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J Thorac Cardiovasc Surg 1995;110:1063-1072
© 1995 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
London, England
Supported in part by grants from the British Heart Foundation and STRUTH.
Received for publication Jan. 12, 1995. Accepted for publication April 12, 1995. Address for reprints: Yumin Qiu, MD, PhD, Section of Cardiology, University of Louisville, Louisville, KY 40202.
Abstract
Experiments were designed to assess whether (1) nicorandil given before global low-flow ischemia or (2) included in low-flow continuous cardioplegia improved the recovery of cardiac function in the isolated rat heart. The first investigated the effect of nicorandil (2, 10, or 100µmol/L), given for 3 minutes before 30 minutes of normothermic global ischemia, on recovery after 30 minutes of reperfusion. In aerobically perfused hearts, doses of 10 and 100µmol/L significantly increased coronary flow; the dose of 100µmol/L exerted a negative inotropic effect. These doses shortened the time to contractile arrest (282±18 and 276±22 seconds versus 354±16 seconds in the control hearts with unmodified ischemia; p <0.05 in both instances). Nicorandil also improved the postischemic recovery of coronary flow (79.1%±1.7% and 78.0%±1.6%, respectively, versus 71%±1.8%; p <0.05). However, there was no significant improvement in recovery of contractile function, creatine kinase leakage, or tissue adenosine triphosphate and creatine phosphate contents. Second, pretreatment with nicorandil (10µmol/L) was shown to increase susceptibility of the hearts to reperfusion-induced ventricular fibrillation from 0% (n = 8) in control hearts to 50% in the drug-treated group (p <0.05). Third, nicorandil (10µmol/L) was added to cardioplegic and noncardioplegic solutions infused into the coronary tree throughout 100 minutes of low-flow (0.7 ml/min) ischemia: in eight of nine control hearts electrical activity was maintained throughout, whereas in all nicorandil-treated hearts electrical activity was suppressed for at least part of the time. Nicorandil also reduced the prevalence of ischemic contracture to 0% during continuous infusion of cardioplegic solution (compared with 30% in nicorandil-free control hearts) and improved the recovery of contractile function after 40 minutes of reperfusion. Thus, in the noncardioplegia groups, left ventricular developed pressure recovered to 77.8%±4.0% versus 51.7%±2.6% in control hearts (p <0.05) and in the cardioplegia groups to 96.2%±4.2% versus 79.7%±5.5% (p <0.05). Ventricular compliance (the ventricular volume required to achieve a left ventricular end-diastolic pressure of 4 mm Hg) was better preserved in the nicorandil-containing noncardioplegia group (133±6µl) than in the control group (88±10µl; p <0.05). In conclusion, nicorandil has been shown to (1) reduce ischemic contracture, (2) lessen the effects of ischemic arrest, and (3) improve the postischemic recovery of contractile function. In this species and preparation it may, however, enhance vulnerability to reperfusion-induced arrhythmias. (J THORACCARDIOVASCSURG1995;110:1063-72)
Nicorandil, a nicotinamide nitrate with the ability to promote opening of the adenosine triphosphate (ATP)-sensitive potassium channel, has been shown to protect against injury during ischemia and reperfusion in a variety of experimental models and species. 
1-3 It may either reduce infarct size after severe regional ischemia or attenuate stunning after a brief period of global ischemia. The underlying protective mechanism is thought to be a direct effect operative through the activation of ATP-sensitive potassium channels. 3 It has also been suggested, however, that part of the protective effect might involve the acceleration of the onset of ischemic arrest, that is, a cardioplegic effect, which thereby conserves the limited supplies of ATP during ischemia. 2 In addition, nicorandil might provide added protection by nitrate-mediated (and potassium channel–mediated) effects on coronary flow. 4 This property distinguishes it from other drugs in its class.
Continuous warm delivery of cardioplegic solution, which minimizes ischemia and avoids hypothermia, has recently been advocated as a new approach to myocardial preservation during coronary bypass operations. 5,6 However, cardiac electrical activity may resume during this procedure, 6,7 and this may limit the protective effect. Maintenance of electrical quiescence of the heart is important not only to maximize recovery of cardiac function, but also to facilitate surgical correction.
It may be hypothesized that the addition of a potassium-channel opener to the solution used for continuous warm cardioplegia may help to ensure cardiac electrical arrest and improve the recovery of cardiac function. We have therefore studied the effect of nicorandil as an additive in the use of this form of cardioplegia and have assessed whether it is of any benefit in the absence of cardioplegia, either as pretreatment or continuously administered throughout a period of reduced coronary flow.
MATERIALS AND METHODS
Animals and drugs
Adult male rats (220 to 280 gm body weight) of the Wistar strain were used in the study. The animals received humane care 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 National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1985). Nicorandil was donated by Rhône-Poulenc Rorer, Antony, France.
Perfusion preparation
Rats were anesthetized with diethyl ether and heparinized (1000 IU/kg, intravenously); 30 seconds later the heart was excised and placed in cold (4° C) perfusion solution until contraction had ceased. The aorta was mounted on a stainless steel cannula, the pulmonary artery incised to facilitate coronary drainage, and the heart subjected to nonrecirculating Langendorff perfusion (37° C) at a pressure equivalent to 100 cm H2O. The perfusion solution was bicarbonate buffer, containing (in millimoles per liter) glucose 11.1, NaCl 118.5, KCl 4.75, MgSO4 1.19, KH2PO4 1.18, NaHCO3 25.0, and CaCl2 1.36. This solution was gassed with 95% O2 plus 5% CO2(pH 7.4 at 37° C) and filtered before use through a 5 µm porosity membrane to remove any particulate matter. A side arm of the aortic cannula allowed either infusion with cardioplegic solution or the establishment of continuous low-flow perfusion by a pump set at a constant flow rate.
Cardioplegic solution
The cardioplegic solution was prepared by mixing the Fremes' solution 7 (containing, in millimoles per liter, KCl 30,MgSO49, tromethamine (THAM) 12, and glucose 250 plus citrate-phosphate-dextrose solution 20 ml/L) with perfusion solution in a ratio of 1:4. The final solution contained (in millimoles per liter) NaCl 95.0, KCl 9.8, MgCl22.8, CaCl21.1, NaHCO320.0; THAM 2.4, and glucose 58.9, at pH 7.4. During the initial 3 minutes of infusion with this solution, the potassium concentration was increased to 26 mmol/L to achieve a rapid cardiac arrest. 6,7 The cardioplegic solution was filtered beforeuse through a 5 µm porosity membrane and gassed with 95% O2 plus 5% CO2. The solution was kept in a temperature-regulated reservoir (37° C) and infused through a side arm of the aortic cannula at a constant flow rate of 0.7 ml/min.
Experimental protocols
Study I: Dose-response study of nicorandil as preischemic treatment
This protocol was designed to assess the ability of nicorandil to shorten the time to arrest during ischemia and also its ability, when given as pretreatment, to improve the postischemic recovery of cardiac function. Three doses of nicorandil (2, 10, and 100 µmol/L) were studied. Four groups of hearts (6 per group) were initially perfused aerobically for 10 minutes; a fluid-containing compliant balloon, attached to the proximal end of a cannula, was then introduced into the left ventricle through the mitral valve. The distal end of the cannula was connected to a pressure transducer to permit recording of the intraventricular pressure. The balloon was next filled with sufficient fluid to produce an end-diastolic pressure of 4 mm Hg. Control measurements of cardiac function, including left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and coronary flow, were recorded 10 minutes later. The hearts were then subjected to 3 minutes of continuous perfusion with oxygenated perfusion buffer, to which had been added varying doses of nicorandil (0, 2, 10, or 100 µmol/L). This was followed by 30 minutes of normothermic global ischemia and 30 minutes of reperfusion. All hearts were paced at 320 beats/min during the preischemic and reperfusion periods. Cardiac contraction was recorded on chart paper and time to mechanical arrest for each heart after the onset of ischemia was analyzed retrospectively. Intraventricular pressure was monitored continuously during ischemia to assess ischemic contracture. During reperfusion, LVDP, LVEDP, and coronary flow were monitored and coronary effluent was collected and taken for the determination of total creatine kinase (CK) leakage, which was expressed in international units per 30 min/gm dry weight. If sustained ventricular fibrillation (VF) occurred during reperfusion, the heart was gently compressed. All fibrillating hearts were successfully defibrillated by this method.
Study II: The effect of nicorandil pretreatment on vulnerability to reperfusion-induced arrhythmias
On the basis of the preceding study, a 10 µmol/L dose of nicorandil was selected for assessment of the effect of pretreatment on the susceptibility of the heart to reperfusion-induced arrhythmias after global ischemia. Two groups of hearts were studied by a protocol similar to that described in the previous section (except that the hearts were not paced). Hearts (8 per group) were initially perfused aerobically for 20 minutes and this was followed by a 3-minute period of perfusion with oxygenated buffer with or without added nicorandil (10 µmol/L). The hearts were then subjected to 20 minutes of normothermic global ischemia and 10 minutes of aerobic reperfusion. A unipolar electrogram was obtained via silver electrodes attached to the left ventricular free wall. This was displayed on a digital storage oscilloscope and recorded on chart paper throughout the experiment to permit the retrospective analysis of changes in the heart rate and of the occurrence of arrhythmias. In view of their arrhythmogenic effects, intraventricular balloons were not used in this series of studies. Heart rate, time to arrest of ventricular electrical activity, and the prevalence of reperfusion-induced ventricular fibrillation and tachycardia were derived from the electrogram traces.
Study III: The effect of nicorandil during low-flow ischemia with or without cardioplegia
On the basis of the results of the previous dose-response study, nicorandil in a dose of 10 µmol was also used in study III. Four groups of hearts (9 per group) were aerobically perfused for 20 minutes and control values for LVDP, LVEDP, and cardiac flow were recorded. The hearts were then subjected to low-flow perfusion (0.7 ml/min) with either oxygenated buffer with or without added (10 µmol/L) nicorandil (groups 1 and 2) or cardioplegic solution with or without added (10 µmol/L) nicorandil (groups 3 and 4). The low-flow rate (0.7 ml/min for a heart of 1 gm wet weight) was selected so as to match the myocardial oxygen consumption of the arrested heart (approximately 10% of the oxygen consumption that occurs during normal contractile activity) and to mimic the flow used in the clinical setting during continuous delivery of warm cardioplegic solution (>200 to 300 ml/min for a heart of 500 gm wet weight). During the period of low-flow perfusion the aortic pressure was greater than 20 mm Hg and the infused solution was mainly recovered in the coronary effluent, which suggests that the aortic valve remained competent during this time. Finally, all hearts were aerobically reperfused for 40 minutes at a perfusion pressure equivalent to 100 cm H2O. Hearts were paced at a rate of 320 beats/min before and after the period of low-flow perfusion.
For the assessment of control contractile function, the intraventricular balloon was inflated with sufficient water to generate an LVEDP of 4 mm Hg; the LVDP and volume of the balloon were recorded. During low-flow perfusion, cardiac electrical activity was continuously monitored by means of an electrode attached to the left ventricle. To avoid overstretching of the left ventricle during low-flow perfusion, the volume of the balloon was reduced to one third of its control value. At the end of the reperfusion period, the balloon was reinflated to achieve an LVEDP of 4 mm Hg, and the LVDP and balloon volume were again recorded.
Coronary effluent was collected throughout the reperfusion period and this was taken for the determination of CK leakage. At the end of the experiment, six hearts in each group were freeze-clamped and taken for assessment of tissue ATP and creatine phosphate contents.
Exclusion criteria
During preischemic perfusion, any heart with a coronary flow rate less than 7 ml/min or an LVDP less than 90 mm Hg (at an LVEDP of 4 mm Hg) was excluded. Fewer than 10% of all hearts were excluded.
Statistical analysis
All results are expressed as the mean plus or minus the standard error of the mean and an analysis of variance was used for multiple comparisons. When a significant F value was obtained, comparison between means was done by Tukey's test. A two-tailed unpaired t test was used for comparison between two means when appropriate. A difference was considered statistically significant if p < 0.05.
RESULTS
Study I: Dose-response study of nicorandil as preischemic treatment
Preischemic cardiac function
Before the administration of nicorandil, there were no differences in coronary flow or LVDP among the study groups (Fig. 1). After 3 minutes of perfusion with nicorandil-containing buffer, there was a dose-dependent increase in coronary flow, which, at the highest concentration (100 µmol/L) reached 34% ± 5% higher than the control value (from 12.1 ± 0.3 to 16.2 ± 0.4 ml/min; p < 0.05) (Fig. 1). There were no statistically significant changes in LVDP in the hearts that received nicorandil at concentrations of 2 and 10 µmol/L; however, a small (9% ± 3%) but significant (p < 0.05) decrease in LVDP was observed in the hearts perfused with nicorandil at a concentration of 100 µmol/L (Fig. 1).
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Table I). Pretreatment with nicorandil at a dose of 2 µmol/L had no significant effect (Table I).
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Table I).
Postischemic recovery of cardiac function
Fig. 2 shows the profile for the recovery of coronary flow in the four study groups. At the end of 30 minutes of reperfusion, a significantly better recovery of coronary flow was observed in the hearts that received preischemic nicorandil at concentrations of 10 and 100 µmol/L (9.4 ± 0.2 and 9.4 ± 0.2 ml/min versus 8.6 ± 0.2 ml/min in control hearts; p < 0.05 in both instances). The recovery of coronary flow in the hearts receiving a 2 µmol/L dose of nicorandil tended to be lower than that in control hearts during the initial reperfusion period, but the difference failed to achieve statistical significance and by the end of the reperfusion period the recoveries were similar (8.8 ± 0.2 versus 8.6 ± 0.2 ml/min; p = not significant).
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Table II).
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Table III). Fig. 4 shows the occurrence of electrical activity during low-flow perfusion and continuous cardioplegia with or without added (10 µmol/L) nicorandil. In the hearts subjected to low-flow perfusion without nicorandil, electrical activity was sustained in nearly all hearts (8/9) throughout the 100 minutes. Nicorandil attenuated the electrical activity in all hearts during the first 10 to 30 minutes. However, the activity recurred in all hearts after 40 to 60 minutes irrespective of the presence or absence of nicorandil. During continuous infusion of cardioplegic solution most hearts were electrically quiescent for a large part of the 100 minutes of low-flow perfusion. However, in the nicorandil-free group electrical activity returned in three hearts after 40 to 60 minutes whereas in the nicorandil-treated group this only occurred in one heart.
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Postischemic coronary flow
Fig. 5 shows the profile for the recovery of coronary flow in the four study groups. Recovery in the continuous cardioplegia groups and in the low-flow perfusion with nicorandil group was statistically significantly better than that in the low-flow perfusion alone group during the first 30 minutes of reperfusion. However, by the end of 40 minutes of reperfusion, there were no significant differences among the four study groups.
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Table IV).
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The present study in the isolated rat heart demonstrated that the inclusion of nicorandil in the solution used for continuous low-flow warm crystalloid cardioplegia improved the recovery of contractile function on restoration of full flow. Nicorandil also accelerated the onset of cardiac arrest and suppressed cardiac electrical activity during low-flow perfusion with or without cardioplegia. Despite this, the agent had no significant effect on CK leakage or tissue high-energy phosphate content. It is interesting to note that, although pretreatment with nicorandil accelerated the onset of cardiac arrest and improved the postischemic recovery of coronary flow, it had no beneficial effect on the recovery of LVDP. Pretreatment with nicorandil, however, increased susceptibility to reperfusion-induced arrhythmias.
Advantages and disadvantages of continuous low-flow cardioplegia
Continuous cardioplegia involves normothermic potassium arrest maintained by continuous perfusion of a warm (37° C) cardioplegic solution. This procedure avoids the possible side effects of hypothermia and minimizes the extent of high-energy phosphate depletion and calcium overload. As a consequence, continuous cardioplegia has been used in patients at high risk undergoing valvular operations or revascularization procedures. 8 On the negative side, occasionally a heart cannot remain arrested with warm cardioplegia and may fibrillate or beat, thereby reducing the protective value of the procedure. The danger of overloading the patient with potassium and the possible detrimental effects of high concentrations of potassium on the endothelium 9 preclude solving the problem by increasing the potassium concentration of the warm cardioplegic solution. When cardiac contractions resume, hypothermia and continuous infusion of cold cardioplegic solution may have to be used; 7 however, this is contrary to the fundamental principle of protection by warm cardioplegia and the protective effect may again be reduced. The present study has demonstrated that the problem might be solved through the inclusion of a potassium-channel opener such as nicorandil in the solution used for continuous cardioplegia. Our results indicate that this can accelerate the onset of cardiac arrest, limit the resumption of electrical activity, and improve the recovery of contractile function. However, the present study does not allow us to determine whether the beneficial effect of nicorandil on the recovery of contractility was because of an antiischemic effect, a reduction in electrical activity, or both.
The protective actions of nicorandil and potassium-channel openers during ischemia
Nicorandil exerts a variety of cardioprotective effects against injury in several experimental models of myocardial ischemia and reperfusion. 1-3 Evidence suggests that these effects may be a direct consequence of ATP-sensitive potassium-channel activation. 3,4 During the early moments of ischemia, potassium channels are thought to be activated as a consequence of various regulatory changes, including a decrease in tissue ATP levels and an increase in adenosine diphosphate levels. 10,11 It has been hypothesized that potassium-channel activation can increase K+ efflux or conductance and, as a consequence, produce a hyperpolarization from the resting membrane potential toward the equilibrium potential for K+. 10,11 This hyperpolarization is thought to close voltage-dependent Ca2+ channels (or prevent the opening of these channels on exposure to depolarizing stimuli) and, as a result, to inhibit cardiac contraction. 2,12 This inhibitory effect may, in turn, prevent loss of energy and thereby benefit the ischemic myocardium. 2 Factors, other than electrophysiologic effects, such as reduction of calcium release from the sarcoplasmic reticulum or decreased sensitivity of the contractile elements to calcium may also be involved. 13
The protective actions of nicorandil during continuous delivery of low-flow warm cardioplegic solution
The precise mechanism underlying the protective effect of nicorandil during continuous cardioplegia is not clear. It has been shown that the myocardium of hearts receiving continuous cardioplegia conserves tissue high-energy phosphates better than ischemic myocardium. 5,14 As a consequence, it may well be that ATP-sensitive potassium channels are less likely to be activated during low-flow ischemia. Under these conditions, nicorandil may activate potassium channels and thereby accelerate cardiac arrest by increasing the extracellular potassium concentration, thereby inducing hyperpolarization. A further consideration is that, in the present studies with continuous cardioplegia, the extracellular potassium concentration was only about 10 mmol/L. This concentration on its own may be inadequate to induce a degree of depolarization that would block myocardial contraction under conditions of normothermia and continuous perfusion. In such a situation, potassium-channel activation may increase potassium conductance and accelerate cardiac arrest. 15
The protective actions of nicorandil during low-flow ischemia
In the present study, a protective effect of nicorandil was also demonstrated in hearts subjected to low-flow perfusion (without cardioplegia). The infusion of nicorandil significantly depressed cardiac electrical activity during the first 10 minutes of ischemia and also improved the recovery of postischemic LVDP.
Nicorandil and the diastolic state
Our studies demonstrated that left ventricular compliance was better preserved by nicorandil in low-flow ischemia both with and without cardioplegia. This was evidenced by the fact that the balloon volume required to achieve an LVEDP of 4 mm Hg was significantly greater in the nicorandil-treated groups. However, when the same volume of water was introduced into the balloons of both groups, there was no significant difference in LVDP between nicorandil-treated and nicorandil-free groups (Qiu, Galiñanes, and Hearse, unpublished data). This observation may suggest that the protective effect of nicorandil is exerted mainly on diastolic function.
It is unclear why, after 15 minutes of low-flow ischemia, nicorandil did not continuously depress electrical activity. However, we could speculate that during the later period of ischemia, potassium-channel activation no longer plays an important role in maintaining cardiac arrest 16 and that stimulatory factors (such as the accumulation of intracellular calcium) may determine contractile status at this time.
Studies with nicorandil pretreatment before zero-flow ischemia
Pretreatment with nicorandil alone had no significant protective effect on postischemic LVDP or LVEDP, nor did it affect the time to onset of ischemic contracture. However, there was a statistically significant effect on the time to cardiac arrest and an improvement in the recovery of coronary flow was also recorded. It is possible that the higher prevalence of reperfusion-induced arrhythmias in the nicorandil group may have impaired the recovery of contractile function, thus masking any inherent protective effect of the drug on the recovery of LVDP. Another possible explanation for the failure of pretreatment to improve postischemic LVDP might relate to the dosage selected. In this connection, Grover, Sleph, and Parham, 17 using the isolated rat heart, reported that, although pretreatment with nicorandil at doses of 10 and 100 µmol/L did not improve the recovery of contractile function after 25 minutes of normothermic global ischemia, increasing the dose to 300 µmol/L resulted in a significant improvement. Another recently reported study with guinea pig papillary muscle preparations also indicated that pretreatment with nicorandil at a concentration of 1 mmol/L for 15 minutes, although it induced a significant negative inotropism, could enhance the recovery of contractile function after long-term hypoxia. 18 However, in the present study, we did not use doses of nicorandil higher than 100 µmol/L owing to the significant negative inotropic effect that would result from the use of such a dosage.
Drug dose and arrhythmogenesis
Several in vivo and in vitro studies have demonstrated that high doses of nicorandil can exert a negative inotropic effect and induce arrhythmias. 19,20 Thus Kojima and associates 19 reported that the intracoronary administration of large doses (1 mg or more, as a bolus infusion) of nicorandil suppressed myocardial contractility in areas of regional ischemia and precipitated ventricular arrhythmias (including VF) in dog hearts. However, they also reported that they had found a "safe dose" that effectively produced coronary vasodilation without deleterious mechanical or electrical effects. In the present study, nicorandil at a dose of 100 µmol/L given for 3 minutes before ischemia was shown to suppress LVDP significantly and when used at a dose of 10 µmol/L to increase significantly the susceptibility of the heart to reperfusion-induced arrhythmias including VF. These doses were within the concentration range required to accelerate the appearance of cardiac arrest and to improve the recovery of coronary flow. It appears therefore that, at least in the present model, the optimal dose range for nicorandil may be relatively narrow. Nevertheless, it should be noted that arrhythmogenic effects have been reported with other potassium-channel openers such as lemakalim. 21 Awareness of this property may be important when potassium-channel openers are used experimentally or clinically as cardioprotective agents. Furthermore, although the results of the present study revealed the beneficial effects of nicorandil as an additive to the solution used for continuous warm crystalloid cardioplegia, it is important that these findings be evaluated in in vivo preparations, especially with sanguineous cardioplegia.
Acknowledgments
We gratefully acknowledge the advice and discussion of Drs. M. J. Shattock and W. A. Coetzee.
References
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