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Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-01, Japan
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
References
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Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 ± 3% (mean ± SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 ± 2, 17 ± 2, and 12 ± 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 ± 4 and 41 ± 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.
infarct size; glibenclamide; cromakalim; verapamil
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
References
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EXPOSURE OF THE MYOCARDIUM to one or more brief periods of ischemia, known as ischemic preconditioning (IPC), can result in marked resistance to subsequent prolonged episodes of ischemic stress in various mammalian species. It is now well recognized that adenosine, released from the ischemic myocardium during IPC, triggers the cardioprotective process (4, 9). Because A1-adenosine receptors are coupled to ATP-sensitive potassium (KATP) channels via pertussis toxin-sensitive inhibitory G proteins (7), attention is increasingly focused on the role of these channels in IPC. Indeed, Auchampach and Gross (2) and Rohmann et al. (22) revealed the key role of these channels in IPC of dog and pig hearts, showing that their cardioprotective effect was prevented by the KATP channel blocker glibenclamide.
On the other hand, Ashraf et al. (1) have reported that short cycles of calcium depletion and repletion in perfusate protect the Langendorff-perfused rat heart against calcium paradox injury. This phenomenon was originally termed Ca2+ preconditioning (CPC). Further studies from the same group (13-15) have shown that a transient increase in intracellular calcium concentration ([Ca2+]i) can precondition the perfused rat heart against subsequent global ischemia. Similarly, Node et al. (17) have shown that intracoronary infusion of calcium chloride followed by a washout period can mimic IPC in dog hearts. A rise in [Ca2+]i during brief periods of ischemia possibly relates to the underlying mechanism for the cardioprotection of IPC because it occurs within a few minutes of the onset of ischemia in myocytes (6, 24). If so, because IPC is a ubiquitous phenomenon independent of species differences, CPC should provide similar cardioprotection in other animals. Moreover, it is an interesting question as to whether the two types of cardioprotective effects provided by IPC and CPC share a common target of signal transduction, i.e., KATP channel activation.
However, in rabbit hearts, the contribution of KATP channels to IPC is thought to be anesthetic dependent. Toombs et al. (27, 28) have shown that glibenclamide abolished the reduction in infarct size induced by IPC in rabbits anesthetized with ketamine-xylazine, whereas Thornton et al. (25) have demonstrated that this reduction in infarct size was not prevented by glibenclamide in rabbits anesthetized with pentobarbital sodium. On the other hand, Schultz et al. (23) have indicated that the timing of glibenclamide administration is an important factor in its ability to abolish IPC in rats. Because Thornton et al. (25) administered the antagonist only 5 min before IPC, it is also possible that changing the timing of glibenclamide administration leads to prevention of the infarct size-limiting effect of IPC even in rabbits anesthetized with pentobarbital sodium.
Thus our objectives in the present study were 1) to reevaluate whether activation of KATP channels mediates the infarct size-limiting effect of IPC in rabbits anesthetized with pentobarbital sodium; 2) to examine whether CPC can mimic the cardioprotection of IPC in these animals; and 3) if so, to investigate whether glibenclamide prevents this type of cardioprotection.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
References
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Animal preparation. Female Japanese white rabbits weighing between 2.5 and 3.2 kg were anesthetized with 30 mg/kg of pentobarbital sodium, intubated, and then mechanically ventilated with 100% oxygen using a volume-cycled respirator (model SN-485-5; Shinano Apparatus, Tokyo, Japan). A fluid-filled catheter was placed in the right femoral artery and was connected to a transducer (Statham p-23Db; Gould, Cleveland, OH) for measurement of arterial pressure. Ventilation was maintained at 15-20 breaths/min; tidal volume was ~40 ml. The respiratory rate was adjusted to keep the blood pH in the physiological range. A left thoracotomy was performed in the fourth intercostal space, and the pericardium was opened. A 4-0 silk thread was then passed around the circumflex branch of the left coronary artery, with its ends being threaded through a small polyethylene tube. Precordial electrocardiography was monitored using bipolar chest leads. Rabbits were allowed at least 20 min to reach a steady state after surgical preparation. Coronary occlusion was produced by pulling the snare and clamping it with a mosquito hemostat. Reperfusion was produced by releasing the clamp. Myocardial ischemia was confirmed by S-T segment elevation of the electrocardiogram as well as observation of regional cyanosis over the myocardial surface. Reperfusion was confirmed by reactive hyperemia over the surface after releasing the snare.
Experimental protocols. The experimental protocols are shown in Fig. 1. All animals were subjected to a 30-min period of coronary artery occlusion followed by 180 min of reperfusion. Rabbits were assigned randomly to 1 of 10 groups.
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To achieve IPC, the coronary artery was occluded for 5 min and reperfused for 10 min before sustained occlusion. The role of KATP channels in the cardioprotection of IPC was examined in the following five groups of animals: control animals given vehicle (for glibenclamide) before sustained ischemia (C group); animals treated with glibenclamide (1 mg/kg; Sigma Chemical) before sustained ischemia (G group); animals given vehicle before IPC (IPC group); and animals treated with the same dose of glibenclamide 5 or 30 min before the IPC (IPC + G5 group and IPC + G30 group, respectively). In the sixth group, animals received cromakalim (40 µg/kg; Sigma Chemical), a KATP channel opener, over a period of 10 min as an intravenous infusion 10 min before sustained ischemia (Cro group).
In the remaining four groups, the potential reduction of infarct size
induced by CPC and the antagonistic effects of glibenclamide or a
calcium channel blocker, verapamil, on this form of cardioprotection were examined. To precondition animals with calcium, a 8.5% (wt/vol) solution of calcium gluconate (20 mg · kg
1 · min1,
with an infusion rate of 0.235 ml · kg1 · min1;
Dainippon Pharmaceutical, Osaka, Japan) was given intravenously for two
cycles of 5-min infusion separated by a 15-min drug-free period before
ischemia. Vehicle (CPC group) and 1 mg/kg of glibenclamide (CPC + G group) were administered intravenously as slow bolus injections 5 min before the start of calcium infusion. In accordance with the cycles
of infusion and interval of calcium gluconate, verapamil (45 µg · kg1 · min1;
Sigma Chemical) was intravenously given alone (V group) or in addition
to CPC (CPC + V group).
Glibenclamide was dissolved in the vehicle consisting of 1 N NaOH, ethanol, and polyethylene glycol 200 (1:1:1, vol/vol/vol) and made a final concentration of 3 mg/ml. Cromakalim was dissolved in dimethyl sulfoxide, polyethylene glycol 200, and distilled water (5:7:3, vol/vol/vol) and was prepared as a 1,000-fold stock solution. Verapamil was dissolved in saline to a concentration of 0.45 mg/ml.
Determination of infarct size. In each protocol, the heart was rapidly excised at the end of the 180 min of reperfusion and mounted by the aortic root on a Langendorff apparatus. The snare was retightened, and 0.5% phthalocyanine blue pigment (Sigma Chemical) was infused into the perfusate to demarcate the risk zone as the tissue without blue dye. The heart was then removed, isolated into the left ventricle, and cut into transverse slices 2 mm in thickness. The area at risk (nonblue area) was separated from each slice, weighed, and incubated at 37°C for 15 min in 1% triphenyl tetrazolium chloride (TTC; Sigma Chemical) in pH 7.4 phosphate buffer. TTC stained the noninfarcted myocardium to a deep red color. The sections were fixed in 10% Formalin solution for a minimum of 3 h. Their digital images were then captured using a CCD camera and input to an Apple Power Macintosh computer. The area at risk and the area of infarction (TTC negative) were determined using image analysis software (National Institutes of Health Image V1.57), corrected for the weight of each tissue slice and summed for each heart. The infarct size was expressed as a percentage of the area at risk.
Left ventricular contractile response to calcium and verapamil. In other animals in each of the CPC, V, and CPC + V groups, after the anesthesia and ventilation described above, a catheter with a Y-type connector was inserted into the left ventricle via the right carotid artery. A 2-F micromanometer-tipped catheter (Millar Instruments, Houston, TX) was inserted into the lumen of the connector. The micromanometer pressure tracing was superimposed onto a conventional pressure tracing obtained from the side lumen of the connector with the use of a fluid-filled system attached to a transducer (Statham p-23Db; Gould, Cleveland, OH). The micromanometer catheter was then advanced into the left ventricle. The first derivative of the left ventricular pressure curve (dP/dt) was obtained using a differentiating circuit in the recorder with the high-frequency filter cut-off set at 70 Hz. These rabbits were also allowed at least 20 min after surgical preparation to reach a steady-state condition, at which point the left ventricular pressure, dP/dt, and electrocardiogram in the baseline condition were recorded at a paper speed of 100 mm/s (model R-60; TEAC, Tokyo, Japan). After recording of baseline left ventricular pressure, animals were administered calcium gluconate or verapamil. In these animals, left ventricular hemodynamic measurements were made at the end of each infusion and each interval period.
Statistical analysis. Data in the text, Figs. 1-3, and Tables 1-3 are expressed as means ± SE. The differences in hemodynamics between groups and the serial left ventricular hemodynamic changes in the CPC group were analyzed by one-way analysis of variance (ANOVA) using Fisher's least significant difference as the post hoc test. In the infarct size study, the differences between groups were compared using one-way ANOVA with Scheffé's post hoc test. A level of P < 0.05 was accepted as statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
References
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Hemodynamics. The hemodynamic data are summarized in Table 1. No significant differences were observed in mean arterial pressure or heart rate among the 10 groups at any of the following experimentally determined time points: baseline, preischemia, end of ischemia, and end of reperfusion.
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Table 2 represents serial left ventricular hemodynamic responses to two cycles of intravenous infusion of calcium gluconate and/or verapamil followed by a drug-free period. In the CPC group, left ventricular peak positive dP/dt significantly increased during each infusion period and returned to the baseline value at the end of each interval period. By contrast, in the V group, it decreased during each infusion period and returned to the baseline value at the end of each interval period. These calcium-induced changes in left ventricular peak positive dP/dt were completely antagonized by verapamil in the CPC + V group. Neither heart rate nor left ventricular end-diastolic pressure changed during two infusion/interval cycles in the CPC, V, and CPC + V groups.
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Infarct size. Data from the study of infarct size are summarized in Table 3. Body weights, left ventricular weights, and the area at risk weights did not differ among any of the experimental groups. Figure 2 shows the area at risk as a percentage of the left ventricle and shows the infarct size as a percentage of the area at risk in each experiment. These data resulted in comparable risk zone sizes in all groups and in significant (P < 0.01) reduction in infarct size of the IPC, Cro, and CPC groups compared with the C group (13 ± 2, 12 ± 3, and 17 ± 2% vs. 38 ± 3%, respectively). The administration of glibenclamide alone had no effect on infarct size in the G group (35 ± 4%). Importantly, glibenclamide administered 5 min before IPC did not block the beneficial effect of IPC on limitation of infarct size in the IPC + G5 group (16 ± 3%), whereas the same agent given 30 min before IPC did block such effect in the IPC + G30 group (31 ± 4%). In addition, glibenclamide also inhibited the infarct size-limiting effect of CPC in the CPC + G group (41 ± 6%). Intermittent intravenous administration of verapamil did not affect the infarct size in the V group (28 ± 5%), but it attenuated the cardioprotective effect induced by CPC in the CPC + V group (33 ± 4%).
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Figure 3 represents the relationship between infarct size and risk-zone size in the 10 groups of animals studied. When the data of protected groups (IPC, IPC + G5, Cro, and CPC) were separated from those of unprotected groups (C, G, IPC + G30, CPC + G, V, and CPC + V), each regression line showed a significantly different slope (0.49 with r = 0.73 in protected groups and 0.19 with r = 0.52 in unprotected groups) with positive x-intercepts (31). It is apparent that the data points of the protected groups are located below those of the unprotected groups. These observations indicate that the smaller infarcts in the three preconditioned and Cro groups are not merely the result of smaller risk-zone sizes.
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DISCUSION |
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This study revealed that glibenclamide, a KATP channel blocker, blocked the infarct size-limiting effect of IPC in rabbits anesthetized with pentobarbital sodium in a time-dependent manner and that pretreatment with a potent KATP channel opener, cromakalim, reduced infarct size in these animals. It also demonstrated that CPC could mimic IPC in in vivo rabbit hearts and that glibenclamide inhibited this CPC-mediated reduction of infarct size.
KATP channels in reduction of infarct size in rabbit hearts. Auchampach and Gross (2) and Rohmann et al. (22) have revealed that, in dogs and pigs, the infarct size-limiting effect of IPC was abolished by the KATP channel blocker glibenclamide, implying that the KATP channel is involved in this form of cardioprotection. On the other hand, considerable controversy exists concerning the contribution of KATP channels to IPC in rat and rabbit hearts. Liu and Downey (10) and Grover et al. (3) failed to induce glibenclamide to prevent these beneficial effects in rat hearts. However, the failure of blockade of cardioprotection by glibenclamide in these studies does not necessarily rule out the involvement of KATP channels in IPC. In these studies, glibenclamide administration was started within 10 min before IPC. Schultz et al. (23) have revealed a time dependency for glibenclamide-induced blocking of IPC in rats. When the period of pretreatment of 0.3 mg/kg of glibenclamide was extended to 30 min as opposed to 5 min, it was able to block the infarct size-limiting effect of IPC. Qian et al. (20) have recently been able to confirm the antagonistic effect of glibenclamide given as two doses of 0.3 mg/kg each at 60 and 30 min before IPC in rats. These results suggest that KATP channels are involved in IPC in mammalian species other than rabbits.
In rabbits, Toombs et al. (27, 28) demonstrated that the infarct size-limiting effects of both IPC and exogenous adenosine were blocked by glibenclamide under ketamine-xylazine anesthesia. In contrast, Thornton et al. (25) showed that the IPC-induced reduction in infarct size was not prevented by glibenclamide given 5 min before IPC in rabbits anesthetized with pentobarbital sodium. In the present study, similar to the study of Schultz et al. (23) in rats, we tested two different protocols with regard to the scheduling of the administration of glibenclamide (given at 5 or 30 min before IPC). Importantly, we were able to prevent the infarct size-limiting effect of IPC only with glibenclamide given 30 min (but not 5 min) before IPC in rabbits anesthetized with pentobarbital sodium. Moreover, Thornton et al. (25) reported that the KATP channel opener pinacidil did not offer myocardial protection in rabbits anesthetized with pentobarbital sodium, whereas we observed that a more potent KATP channel opener, cromakalim, reduced infarct size in these animals. Thus it appears that KATP channels play an important role in the reduction of infarct size, even in rabbits anesthetized with pentobarbital sodium. We have recently demonstrated that IPC prevents ischemia-induced reduction in sarcolemmal enzymatic activities and that glibenclamide abolishes this preservation in preconditioned hearts of rabbits anesthetized with pentobarbital sodium (16). These results of our previous and present studies are important, since we can now draw the conclusion that KATP channels are ubiquitously involved in the cardioprotective effect of IPC independent of differences in species or anesthetic regimen. CPC in rabbit hearts. This study demonstrates that, as has previously been reported in rats (1, 13-15) and dogs (17), CPC limits infarct size in rabbit hearts. Furthermore, to our best knowledge, this is the first report to disclose that, as with IPC, the infarct size-limiting effect of CPC is blocked by a KATP channel blocker, suggesting that activation of these channels is involved in this type of cardioprotection. These findings also lead us to the unique hypothesis that a short period of rise in [Ca2+]i activates KATP channels. However, it is not clear that calcium gluconate infusion actually increases [Ca2+]i and thus causes the cardioprotection of CPC. We therefore examined whether a calcium channel blocker, verapamil, could antagonize the CPC-induced infarct size-limiting effect. A preliminary study at our laboratory demonstrated that 30 min of continuous intravenous administration of verapamil (45 µg · kg1 · min1)
before sustained ischemia showed a trend toward infarct size reduction (data not shown) probably due to a blockade of calcium entry,
i.e., reduction of calcium overload (8). On the other hand, we found
that two cycles of 5-min infusion of verapamil separated by a 15-min
drug-free period before sustained ischemia, the same infusion
protocol as that we used for CPC, impeded such protective effect. In
addition, this intermittent infusion of verapamil completely abolished
the infarct size-limiting effect afforded by CPC. These observations
strongly suggest that an increase in
[Ca2+]i
does indeed trigger the KATP
channel-mediated cardioprotection of CPC.
A growing body of evidence indicates that the activation of protein
kinase C (PKC) also plays an important role in IPC (11, 12, 19).
Previous studies (18, 29) have shown that a rise in
[Ca2+]i
stimulates the turnover of phospholipids, leading to production of
diacylglycerol, an activator of PKC, and also could directly activate
calcium-dependent isoforms of PKC. It has recently been demonstrated
that the activation of PKC is involved with the cardioprotective effect
elicited by a rise in
[Ca2+]i
in the isolated rat heart (13, 15), and also in the in situ canine
model (17). This conclusion was confirmed by painstaking studies,
including pharmacological inhibition, immunofluorescence, and activity
assays (13, 15). At present, the link between PKC and
KATP channel activation is an
intriguing subject for investigation. Employing patch-clamp techniques,
Hu et al. (5) have recently demonstrated that PKC can activate
KATP current in rabbit and human myocytes by
reducing channel sensitivity to intracellular ATP. From these
observations, a rise in
[Ca2+]i,
activation of PKC, and subsequent opening of
KATP channels may potentially
constitute a chain of intracellular signaling pathways during
cardioprotection against ischemic injury in rabbit hearts.
Limitations of the study. This study
did not confirm whether an increase in cytosolic calcium was actually
induced at the myocyte level during intravenous administration of
calcium gluconate and/or verapamil. However, we instead
measured left ventricular peak positive
dP/dt to evaluate contractile response
to these interventions. Repetitive 5-min calcium infusion periods were associated with repetitive increments of left ventricular peak positive
dP/dt; such repetitive infusion of
verapamil generated the opposite results. Left ventricular peak
positive dP/dt is both dependent on
myocardial contractility and influenced by loading conditions and heart
rate. Because neither heart rate nor left ventricular end-diastolic
pressure changed during these procedures, any alteration in left
ventricular peak positive dP/dt can be attributed to changes in myocardial contractility. Thus, although we
did not directly measure
[Ca2+]i
in this study, changes in left ventricular peak positive
dP/dt appeared to reflect those of
[Ca2+]i.
In this study, we attributed the pharmacological action of
glibenclamide to a blockade of
KATP channels. However, several studies have recently revealed that glibenclamide is not a specific inhibitor of these channels; it also inhibits chloride channels (26,
30) as well as
Na+-K+-ATPase
activity (21). In this regard, further studies are required to clarify
the precise underlying mechanism of calcium-dependent cardioprotection.
In summary, the reduction of infarct size induced by both IPC and CPC
is prevented by the KATP channel
blocker glibenclamide in rabbit hearts. Moreover, the
KATP channel opener cromakalim can
mimic the infarct size-limiting effect of these cardioprotective mechanisms. Thus activation of
KATP channels plays an important role in the cardioprotection of IPC and CPC in rabbits. Brief period(s)
of rise in
[Ca2+]i
may, at least in part, trigger this channel activation in the two types
of preconditioning.
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ACKNOWLEDGEMENTS |
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This study was supported in part by research grants from the Japanese Ministry of Education, Science and Culture.
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FOOTNOTES |
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Address for reprint requests: T. Murakami, Dept. of Cardiovascular Medicine, Kyoto Univ. Graduate School of Medicine, 54 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-01, Japan.
Received 21 July 1997; accepted in final form 9 December 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
References
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) and in 4 protected groups of animals (
). Solid lines
represent linear correlation between risk-zone and infarct size in
unprotected and protected animal groups.