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Ann Thorac Surg 1996;61:1680-1688
© 1996 The Society of Thoracic Surgeons
Department of Surgery, Medical College of Virginia, Richmond, Virginia
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Abstract |
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Methods. A blood-perfused, parabiotic, isolated rabbit heart Langendorff preparation was used. Fifty-six hearts underwent 30 minutes of global normothermic ischemia after a 50-mL infusion of cardioplegia, followed by 60 minutes of reperfusion. The cardioplegia consisted of Krebs-Henseleit solution with either vehicle alone (control), 20 mmol KCl, or pinacidil (10, 50, 100, 150, or 200 µmol/L). The developed pressure was measured at baseline and after reperfusion. Coronary blood flow was measured with an in-line ultrasonic probe.
Results. Pinacidil (50 µmol/L), as opposed to potassium cardioplegia, provided significantly better postischemic percentage recovery of developed pressure compared with controls (68.3% ± 4.0% versus 44.6% ± 5.5%; p < 0.05). The time until electrical arrest was significantly shorter in the hyperkalemic group than in all other groups. Linear end-diastolic pressure-volume relationships revealed an increase in slope after ischemia in all groups. Coronary flow after 5 minutes of reperfusion was significantly higher in both the 50-µmol/L and 100-µmol/L pinacidil groups compared with traditional hyperkalemic arrest, and this returned to baseline after 15 minutes.
Conclusions. The potassium channel opener pinacidil provided dose-dependent myocardial protection during global ischemia in the blood-perfused rabbit heart model. Potassium-channel openers are a promising class of drugs that may provide an alternative to traditional hyperkalemic cardioplegia.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The cardiac action potential is generated by the opening and closing of specific membrane ion channels [1]. During myocardial ischemia, there are dramatic changes in the action potential. There is a decrease in the resting membrane potential (depolarization), a decrease in the rate of rise of the action potential upstroke, and a marked shortening of action potential duration [2–5]. Many of these electrophysiologic changes associated with myocardial ischemia have been attributed to an efflux of intracellular potassium [2]. Noma [6] described a specific potassium channel in guinea pig and rabbit ventricular myocytes that was inhibited by intracellular adenosine triphosphate (ATP) and opened during times of ischemia. The opening of this ATP-sensitive potassium channel (KATP) causes an outward potassium current, which hyperpolarizes the cell membrane. This channel has since been shown to be responsible for many of the electrophysiologic responses to ischemia [5, 7, 8], particularly the marked shortening of the cardiac action potential. This results in a marked shortening of the duration of the plateau phase, during which most of the inward calcium transport occurs. This reduction in calcium influx causes a decrease in contractility. Activation of KATP channels has been shown to underlie the contractile failure seen during prolonged periods of ischemia and metabolic inhibition [9]. This decrease in mechanical activity conserves ATP, and thus is cardioprotective during ischemia [6].
Pharmacologic activation of the KATP channel by potassium-channel openers (PCOs) has been shown to be cardioprotective in various animal models of myocardial ischemia [8, 10–14]. Benefits include preservation of ventricular function and high-energy nucleotides, and limitation of infarct size after ischemia. These channels also have been found to play an important role in the phenomenon of ischemic preconditioning [15, 16]. Opening of KATP channels also results in vascular smooth muscle relaxation, and these agents are potent vasodilators.
Our laboratory previously investigated the myocardial protection afforded by hyperpolarized arrest with the PCO aprikalim during global ischemia. Myocardial protection with hyperpolarizing cardioplegia containing aprikalim was superior to standard hyperkalemic depolarizing arrest in both a crystalloid-perfused [17] and a blood-perfused [18] isolated rabbit heart model. However, aprikalim was found to have substantial toxicity at high doses and to be proarrhythmic upon reperfusion. Because of this, another widely used PCO, pinacidil, was investigated using a blood-perfused isolated rabbit heart model, in the hope of finding a more effective agent. Pinacidil has been demonstrated to increase the open-state probability of the ATP-sensitive K+ channel, and the threshold concentration of pinacidil for activation of the channel has ranged between 20 and 100 µmol/L [19–22]. Pinacidil administration before myocardial ischemia has been shown to decrease the action potential duration and to be cardioprotective during ischemia [3, 4, 8].
The purposes of this study were to investigate the dose-dependent cardioprotective effects of the PCO pinacidil as a cardioplegic agent in the isolated blood-perfused rabbit heart model, and to compare this agent with traditional hyperkalemic cardioplegia and unprotected ischemia. Moreover, we investigated the effect of these potent vasodilators on coronary blood flow and cardioplegia flow using an in-line ultrasonic flow probe.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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After support-animal preparation, the donor animal was administered heparin and ventilated through a tracheostomy. The animal then underwent rapid sternotomy and cardiectomy. The aorta was cannulated, and coronary perfusion was instituted through the Langendorff column. The support animal was given indomethacin (1 mg/kg) intravenously to promote blood pressure stability [23]. The systolic arterial blood pressure of the support animal was maintained above 65 mm Hg by transfusion with Plasmalyte (Baxter Healthcare Corp, Deerfield, IL) or with blood collected from the donor animal at the time of cardiectomy. Arterial blood gases, electrolytes, and the hematocrit of the support animal were monitored at regular intervals and maintained within physiologic limits. The support animal was given supplemental anesthesia intramuscularly as needed throughout the experiment. Heparin (500 U) was given to the support animal at hourly intervals.
After aortic cannulation, a left atriotomy was performed and a vent (polyethylene tubing, internal diameter 0.86 mm; Clay Adams, Parsippany, NJ) was placed in the left ventricle. A fluid-filled latex balloon was placed in the left ventricle and secured with a pursestring suture in the mitral annulus. The balloon was connected to a pressure transducer (Model 42559-01; Abbott Laboratories, North Chicago, IL) and to a Gould amplifier (model 13-4615-50; Gould, Inc). The zero-pressure reference was set at the level of the aortic valve. Two right atrial electrodes were positioned and connected to a pacemaker (model DTU101; Bloom Associates Ltd, Reading, PA). The heart was paced at a constant rate (180 to 240 beats/min) throughout the study. Two left ventricular epicardial bipolar electrodes were positioned and connected to a preamplifier (model 11-G5407-58; Gould Inc) and to a Universal Amplifier (model MU13-4615-58; Gould Inc), and filtered between 0.05 and 1,000 Hz.
The pressure and electrogram waveforms were displayed continuously on an oscilloscope (Gould ES1000) and digitized on-line using an AT-CODAS system (DATAQ Instruments, Akron, OH) at a sampling rate of 1,000 Hz. The heart was enclosed in an air bath surrounded by a glass-jacketed water beaker.
Myocardial temperature was monitored throughout the experiment using a temperature probe (Model 0112; Shiley Inc, Irvine, CA) placed in the right ventricle. Myocardial temperature was maintained at 37°C by adjusting the water bath (model 71; Polyscience, Niles, IL) temperature. Coronary flow was monitored using an in-line flow probe (model 2N; Transonic Systems, Ithaca, NY) and an ultrasonic blood flow meter (model 101; Transonic Systems).
Experimental Protocol
Hearts were excluded from the study if they did not attain a developed pressure of 80 mm Hg at an end-diastolic pressure of 10 mm Hg, or if the baseline developed pressure did not remain stable during the 30 minutes after instrumentation.
After a 30-minute equilibration period, the left ventricular pressure-volume relationships were measured. A wide range of volumes were infused into the intraventricular latex balloon to generate end-diastolic pressures (EDP) of 0, 2.5, 5, 7.5, 10, 12.5, 15, 20, and 25 mm Hg. After baseline data acquisition, fluid was adjusted in the latex balloon to obtain an EDP of 5 mm Hg before the ischemic period.
Fifty-six hearts were randomly assigned to receive a different cardioplegic solution for myocardial protection during a 30-minute period of global normothermic ischemia. The cardioplegia consisted of Krebs-Henseleit solution (in mmol/L distilled water: NaCl, 118.5; NaHCO3, 25.0; KCl, 3.2; MgSO4, 1.2; KH2PO4, 1.2; glucose, 5.5; CaCl2, 2.5) with either vehicle alone (dimethyl sulfoxide 0.2%; Sigma Chemical Co, St. Louis, MO) (n = 8); 20 mmol KCl with vehicle (n = 8); or pinacidil at a concentration of 10 µmol/L (n = 8), 50 µmol/L (n = 8), 100 µmol/L (n = 8), 150 µmol/L (n = 8), or 200 µmol/L (n = 8). Pinacidil was provided by Leo Pharmaceuticals, Denmark. A concentrated pinacidil stock solution was made by dissolving pinacidil in dimethyl sulfoxide. The appropriate amount of the pinacidil stock solution was added to the Krebs-Henseleit solution before each cardioplegia infusion. Heparin (12.5 U/mL) was added to each of the cardioplegia solutions.
At the start of the ischemic period, the Langendorff perfusion column was clamped and 50 mL of normothermic (37°C) cardioplegia was infused from a height of 80 cm H2O through a separate column. The cardioplegia effluent was collected and discarded. Both the time until cessation of mechanical activity and the time until electrical quiescence were recorded. Cessation of mechanical activity was defined as the absence of a developed pressure.
After 30 minutes of normothermic global ischemia, the Langendorff column was unclamped and the heart was reperfused for 60 minutes. If ventricular fibrillation persisted after reperfusion, the heart was defibrillated (Model D84; Electrodyne Co, Inc, Westwood, MA). Electrolytes, hematocrit, and arterial blood gas measurements of the support animal were repeated to ensure stability. After 60 minutes of reperfusion, data were collected at the identical balloon volumes used during baseline preischemic data acquisition. At the conclusion of the experiment, a sample of the left ventricle was excised, blotted, and weighed to obtain the wet weight. The sample was dried until a constant dry weight was achieved. Percentage tissue water (%TW) was determined using the equation: %TW = (wet weight - dry weight)/wet weight.
All animals received humane care in AAALAC-accredited (no. 00036), USDA-registered (no. 52-R-007) facilities in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Data Analysis
Left ventricular systolic and diastolic pressures were determined from the digitized data files using software developed in our laboratory.
END-SYSTOLIC PRESSURE.
The end-systolic pressure (ESP) of a beat was defined as the maximum point of the digitized pressure waveform. The average ESP was calculated by averaging the ESPs of 10 beats. Average ESPs were obtained for each balloon volume at baseline and after reperfusion. The ESP versus balloon volume (BV) data for baseline and postreperfusion data were fitted to the linear end-systolic pressure-volume relationship using a least-squares linear regression algorithm: ESP = Emax x BV + k, where Emax the slope and k = the y intercept.
END-DIASTOLIC PRESSURE.
The end-diastolic pressure (EDP) of a beat was defined as the point at which the increase in slope of the pressure waveform exceeded a threshold of 0.5 mm Hg/ms. This was visually confirmed for each beat. The average EDP was calculated by averaging the EDPs of 10 beats, and was obtained for each balloon volume at baseline and after reperfusion. The EDP versus balloon volume data were fitted to the linear end-diastolic pressure-volume relationship using a least-squares linear regression algorithm: EDP = m (BV - BV0), where m = the slope and BV0 = the balloon volume corresponding to an EDP of zero, or the x intercept [24]. The mean linear regression coefficient for the diastolic pressure-volume curves was 0.97 ± 0.01 for each group (control, 20 mmol KCl, and 50 µmol/L pinacidil). Thus, a linear representation of the diastolic pressure-volume relationships was appropriate over the limited range of end-diastolic volumes examined in this model [25].
DEVELOPED PRESSURE.
The left ventricular developed pressure was obtained by subtracting the EDP from the ESP for each data point. An average of 10 data points were used for each balloon volume. The developed pressure (DP) versus balloon volume data for baseline and postreperfusion were fitted to a linear pressure-volume relationship using the following linear regression algorithm: DP = ESP - EDP = (Emax x BV + k) - m (BV - BV0).
PERCENTAGE RECOVERY OF DEVELOPED PRESSURE.
The percentage recovery of developed pressure was calculated as the percentage of the postreperfusion average developed pressure to the baseline average developed pressure at the same balloon volume. This was calculated for each of the postreperfusion matched balloon volumes. The average percentage recovery of developed pressure was obtained using the trapezoidal rule, as described previously by our laboratory [18, 26].
Statistical Analysis
Values are presented as the mean ± standard error of the mean. Analysis of variance or Kruskall-Wallis, as appropriate, was used for multiple comparisons of means, with a Dunnett's test for individual comparisons. An analysis of variance was used to compare the time for cardioplegia infusion, the times until mechanical and electrical arrest, the percentage recovery of developed pressure, the differences in coronary blood flow, and the differences in myocardial tissue water between all groups. Fisher's exact test was used to compare the incidence of reperfusion ventricular fibrillation between groups. Student's t test (or the Mann-Whitney test when appropriate) was used to compare two means. A paired Student's t test was used to compare means before and after an intervention. Differences were considered statistically significant at p < 0.05. Statistical analysis was performed using Sigma Stat (Version 1.01; Jandel Corp).
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Results |
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Cardioplegia Delivery
The mean time to infuse the cardioplegia solution ranged from 1.94 ± 0.17 minutes to 2.60 ± 0.43 minutes, and was not significantly different between groups (Table 1
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for each group. The control group had prolonged mechanical activity compared with all other groups, although this was statistically significant only when compared with the 20-mmol KCl and the 200-µmol/L pinacidil groups. There was no difference in the time until mechanical arrest between the 20-mmol KCl and the pinacidil groups. Electrical quiescence was achieved most rapidly in the 20-mmol KCl group (3.44 ± 0.81 minutes), and this was statistically shorter than all other groups. Electrical activity was prolonged in all of the pinacidil groups when compared with the 20-mmol KCl group. However, all pinacidil groups with a concentration greater than 10 µmol/L had a statistically shorter time until electrical arrest when compared with the control group.
Reperfusion Arrhythmias
Upon reperfusion, 50% of the hearts given pinacidil exhibited ventricular fibrillation, compared with no hearts in either the control or hyperkalemic cardioplegia group (see Table 1). The highest incidence of ventricular fibrillation, 63%, was seen in the 150-µmol/L and the 200-µmol/L pinacidil groups. All groups receiving 100 µmol/L pinacidil or greater had a statistically higher incidence of ventricular fibrillation than the control and KCl groups.
Dose-Response Curve of Pinacidil Cardioplegia
The dose dependence of the postischemic recovery of developed pressure after protection was examined over a range of pinacidil concentrations. The best percentage recovery of developed pressure was noted in the 50-µmol/L pinacidil group. This dose was the only group that was significantly better than the control group of Krebs solution alone. There was a biphasic response in postischemic recovery of function as the pinacidil concentration was increased. This was best described by a nonlinear least-squares fit of the data to a second-order polynomial equation (Fig 1).
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). Recovery of developed pressure was 68.30% ± 3.95% in the 50-µmol/L pinacidil group, compared with 56.92% ± 4.33% in the hyperkalemic group and 44.60% ± 5.46% in the control group.
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). There was an increase in slope compared with baseline after reperfusion in all groups, and this was statistically significant in the control, 10-µmol/L, 100-µmol/L, 150-µmol/L, and 200-µmol/L pinacidil groups. There was no statistically significant difference in slope in the potassium and 50-µmol/L pinacidil groups; however, the increase in slope was of similar magnitude to the other groups. The x intercepts were not significantly different between baseline and reperfusion in any group.
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Reperfusion Coronary Blood Flow
The mean baseline coronary flow before ischemia at an EDP of 5 mm Hg ranged between 4.30 ± 0.47 to 7.78 ± 2.04 mL/min and was not significantly different between groups (Table 3). When compared with baseline coronary blood flow, the flow immediately upon reperfusion was significantly higher in all groups except for the potassium group. There was no statistically significant difference in immediate reperfusion flow among groups.
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100-µmol/L, 150-µmol/L, and 200-µmol/L pinacidil groups had a significantly higher coronary blood flow than at baseline. The hearts in the 20-mmol KCl group had a further decline in coronary flow, which was significantly lower than that in the 50-µmol/L, 100-µmol/L, and 200-µmol/L pinacidil groups.
After 15 minutes of reperfusion, the coronary flow returned to values near baseline in all groups, and there were no statistically significant differences among groups.
Myocardial Tissue Water
The mean percentage tissue water was 80.6 ± 0.5, 78.7 ± 0.5, 80.1 ± 0.5, 78.9 ± 0.3, 79.3 ± 0.2, 79.1 ± 0.4, and 79.4 ± 0.6 for the control, KCl, 10-µmol/L, 50-µmol/L, 100-µmol/L, 150-µmol/L, and 200-µmol/L pinacidil groups, respectively. There was no statistically significant difference in percentage tissue water between groups.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Potassium Channel Openers as Cardioplegic Agents
Previous work from our laboratory has documented that the PCO aprikalim was an effective cardioplegic agent in a crystalloid-perfused isolated rabbit heart model [17] and in a blood-perfused model [18]. However, these studies revealed several drawbacks to hyperpolarized arrest with KATP channel openers. Aprikalim was found to be toxic at high doses. Moreover, there was a significant increase in reperfusion ventricular fibrillation compared with hyperkalemic cardioplegia. A final shortcoming of hyperpolarized arrest with aprikalim was that although there was a rapid mechanical arrest after infusion, there was persistent electrical activity during most of the ischemic period. Because of these problems, and knowing the diverse chemical structures of the different PCOs, we conducted the present study to investigate the efficacy of the PCO pinacidil as a cardioplegic agent. Pinacidil's chemical structure is markedly different from that of aprikalim, suggesting that it may have a different pharmacologic profile.
Myocardial Protection With Pinacidil
DOSE-RESPONSE CURVE OF PINACIDIL.
The dose-response relationship for pinacidil was biphasic over the range of doses tested (see Fig 1). The appearance of this curve may be due to a saturation phenomenon of the KATP channel by pinacidil at a dose of 100 µmol/L, with improved recovery with 150 µmol/L pinacidil by supersaturation of the KATP channel. However, this appearance may also be due to the large variability in the 150-µmol/L pinacidil group. The best percentage recovery of developed pressure after ischemia was in the 50-µmol/L group. Although all groups receiving pinacidil cardioplegia had a higher percentage recovery of developed pressure than control unprotected ischemia, the difference was statistically significant only in the 50-µmol/L group. Therefore, at dosages both lower and higher than this effective concentration, the protective effect of pinacidil cardioplegia was lost. This is similar to our previous results with aprikalim [17]. The inefficacy of pinacidil at higher doses may be related to a specific toxic effect directly on the KATP channel or on other structurally similar potassium channels, or to a nonspecific effect not involving the KATP channel [17]. Further research is needed to delineate the precise mechanism.
POSTISCHEMIC FUNCTIONAL RECOVERY: DEPOLARIZED VERSUS HYPERPOLARIZED ARREST.
The 50-µmol/L pinacidil group, in contrast to traditional hyperkalemic, depolarizing cardioplegia, afforded a significantly better postischemic recovery of developed pressure than the control group. Thus, pinacidil-induced hyperpolarized arrest provided optimal myocardial protection during ischemia. The advantages of hyperpolarized arrest as compared with depolarized arrest include the limitation of calcium influx into the cells (as calcium channels are closed at hyperpolarized potentials), the limitation of net intracellular ion flux, and the prevention of voltage-gated ion channel activity. There is little metabolic demand on the myocyte at this resting (hyperpolarized) membrane potential, and this is cardioprotective from a cellular perspective. Potassium channel openers may also be better cardioplegic agents because of their potent vasodilatory ability, which may improve cardioplegia distribution and postreperfusion blood flow, as seen in this study.
DIASTOLIC PROPERTIES OF THE LEFT VENTRICLE.
Although the relationship between EDP and end-diastolic volume has traditionally been described as exponential [27], the relationship was linear over the range of volumes tested in our experiments, as described by other investigators [24, 25]. The postreperfusion x intercepts were not significantly different when compared with baseline in any group, and this probably reflects the wide range of balloon volumes due to variable heart sizes in each group. However, the hearts in all groups had an increase in the slope of the pressure-volume relationship after ischemia, indicating a decrease in ventricular compliance as a result of ischemia. This was significant in the control, 10-µmol/L, 100-µmol/L, 150-µmol/L, and 200-µmol/L pinacidil groups (see Table 2). There was no significant change from baseline in the 20-mmol KCl or the 50-µmol/L pinacidil group, suggesting an equal degree of diastolic protection between depolarized and hyperpolarized arrest. This also is similar to previous findings in this model with aprikalim [18].
Development of Electromechanical Arrest With Pinacidil
The ideal cardioplegia solution would provide a quiet, bloodless operative field with minimal or no expenditure of myocardial energy stores. This would require immediate mechanical and electrical arrest. In this study, the time to mechanical arrest with pinacidil cardioplegia was not significantly different from that achieved with potassium cardioplegia. However, electrical activity was significantly prolonged in all of the pinacidil groups as compared with the potassium group. These findings are similar to those of others and to previous studies in our laboratory with aprikalim [14, 17, 18]. This persistent electrical activity did not overcome the cardioprotective effect of pinacidil cardioplegia. This finding can be explained by work from our laboratory, which has shown that this persistent electrical activity during a period of total mechanical arrest consumes little energy and results in no measurable depletion of high-energy stores during ischemia [28]. This electrical activity is the result of persistent sodium channel activity and can be eliminated pharmacologically with the sodium channel blocker procaine. However, the addition of this agent, while resulting in rapid electrical arrest, did not improve myocardial recovery after ischemia during hyperpolarized cardioplegic arrest. This is consistent with the fact that mechanical work has been shown to represent more than 99% of the total basal myocardial oxygen consumption, whereas electrical activity accounts for less than 1% of oxygen consumption [29]. Our study suggests that the beneficial effects of pinacidil were able to compensate for the small amount of energy consumed by the persistent electrical activity.
Reperfusion Coronary Blood Flow
Potassium channel openers were originally developed for use as antihypertensive agents because of their potent vasodilatory effect on vascular smooth muscle [7]. Because of this, it is essential to determine the effect of these agents on coronary blood flow. During the cardioplegia infusion, coronary blood flow was not different between pinacidil and hyperkalemic cardioplegia, as infusion times were similar. This probably represents a state of maximal vasodilation that occurs secondary to the global ischemia produced at the time of clamping of the Langendorff column in this model.
After ischemia and reperfusion, there was a significant increase in coronary blood flow at 5 minutes of reperfusion in the 50-µmol/L and 100-µmol/L pinacidil groups when compared with potassium cardioplegia. This increased flow returned to baseline values by 15 minutes of reperfusion. The greatest increase in flow was noted in the 50-µmol/L pinacidil group, which also was the group with the greatest percentage recovery of developed pressure.
These findings are in agreement with other investigations. An increase in reperfusion myocardial blood flow has been demonstrated in normal dogs receiving intravenous pinacidil during coronary occlusion, compared with dogs given saline [30]. Pinacidil (10 µmol/L) significantly increased reperfusion coronary blood flow in isolated rat hearts, and this effect was reversed with glyburide, suggesting that the effect was due to potassium channel activity [3]. Galinanes and associates [14] found that during reperfusion of globally ischemic rat hearts, glibenclamide (10 µmol/L) had a vasoconstricting effect and lemakalim (10 µmol/L) had a vasodilating effect, which persisted for approximately 20 minutes of reperfusion, similar to our findings with pinacidil. This may represent the time necessary for the PCO to wash out of the coronary circulation.
It is doubtful that the cardioprotective effect of PCOs is related to the vasodilatory effect of these agents. Our study revealed increased reperfusion coronary blood flow in the high-dose pinacidil groups without concomitant improvement in recovery of developed pressure. This is supported by the work of Sargent and coauthors [11], who noted that the cardioprotective effects of the PCO P-1075 were noted only when it was infused before ischemia. No benefit has been demonstrated with the infusion of PCOs during reperfusion alone [3, 11]. Moreover, when reperfusion coronary blood flow after ischemia protected with aprikalim (30 µmol/L) was held constant to that of controls, a significant increase in left ventricular developed pressure was demonstrated despite the controlled flow. The increased coronary blood flow upon reperfusion may be due to an exaggerated hyperemic response to ischemia in the pinacidil-pro- tected hearts. This would suggest a greater ischemic insult. However, this is unlikely given the superior myocardial protection afforded by the 50-µmol/L pinacidil group. Moreover, one would expect a significant difference between groups immediately upon reperfusion, which was not evident in this study.
This finding may simply reflect the well-known vasodilatory properties of KATP channel openers, as these agents are potent coronary vasodilators. In addition, this also may indicate better endothelial protection by PCOs. Further research is needed to determine the cause of the higher reperfusion coronary blood flow with pinacidil as opposed to potassium cardioplegia.
Incidence of Ventricular Fibrillation Upon Reperfusion
There was a dose-related increased incidence of ventricular fibrillation upon reperfusion in hearts receiving pinacidil cardioplegia. No hearts in either the control or potassium groups had ventricular fibrillation upon reperfusion. This is similar to the findings of other investigators [14, 16]. These agents result in a marked decrease in action potential duration, which decreases the refractory period and has been shown to promote reentrant ventricular arrhythmias [31]. This proarrhythmic effect is a potential drawback of this class of drugs when used as cardioplegic agents. However, ventricular fibrillation in the clinical setting immediately after release of the cross-clamp on cardiopulmonary bypass is readily treatable with cardioversion. It is important that no hearts in this study receiving pinacidil cardioplegia developed recurrent ventricular arrhythmias after the initial defibrillation during the 60-minute reperfusion period. It remains to be determined whether these agents cause an increase in ventricular arrhythmias hours or days after their washout from the coronary circulation. Further studies are needed to define the time course of this phenomenon.
Model Shortcomings
The blood-perfused Langendorff model is more physiologic than crystalloid perfusion and more appropriate for the study of ischemia/reperfusion injury [32]. Blood perfusion more closely approximates the clinical situation, affords the benefits of enhanced buffering capacity by circulating plasma proteins and erythrocyte carbonic anhydrase, provides the oxygen-carrying capacity of hemoglobin, provides a higher oncotic pressure than crystalloid solutions, has beneficial effects on the coronary microcirculation, and results in less tissue edema [33]. However, this blood-perfused model does have drawbacks.
The isolated heart allows analysis of interventions on the heart without humoral, neural, adrenergic, or anesthetic influences. However, the parabiotic model allows these influences from the support animal. In this study, every effort was made to maintain a constant level of anesthesia in the support animals, and indomethacin was administered to promote blood pressure stability [23]. However, some of the variation noted in the recovery of developed pressure within each group may be attributable to the model itself. However, the advantages of blood perfusion outweigh these small disadvantages. Even though this model is more physiologic than a crystalloid-perfused preparation, care should be taken in directly extrapolating these results to either the intact animal or the clinical situation. The lack of noncoronary blood flow, cardiac denervation, and the unknown effects of the support animal all may influence the data.
Summary
Pinacidil is an effective cardioplegic agent in the isolated blood-perfused rabbit heart model. Pinacidil (50 µmol/L) significantly improved the percentage recovery of developed pressure after a global normothermic ischemic episode in the rabbit heart when compared with the control. Pinacidil (50 µmol/L) also afforded diastolic protection during ischemia. Pinacidil-induced hyperpolarized arrest was comparable to traditional hyperkalemic depolarized arrest and, as opposed to hyperkalemic cardioplegia, was significantly better than no protection in the control hearts. Despite the possible drawbacks of an increased incidence of ventricular fibrillation and a narrow therapeutic window, pinacidil provides effective myocardial protection during ischemia. This study further demonstrates that hyperpolarized arrest with PCOs is an acceptable alternative to traditional hyperkalemic depolarized arrest.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Damiano, The Milton S. Hershey Medical Center, PO Box 850, Hershey, PA 17033.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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J. S. Lawton, P.-W. Hsia, and R. J. Damiano Jr The adenosine-triphosphate-sensitive potassium-channel opener pinacidil is effective in blood cardioplegia Ann. Thorac. Surg., September 1, 1998; 66(3): 768 - 773. [Abstract] [Full Text] [PDF]
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L. Hebbar, W. V. Houck, J. L. Zellner, B. H. Dorman, and F. G. Spinale Temporal Relation of ATP-Sensitive Potassium-Channel Activation and Contractility Before Cardioplegia Ann. Thorac. Surg., April 1, 1998; 65(4): 1077 - 1082. [Abstract] [Full Text] [PDF]
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 J. S. Lawton, P.-W. Hsia, C. T. Allen, and R. J. Damiano Jr. MYOCARDIAL PROTECTION IN THE ACUTELY INJURED HEART: HYPERPOLARIZING VERSUS DEPOLARIZING HYPOTHERMIC CARDIOPLEGIA J. Thorac. Cardiovasc. Surg., March 1, 1997; 113(3): 567 - 575. [Abstract] [Full Text]
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J. S. Lawton, J. D. Sepic, C. T. Allen, P.-W. Hsia, and R. J. Damiano Jr Myocardial Protection With Potassium-Channel Openers Is as Effective as St. Thomas' Solution in the Rabbit Heart Ann. Thorac. Surg., July 1, 1996; 62(1): 31 - 38. [Abstract] [Full Text]
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