is potassium channel opening an effective form of preconditioning before cardioplegia?

Is Potassium Channel Opening an Effective Form of Preconditioning Before Cardioplegia? Philippe Menasch6, MD, PhD, Christian Mouas, and Christian Grousset, MD, PhD Department of Cardiovascular Surgery and Institut National de la Sant6 et de la Recherche M6dicale U-127, H6pital Lariboisi6re, Paris, France

Background. Opening of adenosine triphosphate-sensitive potassium channels might be one of the mechanisms by which preconditioning preserves the myocardium against ischemic damage. The present study was therefore designed to compare the protective efficacy of ischemic preconditioning with that of pharmacologic preconditioning involving the use of a potassium channel opener in a surgically relevant model of cold cardioplegic arrest.

Methods. Thirty isolated isovolumic rat hearts were subjected to 2 hours of potassium arrest at an average myocardial temperature of 23°C, followed by 1 hour of reperfusion. Three groups (n = 10 per group) were studied: (1) control (no prearrest intervention); (2) ischemic preconditioning, achieved with 5 minutes of no- flow ischemia followed by 5 minutes of reperfusion before arrest; and (3) pharmacologic preconditioning, achieved with a 5-minute infusion of the potassium channel opener nicorandil (10 /~mol/L) followed by 5 minutes of drug-free perfusion before arrest. Standard functional indices were measured at multiple times dur-

ing reperfusion, at the end of which pressure-volume curves were constructed and compared with those ob- tained at baseline.

Results. Both ischemically and pharmacologically preconditioned hearts recovered systolic and diastolic function to a significantly greater extent than the controls. There was no difference in the recovery patterns between the forms of preconditioning. However, analysis of the postischemic pressure-volume curves demonstrated that nicorandil-preconditioned hearts incurred the smallest losses of compliance throughout the ischemia-reperfusion sequence.

Conclusions. The protective effects of a standard ischemic preconditioning challenge on functional recovery after an episode of moderately hypothermic cardioplegic arrest can be duplicated by pharmacologic opening of adenosine triphosphate-sensitive potassium channels. This finding may be of clinical relevance because of the availability of potassium channel openers, such as nicorandil, for human use.

(Ann Thorac Surg 1996;61:1764-8)

p reconditioning is an adaptive phenomenon by which a brief period of reversible ischemia renders the

heart more resistant to a subsequent period of more prolonged ischemia [11. This acquired resistance is primarily manifest as a reduction of infarct size after a coronary artery occlusion and can also encompass an improvement in the recovery of function after an episode of global myocardial ischemia [2]. The therapeutic exploitation of this adaptive phenomenon in cardiac operations is appealing because the possibility of planning the onset of aortic cross-clamping should allow timely, appropriate implementation of the preconditioning challenge. Al- though this challenge usually consists of a brief episode of reversible ischemia, several studies have now demonstrated that the cardioprotection afforded by ischemic preconditioning can be duplicated pharmacologically by a variety of compounds, which primarily include adenosine and adenosine A1 receptor agonists, activators of protein kinase C, and potassium channel openers [1]. The latter approach is of special interest because of the availability of potassium channel opening drugs for hu-

Accepted for publication Feb 8, 1996.

Address reprint requests to Dr Menasch6, Department of Cardiovascular Surgery, H6pital Lariboisi6re, 2, rue Ambroise Par6, 75010 Paris, France.

man use. In a previous study, we showed in a rat model of normothermic cardioplegic arrest that one of these drugs, nicorandil, completely mimicked the cardioprotective effects of ischemic preconditioning [31. The present experiments were designed to assess whether these effects remain operative under the more clinically relevant conditions of hypothermic cardioplegic arrest.

Material and Methods

Perfusion Technique Male Wistar rats weighing 300 g were anesthetized with an intraperitoneal injection of sodium pentobarbital (180 mg) and were given intravenous heparin (0.2 mL). All 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" published by the National Institutes of Health (NIH publication 85-23, revised 1985). The hearts were rapidly excised, mounted on a nonrecirculating Langendorff column, and perfused in a retrograde manner at a constant pressure of 100 cm H20. The perfusion medium consisted of a Krebs-Henseleit bicarbonate buffer solution, filtered (5 /~m), equilibrated with a 95% oxygen-5%

© 1996 by The Society of Thoracic Surgeons 0003-4975/96/$15.00 Published by Elsevier Science Inc PlI S0003-4975(96)00145-2

Ann Thorac Surg MENASCHI~ ET AL 1765 1996;61:1764-8 POTASSIUM CHANNELS AND PRECONDITIONING

Table 1. Effects of Ischemic and Nicorandil Preconditioning on Postischemic Coronary Flow and Left Ventricular Function ~

Coronary Flow Diastolic Pressure Developed Pressure dP/dt (rnL/min) (ram Hg) (mm Hg) (mm Hg/s) Group

(n = 10) Baseline Reperfusion Baseline Reperfusion Baseline Reperfusion Baseline Reperfusion

Control 15.3 _+ 0.6 12.5 _+ 0.3 8.6 -+ 0.5 38.4 _+ 1.6 141.5 _+ 2.1 82.0 _+ 1.7 5,055 _+ 160 2,961 ± 69 Ischemic preconditioning 15.7 ± 0.3 13.5 _~ 0.3 8.5 ± 0.6 24.2 ÷ 2.0 b 139.6 ± 2.2 104.5 ÷ 1.7 b 4,936 ± 185 3,661 + 86 b Nicorandil preconditioning 15.4 + 0.5 12.0 _+ 0.4 8.5 -+ 0.5 20.1 _+ 1.3 b 142.0 ± 1.3 98.7 _+ 2.8 b 5,264 ± 185 3,423 ± 120 c

Reperfusion values represen t the average of values collected at the various s tudy points dur ing the post ischemic period, b p < 0.0001 versus control. C p < 0.0003 versus control.

carbon dioxide mixture (pH 7.4), and mainta ined at 37°C in a heat exchange bath. A latex balloon on the tip of a polyethylene catheter was inserted into the left ventricle and connected to a Statham P23ID pressure t ransducer (Gould Inc, Cleveland, OH) interfaced to a 13-4615-71 differentiator (Gould). Left ventricular developed pressure (defined as the difference between peak systolic pressure and end-diastolic pressure) and the maximum positive rate of rise of left ventricular pressure (dP/dt) were displayed on a Schlumberger OM-4502 recorder (Enertec, St. Etienne, France). Coronary flow was measured by timed collection of the coronary venous effluent. All hearts were paced at a constant rate of 320 beats /min throughout the control and reperfusion periods.

Experimental Protocol

The hearts were allowed to equilibrate for 15 minutes. They were then subjected to 2 hours of cardioplegic arrest induced by a single dose of concentrated potassium chloride added directly to the Krebs buffer (to a final concentration of approximately 20 mEq/L). During the arrest period, the myocardial temperature was allowed to drift and the left ventricular balloon was kept deflated. After the ischemic interval, 1 hour of normothermic reperfusion was used by reinstating retrograde aortic flow.

The hearts were assigned to three groups (n = 10 per group) before potassium arrest. The first group consisted of control hearts that had no intervent ion dur ing the preischemic period. The second group consisted of hearts that were ischemically precondit ioned with 5 minutes of no-flow ischemia followed by 5 minutes of reperfusion with the Krebs buffer before the onset of cardioplegic arrest. In the third group, hearts were pharmacologically precondit ioned with a 5-minute infusion of the potassium channel opener nicorandil (10 /~mol/L) followed by 5 minutes of perfusion with drug-free buffer before arrest. Nicorandil was generously supplied by Rh6ne-Poulenc Rorer (Antony, France). It was dissolved in Krebs buffer immediately before use and was deliv- ered into the aortic retrograde perfusion circuit at a pressure of 100 c m H 2 0 via a separate column.

Baseline hemodynamic data were collected after the left ventricular balloon had been inflated with saline to produce an end-diastolic pressure of approximately 8 to 9 mm Hg. After 15 minutes of aerobic perfusion and before precondit ioning was applied in the two treated

groups, compliance curves were constructed by incre- mental ly increasing the volume of the balloon from 80 p,L to 120 ~,L by 10-/zL aliquots. After cardioplegic arrest, measurements were repeated at 15, 30, 45, and 60 minutes of reperfusion. At this last time point, compliance was assessed again by measur ing functional indices over the same range of balloon volumes as those used during the acquisition of baseline data.

Statistical Analysis

Statistical analysis was performed with two-way analysis of variance with repeated measures or Student 's t test, as appropriate. When analysis of variance yielded a significant F value, comparisons among the three study groups were performed with Scheff6's test. A difference was considered statistically significant at p less than 0.05. All values are expressed as mean + standard error of the mean.

Results

The mean preischemic values for all hemodynamic indices were similar in the three groups. Likewise, myocardial temperature during arrest fell to a similar degree in control hearts (22.8 ° _+ 0.2°C), ischemically precondi t ioned hearts (22.8 ° _+ 0.2°C), and nicorandi l - precondit ioned hearts (23.0 ° _+ 0.3°C).

The main results are summarized in Table 1. Except for postischemic coronary flows, which were not different among the three groups, all other indices recovered to a significantly greater extent in the two precondit ioned groups than in the control group. However, there were no differences in postischemic values for diastolic pressure or contractile indices between hearts precondi- t ioned with a s tandard ischemic challenge and those receiving nicorandil according to a similar protocol.

Analysis of the postischemic compliance curves dis- closed some additional differences in the recovery patterns among the three groups. Diastolic pressures, averaged over the entire range of balloon volumes, were 54.9 _+ 2.8, 44.2 _+ 2.9, and 34.5 _+ 2.0 mm Hg in control, ischemically preconditioned, and nicorandil-precondi- t ioned hearts, respectively. Analysis of variance demonstrated a significant (p < 0.003) treatment-related effect, which was further evident upon comparing diastolic pressures among the three groups of hearts at each balloon volume. As shown in Table 2, it was then found

1766 MENASCHI~ ET AL Ann Thorac Surg POTASSIUM CHANNELS AND PRECONDITIONING 1996;61:1764-8

Table 2. Effects of Ischemic and Nicorandil Preconditioning on Postischemic Pressure-Volume Relationships

Diastolic Pressure (ram Hg) at a Left Ventricular Developed Pressure (mm Hg) at Balloon Volume 0zL) of: a Balloon Volume (~L) of:

Group (n = 10) 80 90 100 110 120 80 90 100 110 120

Control 33.5-+ 2.0 44.3_+ 3.0 55.4 ± 4.9 66.0-+ 5.5 75.6 _+ 5.8 80.6 ± 3.2 77.6_+ 2.5 75.6 ± 2.5 71.6_+ 2.9 68.1 _+ 3.3 Ischemic 21.9 ± 3.5 ~ 33.6 _+ 3.8 44.0 ± 4.6 55.3 ± 5.4 66.1 _+ 6.1 101.5 ~ 3.8 b 97.5 ± 2.2 b 94.2 ± 2.6 b 92.9 ± 3.0 b 88.6 -+ 3.3 b

preconditioning Nicorandil 18.5 _+ 1.6 c 26.1 _+ 2.1 b 34.3 + 2.6 b 42.5 ± 3.4 b 51.1 + 4.0 a 97.4 z 4.6 a 98.4 + 5.3 b 98.4 _+ 5.4 c 94.4 ± 5.5 b 91.4 _+ 5.0 b

preconditioning

a p < 0.05 versus control, b p < 0.01 versus control, c p < 0.001 versus control.

that increasing this volume beyond 80 /~L y ie lded diastolic pressures that were not different be tween control hear ts and ischemically precondi t ioned hearts, whereas they were significantly lower in n icorandi l -precondi- t ioned hear ts compared with their control counterparts . The recovery of contractil i ty featured slightly different patterns. When averaged over the five s tudy points, deve loped pressures were 74.7 _+ 1.4, 94.9 _+ 1.4, and 96.0 -+ 2.2 m m Hg in unt rea ted hearts, hearts p recondi t ioned with no-flow ischemia, and hearts receiving nicorandil , respectively. Again, analysis of variance indicated a significant (p < 0.0002) t rea tment - re la ted effect. However, further comparisons demons t ra ted that, in contrast to the observat ions made for diastolic function, post ischemic deve loped pressures were, at each bal loon volume, significantly higher in the two precondi t ioned groups than in the control group. The recovery of dP/d t grossly paral le led that of deve loped pressure except for bal loon volumes of 90 and 120/~L, for which nicorandi l -precon- d i t ioned hear ts still demons t ra ted significantly higher dP/d t values than controls (p < 0.01), whereas the difference be tween ischemically precondi t ioned hearts and these controls failed to achieve statistical significance.

Nicorandil precondi t ioning did not result in ventr icular arrhythmias , ei ther dur ing the per iod of drug-free perfusion that p receded cardioplegic arrest or subsequent ly dur ing postcardioplegia reperfusion.

C o m m e n t

Preconditioning in Cardiac Operations Several animal models of regional ischemia have now demons t ra ted the abil i ty of ischemic precondi t ioning to reduce significantly myocardia l infarct size. Other s tud- ies involving the use of cardioplegical ly arres ted rat [4, 5] and rabbit [6] hearts have also repor ted an improvemen t of functional recovery when the susta ined per iod of global ischemia was p receded by a precondi t ioning challenge. These observat ions have raised the possibi l i ty that precondi t ioning could enhance the efficacy of myocardia l preservat ion techniques current ly used dur ing open hear t operat ions. This hypothesis has been tested suc- cessfully by Alkhulaifi and co-workers [7], who have found h igher myocard ia l t issue levels of adenos ine t r iphosphate (ATP) in pat ients undergoing bypass operations and subjected to a precondi t ioning regimen (con- sisting of two cycles of 3 minutes of aortic cross-c lamping

and 2 minutes of reperfusion) before a 10-minute per iod of normothermic ventr icular fibrillation.

However, the relevance of precondi t ioning to cardiac operat ions should be examined cautiously in light of the following two caveats: (1) There is a general agreement that the improvemen t of functional recovery repor ted in precondi t ioned hear ts subjected to an episode of global ischemia is pr imar i ly due to a reduct ion in the amount of necrotic tissue, not to an alleviation of s tunning incurred by sti l l-viable myocard ium [2]; and (2) the key mechanism by which precondi t ioning exerts its cardioprotective effects seems to be a slowing of the rate of ATP deplet ion during the susta ined ischemic interval [81. This may account for the benefits of precondi t ioning when used in conjunction with a method that may not fully prevent a decay in tissue h igh-energy phospha te stores, such as the ventr icular fibrillation technique used by Aikhulaifi and co-workers [7]. Conversely, the ATP- spar ing effects of precondi t ioning may become redun- dant with those of cardioplegia [9]. Indeed, the two si tuations in which precondi t ioning has been shown to confer addit ive protect ion to that p rovided by cardioplegia are long ischemic t imes [4] and proximal coronary artery occlusions leading to a maldis t r ibut ion of ante- gradely del ivered cardioplegic solutions [10]. In these two situations, the subopt imal protect ion y ie lded by cardioplegia is likely to result in some degree of tissue necrosis, which would then account for the abil i ty of p recond i t i on ing to improve funct ional p re se rva t ion through its previously ment ioned infarct- l imit ing effects. These considerat ions do not in tend to negate the poten- tial role of precondi t ioning in cardiac operat ions. We only emphas ize that, ins tead of t rying to duplicate the s t anda rd p recond i t i on ing sequence (brief i schemia / reperfus ion/ long ischemia), it might be more effective to identify the pharmacologic mediators of this endogenous adapt ive mechanism and to use them as anti ischemic agents. It is in this context that we became interested in the assessment of po tass ium channel openers.

Role of Potassium Channel Openers The role of ATP-dependen t potass ium channels as mediators of precondi t ioning has been der ived pr imar i ly from the exper imenta l observat ions (made in dogs, pigs, and rabbits) that the protective effects of precondi t ioning can be dupl ica ted by potass ium channel openers, whereas they are abol i shed by drugs that block potas-

Ann Thorac Surg MENASCHE ET AL 1767 1996;61:1764-8 POTASSIUM CHANNELS AND PRECONDITIONING

slum channels [11]. The mechanism that has been postulated is that hyperpolarization of the cell membrane secondary to the opening of potassium channels is ex- pected to reduce the inward calcium current and, conse- quently, to spare high-energy phosphate levels during the subsequent period of sustained ischemia. The mechanism by which the preconditioning ischemia could open potassium channels is not fully elucidated, but might involve an activation of adenosine receptors, the adenosine-mediated translocation of protein kinase C from the cytosol to the membrane, and the protein kinase C-induced phosphorylation of the proteins making up these channels [12, 13]. However, there is accumulating evidence that adenosine is not the mediator of preconditioning in rat heart [14], and an alternate possibility is that, in this species, potassium channels are activated by lipoxygenase metabolites [15] released after the preconditioning stimulus has caused an activation of phospho- lipase A2 mediated by G proteins or protein kinase C [16]. This hypothesis is consistent with the observation that, in rat hearts, the cardioprotective effects of preconditioning are triggered by stimulation of ~l-adrenergic receptors, which, in turn, can activate G proteins and, subsequently, protein kinase C [17].

The previous considerations may explain why, despite the controversy regarding the relevance of the potassium channel hypothesis to rodents [11], several studies have indeed documented an improved recovery of function of rat hearts treated with potassium channel openers given before or during a sustained episode of global ischemia, with [18-22] or without cardioplegia [23]. In a previous series of experiments, we showed that ischemic and nicorandil preconditioning provided the same degree of myocardial protection after a 45-minute period of normothermic potassium arrest, and that this protection was abolished when the preconditioning challenge was pre- ceded by the administration of a potassium channel blocker [3]. The present study extends these previous observations to the more clinically relevant setting of mildly hypothermic cardioplegic arrest. Again, nicorandil preconditioning was found to achieve the same degree of protection as ischemic preconditioning. Drug- treated hearts even demonstrated a slightly better recovery in that they were able to generate similar indices of contractility at the expense of consistently lower left ventricular filling pressures. This finding is consistent with the postulated link between opening of potassium channels and a reduction of calcium overload and the attendant contracture. Although we acknowledge that, by virtue of its design, the present study did not establish direct evidence for a nicorandil-induced opening of these channels, such a mechanism can be reasonably postulated from the following: (1) the well- documented pharmacologic properties of nicorandil; (2) our previous findings [3] that, under experimental conditions similar to those of the present study (except for temperature), the cardioprotective effects of nicorandil were abolished by a pharmacologic blockade of potassium channels; and (3) the present finding that nicorandil preconditioning did not yield higher postischemic coro-

nary flows than the two other treatments, thereby making it unlikely that the drug exerted protection through its vasodilatory properties.

A puzzling observation is that despite the 5-minute period of drug-free perfusion between the end of nicorandil administration and the onset of cardioplegia, nicorandil exerted a sustained protection that extended throughout the 2-hour period of potassium arrest. The mechanism by which cells can keep the "memory" of their exposure to nicorandil (or related drugs) is yet unknown, but might involve maintenance of channel opening or a decrease in the threshold for channel activation during the protracted period of ischemia [12, 24]. This hypothesis is supported by the observation that both ischemic preconditioning and preconditioning with the potassium channel opener aprikalim increase the interstitial concentration of potassium ions during the sustained ischemic interval that follows the preconditioning challenge [23]. In addition, one cannot exclude an effect of potassium channel openers on the mitochondrial inner membrane channels [25]. It remains, however, to be determined how activation of these channels may affect mitochondrial calcium concentrations; this issue is important because a reduced release of calcium from intra- cellular stores is thought to be at least one of the molecular mechanisms of the protection provided by ischemic preconditioning [26].

Limitations and Implications of the Study The results presented in this study cannot be readily extrapolated to the clinical setting because of the various methodologic limitations inherent in the experimental design, including the use of an isolated heart prepara- tion, the nonhemic nature of the perfusate, and the maintenance of only mild hypothermia during arrest. Furthermore, measurements of tissue necrosis were not performed, so that it is not possible to determine by which precise mechanism (ie, reduction in infarct size or reduction in stunning of nonnecrotic myocardium) preconditioning was operative under our experimental conditions. Finally, in line with our previous findings that a pharmacologic blockade of potassium channels completely abolishes the cardioprotective effects of nicorandil, but only partially those of ischemic preconditioning [3], we acknowledge that, at least in rat hearts, the preconditioning-induced preservation of high-energy phosphates is probably not entirely due to potassium channel activation but may involve other mechanisms, such as the inhibition of mitochondrial ATPase [27]. Nevertheless, the clinical applicability of the potassium channel hypothesis is suggested by the observation that patients undergoing coronary angioplasty procedures lose their ability to acquire a progressive tolerance to ischemia during successive balloon inflations when their potassium channels are pharmacologically blocked [28]. Likewise, recent data show that the efficacy of a brief hypoxic episode in preconditioning human atrial trabec- ulae can be duplicated by the potassium channel opener cromakalim, whereas the cardioprotective effects of these two forms of preconditioning are lost when potassium

1768 MENASCHE ET AL Ann Thorac Surg POTASSIUM CHANNELS AND PRECONDITIONING 1996;61:1764-8

channels are blocked by glibenclamide [29]. Thus, should the present data be confirmed by large animal model studies, they could bear some relevance to the practice of open heart operations in two ways. First, nicorandil is now approved for human use, and it might then find a place in the a rmamenta r ium of myocardial preservation techniques. Although the dose-dependent proarrhyth- mic effects of nicorandil (and related drugs) cannot be ignored, these effects do not seem to be a relevant issue under conditions of global ischemia with cardioplegic arrest, possibly because the occurrence of arrhythmias is somewhat prevented by the cardioplegically induced limitation of ischemic injury and its rather homogeneous spatial distribution throughout the globally cross-clamped heart. Second, these results more generally illustrate the benefits of therapeutically exploiting the endogenous mechanisms that allow the heart to ensure its own defense when it has to withstand an ischemic injury. However, because it is intuitively safer and more conve- nient to use pharmacologic rather than ischemic precondit ioning stimuli, it is critically important to identify clearly the chemical mediators of this adaptative phenomenon. In this setting, the two major classes of compounds that are now emerging as key mediators are agents that increase local concentrat ions of endog- enously released adenosine (such as adenosine-regu- lating agents or nucleoside transport inhibitors) and, as shown by the data reported herein, potassium channel openers.

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is potassium channel opening an effective form of preconditioning before cardioplegia?

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