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Am J Physiol Heart Circ Physiol 279: H2694-H2703, 2000;
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Vol. 279, Issue 6, H2694-H2703, December 2000

Differential role of sarcolemmal and mitochondrial KATP channels in adenosine-enhanced ischemic preconditioning

Yoshiya Toyoda, Ingeborg Friehs, Robert A. Parker, Sidney Levitsky, and James D. McCully

Division of Cardiothoracic Surgery and Biometrics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing postischemic functional recovery. The purpose of this study was to determine whether APC is modulated by ATP-sensitive potassium (KATP) channels and to determine whether this modulation occurs before ischemia or during reperfusion. The role of KATP channels before ischemia (I), during reperfusion (R), or during ischemia and reperfusion (IR) was investigated using the nonspecific KATP blocker glibenclamide (Glb), the mitochondrial (mito) KATP channel blocker 5-hydroxydecanoate (5-HD), and the sarcolemmal (sarc) KATP channel blocker HMR-1883 (HMR). Infarct size was significantly increased (P < 0.05) in APC hearts with Glb-I, Glb-R, and 5-HD-I treatment and partially with 5-HD-R. Glb-I and Glb-R treatment significantly decreased APC functional recovery (P < 0.05 vs. APC), whereas 5-HD-I and 5-HD-R had no effect on APC functional recovery. HMR-IR significantly decreased postischemic functional recovery (P < 0.05 vs. APC) but had no effect on infarct size. These data indicate that APC infarct size reduction is modulated by mitoKATP channels primarily during ischemia and suggest that functional recovery is modulated by sarcKATP channels during ischemia and reperfusion.

stunning; myocardial protection; ATP-sensitive potassium channels


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

WE REPORTED PREVIOUSLY (24-27, 38) that adenosine-enhanced ischemic preconditioning (APC), in which a bolus injection of adenosine is used coincident with single-cycle ischemic preconditioning (IPC), extends and amends the cardioprotection afforded by IPC by both significantly decreasing myocardial infarct size (P < 0.05 vs. IPC) and significantly enhancing postischemic functional recovery (P < 0.05 vs. IPC) in both the isolated, perfused rabbit heart and in the in situ blood-perfused sheep heart. Recently, we showed (25) that APC-enhanced infarct size reduction is primarily modulated by adenosine receptors before ischemia, whereas APC-enhanced postischemic functional recovery is modulated by adenosine receptors both before ischemia and during reperfusion.

The downstream effector of adenosine receptor activation was shown previously to be ATP-sensitive potassium (KATP) channels that have been suggested to play a central role in IPC (4, 31, 32, 39). Two KATP channel subtypes exist in the myocardium, with one subtype located in the sarcolemma (sarcKATP) and the other in the inner membrane of the mitochondria (mitoKATP) (21). SarcKATP channels are inhibited by glibenclamide and selectively inhibited by HMR-1883 (2, 3, 11, 13), whereas mitoKATP channels are inhibited by glibenclamide and specifically inhibited by 5-hydroxydecanoate (33). The involvement of KATP channels in APC cardioprotection and the relevance and specificity of these channels during ischemia and reperfusion were unknown. The purpose of this study was to determine whether the cardioprotection afforded by APC was modulated by KATP channels, to determine whether this modulation occurred before ischemia or during reperfusion, and to determine the specificity of KATP channel modulation on APC cardioprotection during ischemia and reperfusion.

Our results indicate that the cardioprotection afforded by APC is modulated by KATP channels. APC myocardial infarct size reduction is completely abolished by mitoKATP channel blockade before ischemia. APC-enhanced postischemic functional recovery is not affected by mitoKATP channel blockade before ischemia and/or during reperfusion. Blockade of sarcKATP channels both before ischemia and during reperfusion significantly decreased APC-enhanced postischemic functional recovery [P < 0.05 vs APC; not significant (NS) vs. global ischemia]. These data suggest that infarct size is modulated by mitoKATP channels primarily during ischemia, whereas postischemic functional recovery is modulated by sarcKATP channels both during ischemia and reperfusion.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals and chemicals. New Zealand White rabbits (n = 95; 15-20 wk, 3-4 kg) were obtained from Millbrook Farm (Amherst, MA). All animals were housed individually and provided with laboratory chow and water ad libitum. All experiments were approved by the Beth Israel Deaconess Medical Center Animal Care and Use Committee and the Harvard Medical Area Standing Committee on Animals (Institutional Animal Care and Use Committee) and conformed to the National Institutes of Health guidelines regulating the care and use of laboratory animals (NIH publication 5377-3, 1996).

Langendorff perfusion. All rabbits were anesthetized with ketamine (33 mg/kg) and xylazine (16 mg/kg) and received heparin (200 U/kg) intravenously via a marginal ear vein (28, 40). The heart was excised and placed in a 4°C bath of Krebs-Ringer solution equilibrated with 95% O2-5% CO2 (pH 7.4 at 37°C), in which spontaneous beating ceased within a few seconds (26, 27). Langendorff retrograde perfusion was performed as previously described (26, 27). In brief, a latex balloon containing a catheter-tip transducer (Millar Instruments, Houston, TX) was inserted into the left ventricle and held in place by a purse-string suture. The volume of the water-filled balloon was maintained at a constant physiological end-diastolic pressure in the range of 5-10 mmHg using a calibrated microsyringe. The aorta was cannulated with a metal cannula, and the heart was subjected to Langendorff retrograde perfusion at a constant pressure of 75 cmH2O at 37°C. Hearts were paced via the right atrium at 180 ± 3 beats/min throughout the experiment using a Medtronic model 5330 stimulator (Medtronic, Minneapolis, MN). Hemodynamic variables were acquired using the PO-NE-MAH digital data acquisition system (Gould, Valley View, OH) with an Acquire Plus processor board and left ventricular pressure analysis software.

Experimental protocol. Hearts were perfused for 18 min to establish equilibrium hemodynamics. Equilibrium was ended when heart rate, coronary flow, and left ventricular peak developed pressure (LVPDP) and end-diastolic pressure (LVEDP) had been maintained at the same level for three continuous measurement periods timed 5 min apart. Control hearts (n = 8) were perfused without global ischemia at 37°C for 180 min. Global ischemia hearts (GI; n = 8) were subjected to 30-min global ischemia and 120-min reperfusion. Global ischemia was achieved by cross-clamping the perfusion line. APC hearts (n = 8) received a 10-ml bolus injection of 1 mM adenosine in Krebs buffer (Adenoscan; Medco, Research Triangle Park, NC) coincident with IPC (5-min zero-flow global ischemia followed by 5-min reperfusion). The bolus was injected into the aortic root via the sidearm of a cannula located proximal to the perfusion cannula.

Effect of KATP channel blockers on functional recovery. To distinguish the effect of glibenclamide, 5-hydroxydecanoate, and HMR-1883 on APC cardioprotection from the persistent drug effect of glibenclamide, 5-hydroxydecanoate, and HMR-1883, control hearts were perfused separately with glibenclamide, 5-hydroxydecanoate, HMR-1883, or both 5-hydroxydecanoate and HMR-1883. Blockers were perfused for 7 min before global ischemia (from 18-20 min of perfusion to 25-30 min of perfusion) and for 2 min at the onset of reperfusion (R; 60-62 min of perfusion) (control+Glb/Glb-R, n = 3; control+5-HD/5-HD-R, n = 3; control+HMR/HMR-R, n = 3). In 5-HD-HMR/HMR-R hearts (n = 3), 5-hydroxydecanoate and HMR-1883 were perfused for 7 min before global ischemia and HMR-1883 was perfused for 2 min at the onset of reperfusion.

Role of KATP channels in APC cardioprotection during ischemia and reperfusion. To determine the role of KATP channels in APC cardioprotection during ischemia and reperfusion, APC hearts were perfused separately with the nonselective KATP channel blocker glibenclamide (18 µM in Krebs-Ringer solution; Sigma Chemical, St. Louis, MO) for 2 min before APC and during the 5-min reperfusion before global ischemia (Glb; n = 6) or for 2 min at the onset of reperfusion (Glb-R; n = 5). The concentration of glibenclamide was determined based on preliminary investigations using serial glibenclamide concentrations based on the data of Hoag et al. (17). A separate group of APC hearts were perfused with glibenclamide for 2 min before APC and during the 5-min reperfusion before global ischemia and for 2 min at the onset of reperfusion (Glb/Glb-R; n = 6).

Role of specific KATP channels in APC cardioprotection during ischemia and reperfusion. To determine the role of mitoKATP channels in APC cardioprotection during ischemia and reperfusion, APC hearts were perfused separately with the rabbit heart selective mitoKATP channel blocker 5-hydroxydecanoate (200 µM, in Krebs-Ringer solution; Research Biochemicals, Natick, MA) for 2 min before APC and during the 5-min reperfusion before global ischemia (APC+5-HD; n = 6) or for 2 min at the onset of reperfusion (APC+5-HD-R; n = 6) (21). A separate group of APC hearts were perfused with 5-hydroxydecanoate (200 µM in Krebs-Ringer solution) for 2 min before APC and during the 5-min reperfusion before global ischemia and for 2 min at the onset of reperfusion (APC+5-HD/5-HD-R; n = 6).

To determine the role of sarcKATP channels in APC cardioprotection during ischemia and reperfusion, APC hearts were perfused separately with the selective sarcKATP channel blocker HMR-1883 (50 µM in Krebs-Ringer solution; the kind gift of H. C. Englert, Hoechst-Marion-Roussel, Frankfurt, Germany) for 2 min before APC and during the 5-min reperfusion before global ischemia (APC+HMR; n = 6) or for 2 min at the onset of reperfusion (APC+HMR-R; n = 6) (2, 3, 11, 13). A separate group of APC hearts was perfused with HMR-1883 (50 µM, in Krebs-Ringer solution) for 2 min before APC and during the 5-min reperfusion before global ischemia and for 2 min at the onset of reperfusion (APC + HMR/HMR-R; n = 6). A final group of APC hearts was perfused with 5-hydroxydecanoate (200 µM, in Krebs-Ringer solution) and HMR-1883 (50 µM, in Krebs-Ringer solution) for 2 min before APC and during the 5 min after APC, before global ischemia, and with HMR-1883 (50 µM, in Krebs-Ringer solution) for 2 min at the onset of reperfusion (APC+5-HD-HMR/HMR-R; n = 6).

Measurement of infarct size. Infarct size was determined as previously described using 1% triphenyltetrazolium chloride (Sigma Chemical) in phosphate buffer (pH 7.4) (18, 24, 26, 41). Left ventricle area and the area of infarcted tissue were measured by an independent, blinded observer using computer planimetry as previously described (24-27, 37, 38).

Wet weight-to-dry weight ratios. Left ventricular tissue samples (~0.1 g) from all experimental groups were weighed (wet weight), dried at 80°C for 24 h for reweighing (dry weight), and then used for the determination of wet-to-dry weight ratios using previously described methods (26, 27).

Statistical analysis. Statistical analysis was performed using SAS (version 6.12; SAS Institute, Cary, NC). Means ± SE are reported in Tables 1-4 and in text. Statistical significance was assessed using repeated-measures analysis of variance with group as a between-subjects factor and time as a within-subjects factor. If this overall test was significant, one-way analysis of variance was performed at individual time points, and, when significant, post hoc comparisons were made between groups at a time point. Dunnett's test was used for comparisons between APC and other groups, because the primary focus was determination of which of the KATP treatments were different from APC. Dunnett's test adjusts for the number of tests being performed but does not adjust for comparisons across all groups. Bonferroni correction was used for comparisons between groups other than APC. One-way analysis of variance was used for area of infarction. P < 0.05 was used for statistical significance.

                              
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  		Table 1.   Functional data for control hearts perfused with KATP channel blockers


                              
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  		Table 2.   Functional data for control, global ischemia, and APC hearts and Glb-perfused APC hearts


                              
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  		Table 3.   Functional data for APC hearts perfused with 5-HD


                              
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  		Table 4.   Functional data for APC hearts perfused with HMR-1883


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of KATP channel blockers on functional recovery. The results shown in Table 1 indicate that LVPDP and the positive first derivative of pressure over time (+dP/dt) were significantly decreased and LVEDP was significantly increased in control+Glb/Glb-R, control+5-HD/5-HD-R, control+HMR/HMR-R, and control+5-HD-HMR/HMR-R hearts (P < 0.05 vs. control and APC) at 20 min of perfusion and at 30 min of perfusion (after perfusion of KATP channel blockers). No significant difference in LVPDP, LVEDP, +dP/dt, or coronary flow was observed within or between groups during 120-min reperfusion (NS vs. control and APC, Table 1).

Infarct size was 2.5 ± 0.5% in control+Glb/Glb-R, 2.2 ± 0.5% in control+5-HD/5-HD-R, 1.7 ± 0.2% in control+HMR/HMR-R, and 1.4 ± 0.3% in control+5-HD-HMR/HMR-R hearts. No significant difference in infarct size was observed within or between groups, and there was no significant difference between groups compared with control.

Equilibrium hemodynamics. No significant difference in LVPDP, +dP/dt, or coronary flow was observed within or between groups at the end of equilibrium (18 min of perfusion) (Tables 2-4).

Role of KATP channels in APC cardioprotection during ischemia and reperfusion. LVPDP and +dP/dt were significantly decreased in APC+Glb hearts (P < 0.05 vs. APC and APC+Glb-R) at 20 min of perfusion (after 2-min perfusion of glibenclamide before APC; Table 2). After APC (30 min of perfusion), LVPDP and +dP/dt were significantly decreased in APC+Glb hearts (P < 0.05 vs. APC and APC+Glb-R). No significant difference in coronary flow was observed within or between groups at 30 min of perfusion, just before global ischemia.

LVPDP, +dP/dt, and coronary flow were significantly decreased in GI hearts (P < 0.05 vs. APC) during reperfusion (70-180 min of perfusion). LVPDP and +dP/dt were significantly decreased in APC+Glb hearts (P < 0.05 vs. APC) throughout reperfusion (70-180 min of perfusion). Coronary flow was significantly decreased in APC+Glb hearts (P < 0.05 vs. APC) at 70-90 min of perfusion. In APC+Glb-R hearts, LVPDP was significantly decreased (P < 0.05 vs. APC) at 70-80 min of perfusion but was not significantly different from that observed in APC at 90-180 min of perfusion. LVPDP and +dP/dt were significantly decreased in APC+Glb/Glb-R hearts (P < 0.05 vs. APC) throughout reperfusion (70-180 min of perfusion). No significant difference was observed between control and APC hearts.

Infarct size expressed as a percentage of ventricular volume was significantly increased to 32.9 ± 5.1% in GI hearts (P < 0.05 vs. control and APC) compared with 1.0 ± 0.3% in control hearts and 2.8 ± 0.5% in APC hearts after 30 min of normothermic global ischemia and 120 min of reperfusion (Fig. 1). Infarct size was significantly increased to 22.4 ± 4.3% in APC+Glb hearts and 28.8 ± 1.1% in APC+Glb/Glb-R hearts (P < 0.05 vs. control, APC, and APC+Glb-R; NS vs. GI). Infarct size was 14.0 ± 1.5% in APC+Glb-R hearts (P < 0.05 vs. APC+Glb, APC+Glb/Glb-R, APC, and GI). Wet weight-to-dry weight ratios after 180 min of perfusion were 5.02 ± 0.57 in APC+Glb hearts, 5.46 ± 0.86 in APC+Glb-R hearts, 7.43 ± 0.17 in APC+Glb/Glb-R hearts, 7.02 ± 0.66 in GI hearts, 6.24 ± 0.72 in control hearts, and 5.86 ± 0.68 in APC hearts. There was no significant difference in wet weight-to-dry weight ratios between groups.


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  		Fig. 1.   Infarct size expressed as a percentage of ventricular volume after 30 min of global ischemia and 120 min of reperfusion in control, global ischemia (GI), and adenosine-enhanced ischemic preconditioning (APC) hearts and APC hearts perfused with the nonselective ATP-sensitive potassium (KATP) channel blocker glibenclamide for 2 min before APC and during the 5 min of reperfusion before global ischemia (APC+Glb), for 2 min at the onset of reperfusion (APC+Glb-R), or during both periods (APC+Glb/Glb-R). Results are shown as means ± SE; n = 5-8 for each group. *Significant differences at P < 0.05 vs. APC hearts; **significant differences at P < 0.05 vs. GI hearts. There was no significant difference in infarct size between APC and control hearts.

Role of mitoKATP channels in APC cardioprotection during ischemia and reperfusion. LVPDP and +dP/dt were significantly decreased in APC+5-HD and APC+5-HD/5-HD-R hearts (P < 0.05 vs. APC) at 20 min of perfusion (Table 3). After APC (30 min of perfusion), LVPDP was significantly decreased in APC+5-HD and APC+5-HD/5-HD-R hearts (P < 0.05 vs. APC), and LVEDP was significantly increased in APC+5-HD and APC+5-HD/5-HD-R hearts (P < 0.05 vs. APC and APC+5-HD-R). +dP/dt was significantly decreased in APC+5-HD/5-HD-R hearts (P < 0.05 vs. APC) at 30 min of perfusion just before global ischemia. LVPDP and +dP/dt were significantly decreased (P < 0.05 vs. APC) in APC+5-HD hearts at the start of reperfusion (70 min of perfusion), but by 20 min of reperfusion (80 min of perfusion), no significant difference was observed compared with APC hearts. LVPDP and +dP/dt were significantly decreased (P < 0.05 vs APC) in APC+5-HD-R hearts at the start of reperfusion (70-80 min of perfusion), but by 30 min of reperfusion (90 min of perfusion), no significant difference was observed compared with APC hearts. LVPDP was significantly decreased in APC+5-HD/5-HD-R hearts at the start of reperfusion (70-80 min of perfusion) and at the end of reperfusion (180 min of perfusion). +dP/dt was significantly decreased in APC+5-HD/5-HD-R hearts throughout 120 min of reperfusion (70-180 min of perfusion). There was no significant difference in LVEDP and coronary flow within or between groups during reperfusion (70-180 min of perfusion).

Infarct size, expressed as a percentage of ventricular volume, was significantly increased to 23.7 ± 1.9% in APC+5-HD hearts (P < 0.05 vs. APC and APC+5-HD-R, NS vs. GI; Fig. 2). Infarct size in APC+5-HD-R hearts was 8.2 ± 2.3% (P < 0.05 vs. GI and APC+5-HD, NS vs. APC). Infarct size was significantly increased to 27.3 ± 2.0% in APC+5-HD/5-HD-R hearts (P < 0.05 vs. APC and APC+5-HD-R, NS vs. APC+5-HD and GI). Wet weight-to-dry weight ratios after 180 min of perfusion were 7.35 ± 0.53 in APC+5-HD hearts, 5.99 ± 0.61 in APC+5-HD-R hearts, and 6.59 ± 0.19 in APC+5-HD/5-HD-R hearts (NS vs. APC and control).


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  		Fig. 2.   Infarct size expressed as a percentage of ventricular volume in APC+5-hydroxydecanoate (5-HD), APC+5-HD-R, and APC+5-HD/5-HD-R hearts after 30 min of global ischemia and 120 min of reperfusion. Results are shown as means ± SE; n = 6 for each group. *Significant differences at P < 0.05 vs. APC hearts; **significant differences at P < 0.05 vs. GI hearts. No significant difference in infarct size was observed in APC+5-HD or APC+5-HD/5-HD-R hearts compared with GI hearts. There was no significant difference in infarct size between APC+5-HD-R and APC hearts.

Role of sarcKATP channels in APC cardioprotection during ischemia and reperfusion. LVPDP and +dP/dt were significantly decreased in APC+HMR hearts (P < 0.05 vs. APC) at 20 min of perfusion (after 2 min of perfusion of HMR before APC; Table 4). After APC (30 min of perfusion), LVPDP and +dP/dt were significantly decreased in APC+HMR hearts (P < 0.05 vs. APC). LVPDP and +dP/dt were significantly decreased (P < 0.05 vs. APC) in APC+HMR-R hearts at the start of reperfusion (70-80 min and 70 min of perfusion, respectively), but by 90 min and 80 min of perfusion, respectively, no significant difference compared with APC hearts was observed in APC+HMR-R hearts. LVPDP was significantly decreased in APC+HMR hearts throughout reperfusion except at the end of reperfusion (180 min of perfusion). +dP/dt was significantly decreased in APC+HMR hearts at the start of reperfusion (70-90 min of perfusion), but by 120 min of reperfusion, no significant difference compared with APC hearts was observed in APC+HMR hearts.

When sarcKATP channels were blocked with HMR-1883 for 2 min before APC and during the 5-min reperfusion before global ischemia (HMR) and for 2 min at the onset of reperfusion (APC+HMR/HMR-R), LVPDP and +dP/dt were significantly decreased throughout reperfusion (70-180 min of perfusion; P < 0.05 vs. APC).

Combined role of mito- and sarcKATP channels in APC cardioprotection. To investigate the combined role of mito- and sarcKATP channels in APC cardioprotection, APC hearts were perfused with 5-HD and HMR-1883 for 2 min before APC and during the 5-min reperfusion before global ischemia and with HMR-1883 for 2 min at the onset of reperfusion (APC+5- HD-HMR/HMR-R; Table 4). LVPDP and +dP/dt were significantly decreased (P < 0.05 vs. APC; NS vs. GI) throughout reperfusion (70-180 min of perfusion). No significant difference in LVPDP or +dP/dt was observed between APC+5-HD-HMR/HMR-R and APC+HMR/HMR-R hearts.

Infarct size was 10.6 ± 1.3% in APC+HMR, 8.2 ± 2.1% in APC+HMR-R, and 6.1 ± 1.0% in APC+HMR/HMR-R hearts (P < 0.05 vs. GI and APC+5-HD, NS vs. APC and APC+5-HD-R; Fig. 3). Infarct size was significantly increased to 24.0 ± 2.8% in APC+5-HD-HMR/HMR-R hearts (P < 0.05 vs. APC, APC+5-HD-R, APC+HMR, APC+HMR-R, and APC+HMR/HMR-R; NS vs. GI and APC+5-HD). Wet weight-to-dry weight ratios after 180 min of perfusion were 7.77 ± 0.97 in APC+HMR, 7.19 ± 1.00 in APC+HMR-R, 7.38 ± 0.34 in APC+HMR/HMR-R, and 6.23 ± 0.24 in APC+5-HD-HMR/HMR-R hearts (NS vs. APC and control).


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  		Fig. 3.   Infarct size expressed as a percentage of ventricular volume in APC+HMR-1883 (HMR), APC+HMR-R, APC+HMR/HMR-R, and APC+5-HD-HMR/HMR-R hearts after 30 min of global ischemia and 120 min of reperfusion. Results are shown as means ± SE; n = 6 for each group. *Significant differences at P < 0.05 vs. APC hearts; **significant differences at P < 0.05 vs. GI hearts.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Murry et al. (30) were the first to describe an endogenous myocardial protection, IPC, in which the imposition of one or more brief periods of ischemia (3-5 min) followed by reperfusion "preconditions" the heart such that infarct size and myocardial necrosis are significantly reduced during the subsequent induction of sublethal ischemia. The induction of endogenous myocardial protection via preconditioning would appear to be common in all species studied in reducing myocardial infarct volume (19). In previous reports (24-27, 37, 38), we showed that APC extends the cardioprotection afforded by IPC by both significantly decreasing infarct size (P < 0.05 vs. IPC) and significantly enhancing postischemic functional recovery (P < 0.05) in both the in situ and isolated, perfused rabbit heart and the in situ blood-perfused sheep heart. In this report, we have investigated the role of KATP channels in the isolated, perfused Langendorff heart model, and therefore the effects of neutrophils and plasma-borne inflammatory components on infarct size were not assessed. However, in earlier reports (see Ref. 24), we showed that the beneficial effects of APC in reducing myocardial infarct size and enhancing postischemic functional recovery are preserved in the in situ blood-perfused heart model, providing cardioprotection after 30-min global ischemia similar to that of cold blood cardioplegia. We (25) also showed that the cardioprotection afforded by APC occurs through the coincident and synergistic action of a bolus injection of adenosine and IPC. IPC or a bolus injection of adenosine, when used independently, decreased infarct size, but this decrease was significantly less than that achieved with APC and did not enhance postischemic functional recovery (25). Recently, we (25) showed that APC cardioprotection is modulated by adenosine receptors. Our results indicated that APC infarct size reduction was primarily modulated by adenosine receptors before ischemia, whereas significantly APC-enhanced postischemic functional recovery was modulated by adenosine receptors both before ischemia and during reperfusion (25).

Previous reports indicated that the downstream effector(s) of adenosine receptor activation are the KATP channels. Gross and Auchampach (12) were the first to show that KATP channels mediated IPC and that glibenclamide and 5-hydroxydecanoate effectively counteracted these cardioprotective effects. These initial studies performed in the canine model have been repeated by numerous investigators in various animal and human models, and it has been proposed, based on KATP channel openers that mimic preconditioning and KATP channel inhibitors that block IPC, that the KATP channels are central to the mechanism(s) modulating IPC (1, 20, 29, 31, 34-36).

Our results shown in Table 2 and Fig. 1 indicate that the cardioprotection afforded by APC is also modulated by KATP channels. The nonspecific KATP channel blocker glibenclamide completely blocked APC-enhanced infarct size reduction before ischemia, with infarct size in APC+Glb hearts being significantly increased such that no significant difference compared with GI hearts was observed. In APC+Glb-R hearts, infarct size was also increased, but this increase was significantly less (P < 0.05) than that in APC+Glb hearts and was significantly less (P < 0.05) than that observed in GI hearts. Our results also show that blockade of KATP channels either before ischemia (APC+Glb) or during reperfusion (APC+Glb-R) partially modulated postischemic functional recovery; however, when KATP channels were blocked both before ischemia and during reperfusion (APC+Glb/Glb-R), APC-enhanced postischemic functional recovery was significantly decreased.

These results are in agreement with our previous report (25) and that of Gross and Auchampach (12), who showed that intravenous administration of glibenclamide either before or after a single 5-min period of IPC completely abolished IPC-associated infarct size reduction in dogs. Our results also agree with those of Van Winkle et al. (39), who showed that cardioprotection provided by adenosine receptor activation was abolished by blockade of KATP channels, and with those of Toombs et al. (35, 36), who showed that in the rabbit heart both IPC and protection afforded by adenosine pretreatment are abolished by blockade of KATP channels. Our data also extend the results observed by these groups and indicate that KATP channel blockade modulates postischemic functional recovery when used before ischemia and/or during reperfusion.

Two KATP channel subtypes have been shown to exist in the myocardium, with one subtype located in the sarcolemma (sarcKATP) and the other in the inner membrane of the mitochondria (mitoKATP) (13, 21). Activation of KATP channels is hypothesized to be the consequence of ischemia-induced fall of intracellular ATP and activation of adenosine receptors (4, 5, 22, 31, 32, 42). Under normal conditions, the KATP channels are closed; this inhibition occurs by free intracellular ATP and Mg2+-ATP and is responsive to changes in ATP concentration produced by glycolysis but not by increases through application of exogenous ATP (14, 16). The opening of the sarcKATP channels during ischemia occurs as intracellular ATP levels fall (not extracellular ATP) and has been postulated to reduce the action potential plateau phase, reduce Ca2+ current, and, therefore, reduce the Ca2+-related energy cost of contraction (4, 32). However, Grover et al. (15) showed that when action potential duration is blocked the cardioprotective action (decreased infarct size) of the potassium channel opener cromakalim is maintained, suggesting that the sarcKATP channels play a role in cardioprotection other than that of infarct size reduction. Support for the separation of the involvement of KATP channel function in the modulation of infarct size reduction and enhanced functional recovery comes from the experiments of Garlid et al. (10) and the recent studies of Liu et al. (21), who showed that the mitoKATP channels, but not sarcKATP channels, modulate cell viability. To investigate the role of mito- and sarcKATP channels in APC cardioprotection we have used 5-hydroxydecanoate, shown to be a mitoKATP-specific channel blocker in the rabbit, and the cardioselective sarcKATP channel blocker HMR-1883 (2, 3, 11, 13, 33).

In previous studies by others in which the mechanism of IPC has been investigated, KATP channel blockers were perfused before IPC (1, 12, 36, 39). In our studies KATP channel blockers were perfused both before and after APC. This protocol was incorporated after initial experiments indicated that the use of KATP channel blockers only before APC had variable effects on the cardioprotection afforded by APC. We speculate that these results were caused by the bolus injection of adenosine, which competitively inhibited the action of the KATP channel blockers.

Our results show that infarct size, expressed as a percentage of ventricular volume, was significantly increased to 23.7 ± 1.9% in APC+5-HD hearts (P < 0.05 vs. APC and 5-HD-R, NS vs. GI; Fig. 2). These results indicate that mitoKATP channel blockade before ischemia (APC+5-HD) completely abolished APC-enhanced myocardial infarct size reduction (P < 0.05 vs. APC and APC+5-HD-R, NS vs. GI), whereas mitoKATP channel blockade during reperfusion (APC+5-HD-R) had no effect on APC-enhanced myocardial infarct size reduction. MitoKATP channel blockade both before ischemia and during reperfusion (APC+5-HD/5-HD-R) also completely abolished APC-enhanced myocardial infarct size reduction (P < 0.05 vs. APC and APC+5-HD-R, NS vs. GI). Of significance, our results shown in Table 3 indicate that APC+5-HD, APC+5-HD-R, and APC+5-HD/5-HD-R treatments had only transient effect on APC postischemic functional recovery (70-80 min of perfusion) and that, after 30 min of reperfusion (90 min of perfusion), there was no significant difference in LVPDP, LVEDP, or +dP/dt among APC+5-HD, APC+5-HD-R, APC+5-HD/5-HD-R, and APC hearts. These results suggested that mitoKATP channels were involved in the mechanism modulating APC-enhanced infarct size reduction and that this modulation occurred primarily during ischemia. These results further suggested that mitoKATP channel blockade either before ischemia and/or during reperfusion had no effect on APC-enhanced postischemic functional recovery. We speculate that as infarct size is increased the effect on postischemic functional recovery is also increased. The relative level at which a stoichiometric relationship exists requires further investigation and cannot be answered in this report.

Examination of the role of sarcKATP channels using the cardiospecific sarcKATP channel blocker HMR-1883 (2, 3, 11, 13) indicated that APC-enhanced postischemic functional recovery, shown in Table 4, was partially abolished by sarcKATP channel blockade before ischemia (APC+HMR) and partially abolished by sarcKATP channel blockade during reperfusion (APC+HMR-R). However, blockade of sarcKATP channels both before ischemia and during reperfusion (APC+HMR/HMR-R) significantly decreased APC-enhanced postischemic functional recovery throughout reperfusion (P < 0.05 vs. APC and APC+5-HD/5-HD-R, NS vs. GI). No significant difference was observed in infarct size among APC+HMR, APC+HMR-R, and APC+HMR/HMR-R hearts compared with APC hearts. These results are in agreement with the findings of Garlid et al. (10) and Liu et al. (21).

To confirm the role of mito- and sarcKATP channels in cardioprotection, APC hearts were perfused with 5-HD and HMR-1883 for 2 min before APC and during the 5 min after APC, before global ischemia, and with HMR-1883 for 2 min at the onset of reperfusion (APC+5-HD-HMR/HMR-R). This protocol blocked mitoKATP channels before ischemia and sarcKATP channels before ischemia and during reperfusion. Our results shown in Table 4 and Fig. 3 indicate that LVPDP and +dP/dt in APC+5-HD-HMR/HMR-R hearts were significantly decreased (P < 0.05 vs. APC and APC+5-HD/5-HD-R) during reperfusion (70-180 min of perfusion), that infarct size was significantly increased in APC+5-HD-HMR/HMR-R hearts (P < 0.05 vs. APC, APC+5-HD-R, APC+HMR, APC+HMR-R, and APC+HMR/HMR-R), and that these values were not significantly different from those observed in GI hearts. These data are in agreement with our earlier reports and confirm that using specific KATP channel blockade to block both mito- and sarcKATP channels before ischemia and sarcKATP channels during reperfusion completely abolishes the cardioprotection afforded by APC, producing the same effects seen in GI hearts (NS vs. GI). These results also confirm that infarct size is primarily modulated before ischemia and that postischemic functional recovery is modulated both before ischemia and during reperfusion.

Our results indicate that there is a separation of the mechanisms modulating infarct size and functional recovery. The separation of the involvement of KATP channel function in the modulation of infarct size reduction and enhanced functional recovery was previously suggested by Garlid et al. (10) and the recent studies of Liu et al. (21), who showed that the mitoKATP channels, but not sarcKATP channels, modulate cell viability. Our data suggest that in APC cardioprotection KATP channels (sarcKATP and mitoKATP) are opened during the preconditioning phase, in agreement with the earlier investigations of Gross and Auchampach (12) and Auchampach et al. (1), who suggested that the opening of the KATP channels not only triggers IPC but is also involved with the memory phase of IPC. Opening the sarc- and mitoKATP channels would allow for the influx of K+ to the cytoplasm and the mitochondrion and would attenuate cytosolic calcium (Cai2+) and mitochondrial calcium (Camito 2+) accumulation. The modulation of infarct size would presumably occur through the modulation of Camito2+ accumulation and the preservation of mitochondrial function.

Increased Camito2+ accumulation has been shown to destabilize the inner mitochondrial membrane, causing the inner membrane pore to open, which permits further movement of cations across the mitochondrial membrane (8). The opening of these pores renders the mitochondrion incapable of synthesizing ATP and has been suggested to be a key event in the process leading to myocardial cell death (23). We speculate that these events are directly related to infarct size reduction. Support for this hypothesis comes from earlier reports by us (6, 7) and the recent investigation of Fryer et al. (9), who showed that mitoKATP channels play an important role in the preservation of mitochondrial function. We speculate that the opening of the mitoKATP channels before ischemia effectively obviates Camito2+ accumulation. The opening of the sarcKATP channels would allow for Cai2+ accumulation, but Camito2+ accumulation would not occur, thus allowing for the preservation of mitochondrial function and cell integrity.

Recently we showed (37) that APC has anti-stunning effects and that although the anti-infarct effects of APC are significantly extended the anti-stunning effects are transient. These data would suggest that, although the opening of sarcKATP channels during ischemia and reperfusion may allow for decreased Cai2+ accumulation, mechanisms other than sarcKATP channels are involved in the enhancement of postischemic functional recovery.


    ACKNOWLEDGEMENTS

The authors thank Heinrich C. Englert, Hoechst-Marion-Roussel, Frankfurt, Germany, for efforts on our behalf in obtaining HMR-1883 and for kind advice regarding the concentrations used.


    FOOTNOTES

This study was supported by National Heart, Lung, and Blood Institute Grants HL-29077 and HL-59542 and by the American Heart Association.

Address for reprint requests and other correspondence: J. D. McCully, Div. of Cardiothoracic Surgery, Beth Israel Deaconess Medical Ctr., Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Rm. 144, Boston, MA 02115 (E-mail: james_mccully{at}hms.harvard.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 22 February 2000; accepted in final form 9 June 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 279(6):H2694-H2703
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