to stretch. In the present study, cardioplegia and cardioplegia-reperfusion were associated with an impairment of myogenic reactivity and intrinsic tone, whereas CPB impaired intrinsic tone without affecting myogenic reactivity. Furthermore, we observed that glybenclamide significantly improved myogenic reactivity after cardioplegic arrest but had no effect on preservation of intrinsic tone. Thus, the present study and others27 28 imply the presence of different mechanisms underlying myogenic reactivity and the intrinsic tone of the vascular smooth muscle.
The CPB-induced upward shift of the pressure-diameter relation was
markedly attenuated after inhibition of NO synthase, suggesting an
increased basal release of NO associated with CPB. In the same model of
CPB, we previously demonstrated that CPB blunts the agonist-stimulated
endothelium-dependent relaxation response, probably
because of the production of free radicals.15
Because NO is known to be involved primarily in the
endothelium-derived relaxation response, it appears
that CPB may impair the agonist-stimulated but enhance the basal
release of NO. Previous investigations showed that CPB is associated
with activation of neurohumoral factors and release of inflammatory
mediators. Although circulating levels of these factors were not
measured in the present study, a recent study reported an increased
circulatory level of tumor necrosis factor (TNF-) in a similar model
of CPB.29 TNF- is known to play an important role in
modulating endothelium-dependent relaxation. In
isolated perfused hearts and carotid arteries, Lefer and
associates30 31 observed inhibition of the release of
EDRF
by TNF-. In contrast, a number of studies also demonstrated that
TNF- enhances the basal release of NO by inducing NO synthase
activity.32 33 From these observations, it has been
suggested that TNF- selectively inhibits the agonist-stimulated but
increases the basal release of NO. Thus, it is likely that, while
TNF- produced during CPB may be responsible, at least in part, for
the endothelial dysfunction, it may act to increase the
basal release of NO and therefore contribute to the reduction in the
intrinsic tone of the coronary microcirculation. In addition,
the present time control study showed that the upward shift of the
pressure-diameter relation persisted up to 1 hour after CPB, an
implication for a persistent basal release of NO after termination of
CPB. Indeed, a previous investigation demonstrated that
endothelial cells release NO for a prolonged period in
response to TNF- and transiently when stimulated with
agonists.32
Systemic hypotension occurs frequently in patients during and after
CPB. Our results suggest that CPB-associated hypotension may result
from a generalized defect in the intrinsic control of the vascular
smooth muscle. The decreased myogenic reactivity and intrinsic tone of
the vascular smooth muscle may be beneficial because a reduction of
arteriolar resistance would potentially increase blood flow. However,
maintenance of the organ perfusion could be compromised by a
concomitant systemic hypotension that may decrease the effective
perfusion pressure. In addition, the use of
vasoconstrictive substances, such as
phenylephrine (1-agonist) or
norepinephrine (mixed - and ß-agonist) to maintain
systemic vascular resistance may have a net detrimental action on
specific noncardiac organ perfusion (eg, mesenteric and renal) owing to
a differential sensitivity of vascular beds to these substances. The
results of the present study also indicate a potential role of
altered myogenic reactivity in reactive coronary
hyperemia, a phenomenon observed during the postcardioplegia
period. Whereas hyperemic response may increase
coronary blood flow to the myocardium, excessive
and persistent hyperemia could induce detrimental effects (eg,
tissue edema) on the heart, thereby preventing functional recovery of
the myocardium.
In summary, hyperkalemic cardioplegia is associated with decreases in myogenic reactivity and intrinsic tone in the coronary microcirculation. CPB alone maintains myogenic reactivity but impairs the intrinsic tone of the coronary vascular smooth muscle, which may be due to an increased basal release of NO. The cardioplegia-associated decrease in myogenic reactivity may be caused partially by activation of K+ATP channels, whereas it appears to be independent of the endothelium or the release of NO or prostaglandin substances. These findings may have implications for the reduced systemic vascular resistance encountered after CPB during cardiac surgery and the altered coronary vascular resistance and hyperemic responses after ischemic cardioplegia.
|
Acknowledgments |
|---|
This work was supported by NHLBI grant HL-46716 and American Heart Association, Massachusetts Affiliate grant 13-501-912. This work was performed under fellowship training support of the American College of Chest Physicians.
Received February 14, 1995; accepted March 10, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Kuo L, Davis MJ, Chilian WM. Myogenic activity in isolated subepicardial and subendocardial coronary arterioles. Am J Physiol. 1988;255(Heart Circ Physiol 24):H1558-H1562.
2. Osol G, Halpern W. Myogenic properties of cerebral blood vessels from normotensive and hypertensive rats. Am J Physiol. 1985;255(Heart Circ Physiol 18):H914-H921.
3. Falcone JC, Granger HJ, Meininger GA. Enhanced myogenic activation in skeletal muscle arterioles from spontaneously hypertensive rats. Am J Physiol. 1993;265(Heart Circ Physiol 34):H1847-H1855.
4.
Takenaka T, Forster H, Micheli AD, Epstein M.
Impaired myogenic responsiveness of renal microvessels in Dahl
salt-sensitive rats. Circ Res. 1992;71:471-480.
5.
Kuo L, Chilian WM, Davis MJ. Coronary
venular responses to flow and pressure. Circ
Res. 1993;72:607-615.
6.
Chilian WM, Layne SM. Coronary
microvascular responses to reductions in perfusion pressure: evidence
for persistent arteriolar vasomotor tone during coronary
hypoperfusion. Circ Res. 1990;66:1227-1238.
7. Hiratzka LF, Eastham CL, Carter JG, Moyers JR, Elliott DR, Doty DB, Wright CB, Marcus ML. The effects of cardiopulmonary bypass and cold cardioplegia on coronary flow velocity and the reactive hyperemic responses in patients and dogs. Ann Thorac Surg. 1988;45:474-481. [Abstract]
8. Giles RW, Wilcken DEL. Reactive hyperemia in the dog heart: evidence for a myogenic contribution. Cardiovasc Res. 1977;11:64-73. [Medline] [Order article via Infotrieve]
9.
Dube GP, Bemis KG, Greenfield JC. Distinction
between metabolic and myogenic mechanisms of
coronary hyperemic responses to brief
diastolic occlusion. Circ Res. 1991;68:1313-1321.
10.
Ludbrook J. Repeated measurements and multiple
comparisons in cardiovascular research.
Cardiovasc Res. 1994;28:303-311.
11. Belloni FL. The local control of coronary blood flow. Cardiovasc Res. 1979;13:63-65. [Medline] [Order article via Infotrieve]
12.
Feigl EO. Coronary physiology.
Physiol Rev. 1983;63:1-205.
13.
Harder DR. Pressure-induced myogenic activation
of cat cerebral arteries is dependent on intact
endothelium. Circ Res. 1987;60:102-107.
14.
Harder DR, Sanchez-Ferrer C, Kauser K, Stekiel WJ,
Rubanyi GM. Pressure releases a transferable
endothelial contractile factor in cat cerebral
arteries. Circ Res. 1989;65:193-198.
15. Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury following cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation. 1993;88(part 2):395-400.
16.
Kuo L, Chilian WM, Davis MJ. Coronary
arteriolar myogenic response is independent of
endothelium. Circ Res. 1990;66:860-866.
17. Rubanyi FM. Endothelium-dependent pressure-induced contraction of isolated canine carotid arteries. Am J Physiol. 1988;255(Heart Circ Physiol 24):H783-H788.
18. Kulik TJ, Evans JN, Gamble WJ. Stretch-induced contraction in pulmonary arteries. Am J Physiol. 1988;255(Heart Circ Physiol 24):H1391-H1398.
19. Hwa JJ, Bevan JA. Stretch-dependent (myogenic) tone in rabbit ear resistance arteries. Am J Physiol. 1986;250(Heart Circ Physiol 19):H87-H95.
20. Wang SY, Friedman M, Johnson RG, Weintraub EM, Sellke FW. Adrenergic regulation of the coronary microcirculation after extracorporeal circulation and crystalloid cardioplegia. Am J Physiol. 1994;267(Heart Circ Physiol 36):H2462-H2470.
21. Sellke FW, Shafidue T, Schoen FJ, Weintraub RM. Impaired endothelium-dependent coronary microvascular relaxation following cold potassium cardioplegia and reperfusion. J Thorac Cardiovasc Surg. 1993;105:52-58. [Abstract]
22. Van Dijk AM, Wieringa PA, van der Meer M, Laird J. Mechanics of resting isolated single vascular smooth muscle cells from bovine coronary artery. Am J Physiol. 1984;246(Cell Physiol 15):C277-C287.
23. Kirber MT, Walsh JV, Singer JJ. Stretch-activated ion channels in smooth muscle: a mechanism for the initiation of stretch-induced contraction. Pflugers Arch. 1988;412:339-345. [Medline] [Order article via Infotrieve]
24.
Loutzenhiser R, Parker M. Hypoxia
inhibits myogenic reactivity of renal afferent arterioles by activating
ATP-sensitive K+channels. Circ
Res. 1994;74:861-869.
25. Vanelli G, Hussain SNA. Effects of potassium channel blockers on basal vascular tone and reactive hyperemia of the canine diaphragm. Am J Physiol. 1994;266(Heart Circ Physiol 35):H43-H51.
26. Noma A. ATP-regulated K channels in cardiac muscle. Nature. 1983;305:147-148. [Medline] [Order article via Infotrieve]
27. Meininger GA, Davis MJ. Cellular mechanisms involved in the vascular myogenic response. Am J Physiol. 1992;263(Heart Circ Physiol 32):H547-H659.
28. Sparks HV. Effect of quick stretch on isolated vascular smooth muscle. Circ Res. 1964;15(suppl):I-254-I-260.
29.
Dauber IM, Parsons PE, Welsh CH, Giclas PC, Whitman
GJR, Wheeler GS, Horwitz LD, Weil JV. Peripheral
bypass-induced pulmonary and coronary vascular injury:
association with increased levels of tumor necrosis factor.
Circulation. 1993;88:726-735.
30. Lefer AM, Tsao P, Aoki N, Palladino JMA. Mediation of cardioprotection by transforming growth factor-ß. Science. 1990;248:61-64.
31. Aoki N, Siegfried M, Lefer AM. Anti-EDRF effect of tumor necrosis factor in isolated, perfused cat carotid arteries. Am J Physiol. 1989;256(Heart Circ Physiol 25):H1509-H1512.
32.
Lamas S, Michel T, Brenner BM, Marsden PA.
Nitric oxide synthesis in endothelial cell:
evidence for a pathway inducible by TNF-. Am J
Physiol. 1991;261(Cell Physiol 30):C636-C641.
33. Xie J, Wang Y, Lippton H, Cai B, Nelson S, Kolls J, Summer WR, Greenberg SS. Tumor necrosis factor inhibits stimulated but not basal release of nitric oxide. Am Rev Respir Dis. 1993;148:627-636. [Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Segal and S. Y. Wang The Effect of Maternal Catecholamines on the Caliber of Gravid Uterine Microvessels Anesth. Analg., March 1, 2008; 106(3): 888 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Wang, N. G. Shrive, K. H. Parker, and J. V. Tyberg Effects of vasoconstriction and vasodilatation on LV and segmental circulatory energetics Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1216 - H1225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ruel, C. Bianchi, T. A. Khan, S. Xu, J. R. Liddicoat, P. Voisine, E. Araujo, H. Lyon, I. S. Kohane, T. A. Libermann, et al. Gene expression profile after cardiopulmonary bypass and cardioplegic arrest J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1521 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Khan, C. Bianchi, M. Ruel, P. Voisine, J. Li, J. R. Liddicoat, and F. W. Sellke Mitogen-Activated Protein Kinase Inhibition and Cardioplegia-Cardiopulmonary Bypass Reduce Coronary Myogenic Tone Circulation, September 9, 2003; 108(90101): II-348 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Wang, S. Datta, and S. Segal Pregnancy Alters Adrenergic Mechanisms in Uterine Arterioles of Rats Anesth. Analg., May 1, 2002; 94(5): 1304 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cavaliere Impaired carbon dioxide transport during and after cardiopulmonary bypass Perfusion, September 1, 2000; 15(5): 433 - 439. [Abstract] [PDF]
|
|
|
|
|
|
C. Metais, J. Li, J. Li, M. Simons, and F. W. Sellke Serotonin-Induced Coronary Contraction Increases After Blood Cardioplegia-Reperfusion : Role of COX-2 Expression Circulation, November 9, 1999; 100 (2009): II-328 - II-334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Tofukuji, N. Matsuda, C. Dessy, K. G. Morgan, and F. W. Sellke INTRACELLULAR FREE CALCIUM ACCUMULATION IN FERRET VASCULAR SMOOTH MUSCLE DURING CRYSTALLOID AND BLOOD CARDIOPLEGIC INFUSIONS J. Thorac. Cardiovasc. Surg., July 1, 1999; 118(1): 163 - 172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Matsuda, M. Tofukuji, K. G. Morgan, and F. W. Sellke Coronary microvascular protection with Mg2+: effects on intracellular calcium regulation and vascular function Am J Physiol Heart Circ Physiol, April 1, 1999; 276(4): H1124 - H1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F Larson, L. B Gatewood, M. Bowers, G. Sethi, and J. G Copeland Assessment of left ventricular compliance during heart preservation Perfusion, January 1, 1998; 13(1): 67 - 75. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Tofukuji, A. Stamler, J. Li, M. D. Hariawala, A. Franklin, and F. W. Sellke Comparative Effects of Continuous Warm Blood and Intermittent Cold Blood Cardioplegia on Coronary Reactivity Ann. Thorac. Surg., November 1, 1997; 64(5): 1360 - 1367. [Abstract] [Full Text]
|
|
|
|
|
|
S. Y. Wang, A. Stamler, M. Tofukuji, T. E. Deuson, and F. W. Sellke Effects of Blood and Crystalloid Cardioplegia on Adrenergic and Myogenic Vascular Mechanisms Ann. Thorac. Surg., January 1, 1997; 63(1): 41 - 49. [Abstract] [Full Text]
|
|
|
|
|
|
F. W. Sellke, E. M. Boyle Jr, and E. D. Verrier Endothelial Cell Injury in Cardiovascular Surgery: The Pathophysiology of Vasomotor Dysfunction Ann. Thorac. Surg., October 1, 1996; 62(4): 1222 - 1228. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||