Myogenic Reactivity of Coronary Resistance Arteries After Cardiopulmonary Bypass and Hyperkalemic Cardioplegia
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.
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.
Yorkshire pigs (19 to 23 kg) of either sex were premedicated with ketamine (10 mg/kg IM) and anesthetized with α-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.
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.
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.
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
Subepicardial coronary arterioles were dissected from the left ventricular myocardium perfused by the left circumflex coronary artery with a ×10 to ×60 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 (×40 to ×200, 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).
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.
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.
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.
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⇓).
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-α) in a similar model of CPB.29 TNF-α 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-α. In contrast, a number of studies also demonstrated that TNF-α enhances the basal release of NO by inducing NO synthase activity.32 33 From these observations, it has been suggested that TNF-α selectively inhibits the agonist-stimulated but increases the basal release of NO. Thus, it is likely that, while TNF-α 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-α 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 (α1-agonist) or norepinephrine (mixed α- and β-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.
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.
- Copyright © 1995 by American Heart Association
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