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Ann Thorac Surg 2000;70:595-601
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Pharmacological preconditioning with the adenosine triphosphate–sensitive potassium channel opener pinacidil

^a Division of Cardiothoracic Surgery, University Hospital at Stony Brook and the State University of New York, Stony Brook, New York, USA
^b Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Address reprint requests to Dr Saltman, Division of Cardiothoracic Surgery, State University of New York at Stony Brook, T19, 080 Health Sciences Center, Stony Brook, NY 11794-8191
e-mail: saltman{at}surg.som.sunysb.edu

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Ischemic preconditioning (IPC) decreases infarct size after global or regional ischemia. Potassium channel openers also precondition but are subject to dose-limiting vasodilation. We compared the mechanical and electrophysiological effects of ischemic and pharmacological preconditioning in an isolated rabbit heart model.

Methods. Rabbit hearts were preconditioned with either 10 µmol/L pinacidil alone (P-), 10 µmol/L pinacidil with 10 µmol/L phenylephrine (P+), or two cycles of global ischemia and reperfusion (IPC) before 1 hour of LAD occlusion. Left ventricular pressure, epicardial monophasic action potential duration (APD) and coronary flow were monitored throughout. Infarct size was determined at the end of reperfusion.

Results. Regional ischemia uniformly decreased APD (p < 0.05). During reperfusion, APDs were prolonged beyond preischemic values in all preconditioned groups (p < 0.05). P- and P+ reduced the incidence of fibrillation. P- significantly increased coronary flow (+15%, p = 0.001), whereas IPC and P+ did not. However, IPC and P- significantly decreased systolic function (p < 0.05) but P+ did not. In addition, IPC depressed diastolic function (p < 0.05) but P- and P+ did not. Infarct size was reduced by all methods (p < 0.05).

Conclusions. Pinacidil presents a safe and effective alternative to IPC for preserving the heart during regional ischemia. Its coronary vasodilatory effects are safely and effectively reversed by the addition of phenylephrine.

	Introduction

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Short episodes of transient global or regional ischemia have been shown to protect the myocardium against future prolonged ischemia, a phenomenon termed ischemic preconditioning [1]. To date, several researchers have demonstrated ischemic preconditioning (IPC) in a variety of species. Although a number of different end points have been used to determine the effect of a preconditioning stimulus, the one most commonly used is infarct size, which is typically determined after a period of ischemia and reperfusion. Repeatedly, IPC has been shown to decrease infarct size after an ischemic insult. With regard to other measured parameters, some researchers have found that cardiac mechanics improve with IPC [2]. Changes in cardiac electrical function, however, are not as well described. Although it has long been known that the action potential shortens during short periods of ischemia [3], the effect of preconditioning on action potentials remains unknown.

Most work concerning preconditioning has used ischemia as the stimulus. The recent surge in interest in minimally invasive coronary revascularization (MIDCABG) has been driven by the desire to avoid mechanical cardiopulmonary bypass pumping and cardioplegic arrest with their attendant detrimental systemic physiological effects, even though myocardial protection is generally considered to be excellent with this strategy. The technique of MIDCABG, always performed on a warm beating heart, subjects the myocardium to unprotected ischemia during the period of coronary bypass grafting. Ischemic preconditioning has been successfully employed by some surgeons to help minimize ischemic damage from MIDCABG. As demonstrated in this report and elsewhere, however, there is a reduction in work performed by the heart and a derangement in cellular electrophysiology brought about by IPC.

As an alternative, pharmacological preconditioning may offer the beneficial effects of IPC without these detrimental consequences. To date, many drugs and intracellular pathways have been implicated in preconditioning, including adenosine [4, 5], protein kinase C [6], morphine [7], -adrenergic receptors [8], and ß-adrenergic receptors [9]. Recently, ATP-sensitive potassium channel openers (PCO) have been added to the list, as they have been shown to precondition and protect the heart against ischemic injury [10–13].

Potassium channel openers open the transmembrane outward-going potassium channel (I_K,ATP), which is normally activated only when either intracellular adenosine triphosphate (ATP) levels or the intracellular ratio of ATP/ADP drops below a critical level. When this channel is open, the outflow of potassium during the plateau phase of the action potential increases. In cardiac muscle, APD is shortened and developed pressure decreases. In smooth muscle there is a profound vasodilation. In fact, this latter property has led to the use of PCOs as antihypertensives. Unfortunately, possible hypotension would reduce the attractiveness of PCOs as preconditioning agents. This study was therefore undertaken both to determine the efficacy of the PCO pinacidil as a preconditioning agent and to determine the effect of adding the vasoconstricting drug phenylephrine to a PCO preconditioning regimen.

	Material and methods

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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. 85-23, revised 1985).

Adult male white New Zealand rabbits (2.75 to 3.25 kg) were anesthetized with sodium pentobarbital (30 mg/kg) and heparin (1000 IU) through ear vein. Their hearts were rapidly excised by means of a transverse thoracotomy and placed into a beaker of 4°C Krebs-Henseleit solution (Na⁺ 135 mmol/L, K⁺ 4.7 mmol/L, Ca⁺⁺ 1.7 mmol/L, PO₄^- 1.1 mmol/L, Mg 1.2 mmol/L, HCO₃^- 25 mmol/L, glucose 11.5 mmol/L, pyruvate 4.9 mmol/L, fumarate 5.4 mmol/L). The aorta was cannulated and the heart suspended on a Langendorff perfusion apparatus. The coronary arteries were perfused at 75 mm Hg pressure with oxygenated 37°C Krebs-Henseleit solution buffered with 95% O₂/5% CO₂.

Both atria were removed and the heart paced at 150 beats per minute (model 5880A, Medtronic, Minneapolis, MN) by means of two epicardial plunge electrodes placed in the interatrial septum. A balloon with an intraballoon pressure gauge (Millar Instruments Inc, Houston, TX) was placed in the left ventricle and secured with a ligature around the remnants of the left atrial appendage. The balloon was inflated with water until the end-diastolic pressure reached a steady-state value of approximately 10 mm Hg. The balloon volume was clamped at this point, and the balloon remained isovolumic throughout the remainder of the experiment. An 8Fr spring-loaded epicardial monophasic action potential (MAP) probe (EP Technologies, model 200, Sunnyvale, CA) was placed lightly against the left ventricle (LV) in the area supplied by the anterior descending coronary artery. The proximal anterior descending artery and the first obtuse marginal artery (referred to as "LAD") were then surrounded close to their bifurcation with a 3-0 silk suture and a Roummel tourniquet. The entire assembly was then immersed in a heated jacket (Radnoti Glass Technologies Inc, Monrovia, CA) that was filled by warm coronary effluent.

Measurements
After a 30-minute equilibration period, baseline data were obtained for 7.5 seconds. These data sets consisted of LV MAPs, LV pressure, and coronary flow, which was measured directly in a graduated cylinder. These measurements were repeated after each intervention and at 15-minute intervals throughout the experiment.

Experimental protocol
Table 1 displays the experimental protocol. Control hearts (n = 11) received no preconditioning, and underwent 1 hour of LAD occlusion followed by 1 hour of reperfusion. Ischemically preconditioned hearts (IPC, n = 7) underwent two cycles of global preconditioning consisting of 5 minutes of aortic inflow occlusion followed by 5 minutes of reperfusion with oxygenated Krebs solution. After the last cycle of IPC, the LAD was occluded for 1 hour and then reperfused for 1 hour. Pinacidil-preconditioned (P-, n = 11) hearts underwent a single infusion of 10 µmol/L pinacidil alone for 5 minutes followed by a 5-minute washout period, 1 hour of LAD ischemia, and reperfusion for 1 hour. Pinacidil + phenylephrine (P+, n = 5) hearts underwent a single infusion of 10 µmol/L pinacidil with 10 µmol/L phenylephrine for 5 minutes followed by a 5 minute washout period, 1 hour of LAD ischemia, and reperfusion for 1 hour. If the heart fibrillated at any time during the experiment, it was defibrillated with the strike of a fingernail.

Data analysis
Recordings taken from the balloon-tipped pressure gauge and the MAP probe were digitized by an 8-bit analog to digital converter at 1 kHz sample rate (model DT2809, Data Translation Inc, Marlborough, MA) and recorded to the hard disk of an IBM PC-compatible personal computer (model 450, Dell Corp, Austin, TX). The recordings were transferred to a digital spreadsheet (Microsoft Excel version 5.0. Microsoft Corp, Redmond, WA), where custom designed macro programs analyzed the pressure and MAP recordings to determine the systolic and diastolic pressure and action potential duration of each beat. Each recording lasted 7.5 seconds, which included approximately 18 beats. The pressures and action potential duration for each time period were expressed as the mean value taken over all the beats.

Statistical analysis was conducted with the Systat program version 5.02 (Systat, Inc, Evanston, IL). Comparisons among groups were made with multiple analysis of variance (ANOVA); significance was determined at the p less than 0.05 level using the Tukey post hoc test. Comparisons within each group were made similarly with multiple ANOVA after applying a Bonferroni correction. Categorical data were compared with ² analysis. All data are presented as mean plus or minus standard error (SEM).

	Results

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Electrophysiological effects of pinacidil
Figure 1A demonstrates the changes in action potential morphology that result from ischemia and reperfusion. During regional LAD ischemia the action potential duration (APD) shortens when compared to preischemic action potentials, whereas during reperfusion it returns to its preischemic configuration. The IPC itself did not significantly alter the action potential, as seen in Figure 1B. Regional LAD ischemia and reperfusion changed the action potential in IPC hearts in a manner similar to that seen in the control experiments. As seen in Figure 1C, pinacidil alone tended to decrease APD, but these hearts had no different reaction to ischemia than did control or IPC hearts. After 15 minutes of reperfusion, APD increased significantly in pinacidil-treated hearts. The addition of phenylephrine to pinacidil exhibited no significant changes in APD when compared with pinacidil alone.

View larger version (28K): [in this window] [in a new window]   Fig 1. (A) Monophasic action potentials for control experiments. Representative recordings taken from the left anterior descending artery–perfused epicardial zone are shown. The action potentials are normalized and superimposed at the point of greatest voltage. This heart had no pretreatment. Action potential duration shortened during regional ischemia (t = 60) and returned to baseline during reperfusion (t = 120). (B) Monophasic action potentials for ischemic preconditioning experiments as described in A. This heart was preconditioned with global ischemia. Action potential duration was not changed by preconditioning (t = 0), but was shortened during regional ischemia (t = 60) and then prolonged beyond baseline after reperfusion (t = 120). (C) Monophasic action potentials for pinacidil experiments as described in A. These data were taken from a heart preconditioned with pinacidil alone (P-). Preconditioning had no effect on action potential duration (t = 0), which shortened after regional ischemia (t = 60) and was prolonged beyond baseline after reperfusion (t = 120). Similar recordings were obtained from hearts preconditioned with pinacidil and phenylephrine.

View larger version (13K): [in this window] [in a new window]   Fig 2. Changes in time elapsed to 50% repolarization (APD50%) during the experiment. Time course of change in APD50 is shown, starting before pretreatment (t = -20 to 0) and ending after 60 minutes of reperfusion (t = 120). Regional ischemia began at t = 0 and reperfusion at t = 60. The APD shortened uniformly during regional ischemia and was prolonged beyond control values in all preconditioned groups. There were significant differences for each time point after t = 90. (IPC = ischemic preconditioning; Phen + Pinacidil = phenylephrin plus pinacidil.) (*p < 0.05 compared with control.)

With respect to ventricular fibrillation, seven hearts (7/11; p = NS) fibrillated in the control group: five during ischemia and two during reperfusion. A similar percentage (3/7, p = NS) fibrillated in the IPC group, all during ischemia. In contrast, significantly fewer hearts fibrillated in both the P- group (4 of 11, p = 0.06 vs control) and in the P+ group (2 of 5, p = 0.05 vs control), all during ischemia.

Mechanical effects of pinacidil preconditioning
Coronary flow
After the drug infusion period, pinacidil (P-) significantly increased coronary flow by 15% (62.0 ± 3.4 vs 71.0 ± 3.7 mL/s, p = 0.001). In P+ hearts, however, coronary flow increased by only 10% (66.8 ± 1.2 vs 73.2 ± 6.2 mL/s, p = 0.10). An increase in coronary flow was noted after IPC (58.3 ± 2.2 vs 62.6 ± 1.3 mL/s, p = 0.11). During the ischemia and reperfusion periods there were no differences in coronary flow among the four groups.

Systolic function
The changes in systolic function observed during the course of the experiment are detailed in Figure 3. The IPC significantly decreased end-systolic pressure (ESP) before LAD occlusion (123 ± 7 vs 82 ± 9 mm Hg, p < 0.05). P- hearts also had a decrease in ESP before LAD occlusion (118 ± 4 vs 112 ± 6 mm Hg, p < 0.05); however, the decrease in the IPC group was far greater than that in the P- hearts (42 ± 6 vs 6 ± 4 mm Hg, IPC vs pinacidil, p < 0.05). In P+ hearts, however, this preischemic decrease in ESP was abolished (119 ± 3 vs 120 ± 6 mm Hg, p = NS). Systolic function decreased in all groups during ischemia, without any significant differences (Fig 3). During reperfusion ESP did not fully recover in any group, again with no significant differences.

View larger version (13K): [in this window] [in a new window]   Fig 3. Changes in systolic function during the experiment. Changes in the peak pressure recorded from the left ventricular endocavitary balloon are shown; time course is as described in Figure 2. Ischemic preconditioning and P- depressed systolic function, whereas P+ did not. Beyond t = 0, there were no significant differences among groups. (IPC = ischemic preconditioning; P- = pinacidil alone; P+ = pinacidil with phenylephrine.) (*p < 0.05 compared with pretreatment values, t = -20.)

View larger version (12K): [in this window] [in a new window]   Fig 4. Changes in diastolic function during the experiment. The changes in the end-diastolic pressure recorded from the left ventricular endocavitary balloon are shown, with time course as described in Figure 2. Ischemic preconditioning significantly elevated end diastolic pressure at t = 0. Beyond t = 0 there were no significant differences among groups. (IPC = ischemic preconditioning; P- = pinacidil alone; P+ = pinacidil with phenylephrine.) (*p < 0.05 compared with pretreatment values, t = -20.)

Effect of preconditioning on infarct size
In control hearts, infarct size was 47% ± 3% of the area at risk (Fig 5). This was reduced to 29% ± 5% for IPC hearts (p < 0.05), 22% ± 4% for P- hearts (p < 0.05), and 27% ± 4% for P+ hearts (p < 0.05). There were no significant differences in area at risk among the four groups (p = NS).

View larger version (9K): [in this window] [in a new window]   Fig 5. Changes in infarct size, as determined by TTC staining of the left ventricular area at risk. Preconditioning of all types reduced infarct size. Comparisons are made with the control group. (Phe = phenylephrine.) (*p < 0.05 compared with control.)

	Comment

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Pharmacological preconditioning offers many advantages over ischemic preconditioning. Drugs can be infused in some cases directly into the bloodstream, which eliminates the problems of reaching the coronary arteries to induce transient ischemia or inflicting mechanical damage on them from local ischemic maneuvers. Drugs can be reversed or are metabolized away quickly. Their dosages can be precisely controlled and individualized.

There are two very important areas of clinical application for preconditioning. First, interest in minimally invasive direct coronary artery bypass grafting is increasing. Occluding a coronary artery to anastomose a graft in a bloodless field leaves the distal myocardium ischemic. Preconditioning may help to protect this region. As this study shows, pharmacological preconditioning provides superior protection when compared with that of IPC. Further investigation of IPC and pharmacological preconditioning in hearts in situ will be necessary.

A second important area of clinical application for preconditioning is to protect the arrested heart undergoing repair or revascularization. The currently popular myoprotective strategy of infusing cold potassium-rich crystalloid or sanguine cardioplegia still results in significant mechanical and electrical derangements. Many researchers have tried to add the beneficial effects of pharmacological preconditioning to potassium cardioplegia and have had mixed results. Kaukoranta and associates [15] found no beneficial effect of global ischemic preconditioning just before normothermic potassium-rich cardioplegia. Burns and colleagues [16] suggested that initiating cardiopulmonary bypass can alone cause enough stress to precondition the heart. Because of our previous results and the continued debate over the benefit of preconditioning in addition to conventional cardioplegia, we decided to use a regional ischemia model to mimic the situation that the heart sees while undergoing MIDCABG rather than global ischemia, which would be more useful in application of cardioplegia.

The preconditioning period
During the preconditioning phase, pinacidil protected the heart to an equal or better degree than did IPC. The IPC systolic and diastolic pressures were adversely affected. Although preconditioning was achieved by global ischemia, regional ischemia would also have reduced mechanical function in the ischemic zone, while possibly decreasing global function. The coronary flow was significantly increased by pinacidil, which is common with potassium channel openers. Phenylephrine was given in an attempt to reduce the vasodilatory effect of pinacidil. Although coronary flow was still increased in the presence of phenylephrine, this was less than that seen with pinacidil alone. Furthermore, phenylephrine eliminated the decrease in ESP associated with pinacidil infusion. It is logical to assume that coronary flow reflects systemic vasodilation, and therefore this must be controlled if a preconditioning strategy is to be useful without adverse systemic effects.

Cohen and associates [17] have recently used a combination of adenosine and norepinephrine to precondition in situ rabbit hearts against ischemic injury while maintaining systemic blood pressure. Because pinacidil and phenylephrine possess different pharmacokinetic properties than adenosine and norepinephrine, further in situ investigation is warranted to determine an optimal drug mix.

The ischemic and reperfusion period
There were no noticeable differences in mechanical or electrophysiological function among groups during the ischemic period. In fact, the protective effect of preconditioning appears to take place upon reperfusion, and mostly in the form of electrophysiological protection (as shown by an increase in APD₅₀). Although some groups have shown superior mechanical protection with IPC, this was not observed in our study. This may result from our use of a regional ischemia model. Although a large part of the ventricle was at risk, this region may not have been large enough to cause a significant difference in the global function that we measured.

The mechanism behind the observed increase in APD remains unclear. Although an increase in APD should provide protection against arrhythmias, there was no clear association between APD₅₀ and fibrillation. Recent work has pointed out that preconditioning may in fact depend upon the activation of mitochondrial rather than sarcolemmal K-ATP channels [18]. It is therefore not at all clear whether APD₅₀ prolongation reflects the preconditioned state of the myocyte or whether it simply provides protection against reperfusion arrhythmias. In this study, there was no clear association between APD₅₀ and fibrillation. In fact, the shortest APDs were seen during ischemia in the IPC group, which had very few incidents of fibrillation.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Adam E. Saltman Irvin B. Krukenkamp Sidney Levitsky Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saltman, A. E. Articles by Levitsky, S. Search for Related Content PubMed PubMed Citation Articles by Saltman, A. E. Articles by Levitsky, S.