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(Circulation. 1997;96:29-32.)
© 1997 American Heart Association, Inc.

Articles

Oral Sulfonylurea Hypoglycemic Agents Prevent Ischemic Preconditioning in Human Myocardium

Two Paradoxes Revisited

Joseph C. Cleveland, Jr, MD; Daniel R. Meldrum, MD; Brian S. Cain, MD; Anirban Banerjee, PhD; ; Alden H. Harken, MD

From the Department of Surgery, University of Colorado Health Sciences Center, Denver.

Correspondence to Joseph C. Cleveland, Jr, MD, University of Colorado Health Sciences Center, Department of Surgery, Box C-305, 4200 E Ninth Ave, Denver, CO 80262.

	Abstract

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Background Patients receiving oral hypoglycemic agents for diabetes mellitus are at increased risk of cardiovascular mortality. Oral hypoglycemic agents are inhibitors of the ATP-sensitive potassium (K_ATP) channel. Ischemic preconditioning is mediated by K_ATP channel activation. We therefore hypothesized that myocardium from patients taking long-term oral hypoglycemic agents would be resistant to the protection by ischemic preconditioning.

Methods and Results Isolated human right atrial trabeculae were suspended in an organ bath at 37°C, with field stimulation at 1 Hz. Control trabeculae were then subjected to 45 minutes of simulated ischemia (hypoxic, glucose-free buffer with pacing at 3 Hz) and 120 minutes of reperfusion. Ischemic preconditioned (IPC) trabeculae from patients without oral hypoglycemic therapy and from patients taking insulin (Ins+IPC) were given 5 minutes of simulated ischemia before this injury. Trabeculae (Oral Hypo+IPC) were obtained from patients taking long-term oral hypoglycemic agents and were also exposed to 5 minutes of simulated ischemia before this injury. Developed force (DF) was recorded. Recovery of DF relative to preischemic values was 28±4% in control trabeculae, whereas IPC trabeculae showed 52±5% recovery (P<.05 versus control). In patients receiving long-term oral hypoglycemic agents (Oral Hypo+IPC), recovery of DF was 27±3%, but in trabeculae from insulin-treated patients (Ins+IPC), it was 45±6%.

Conclusions Human myocardium from patients without long-term exposure to oral hypoglycemic agents is functionally protected by preconditioning. Long-term oral hypoglycemic intake blocks the protection by preconditioning. These data suggest that ischemic preconditioning in human myocardium relies on K_ATP channels, and long-term inhibition of K_ATP channels with oral hypoglycemic agents may explain the excess cardiovascular mortality in these patients.

Key Words: diabetes mellitus • pharmacology • ischemia

	Introduction

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Diabetes mellitus is traditionally viewed as a predictor of cardiovascular morbidity and mortality. Results of the UDGP study suggested that patients treated with oral hypoglycemic agents sustained an unexplained increased cardiovascular mortality compared with diet treatment alone.¹ This observation generated much controversy but was also reported by Rytter et al,² who noted a paradoxically increased post–myocardial infarction mortality among diabetics on oral hypoglycemic agents compared with those patients on insulin therapy. Despite these observations, the use of oral hypoglycemic agents remains prevalent.

An equally intriguing cardiac phenomenon was appreciated by Murry et al³ a decade ago when they observed that induction of tolerance to myocardial ischemia-reperfusion injury can be conferred by a preceding transient episode of ischemia. This cardioprotection, initially described in dogs, was called ischemic preconditioning. Although preconditioning was originally recognized to result in infarct size reduction, it is now also appreciated to augment postischemic myocardial function⁴ and prevent arrhythmias.⁵ Of additional clinical relevance, however, are recent reports identifying ischemic preconditioning in the human myocardium.^{6 7 8} Indeed, Kloner and colleagues⁹ noted in the TIMI IV trial that angina within 48 hours of myocardial infarction increased survival and reduced infarction size. Others have also observed that the severity of pain, ST-segment depression, and myocardial lactate production are decreased during the second compared with the first percutaneous transluminal coronary angioplasty balloon occlusion.¹⁰ Yellon and colleagues¹¹ reported that patients undergoing coronary artery surgery who received an intentional transient episode of ischemia exhibited preservation of myocardial ventricular ATP levels after ventricular fibrillation. Collectively, these studies suggest that ischemic preconditioning occurs in the human myocardium, and preconditioning could represent a significant endogenous protector against myocardial ischemic injury and perhaps against cardiovascular mortality.

Although these two phenomena may appear unrelated, Yellon's laboratory reported that ischemic preconditioning of human myocardium could be abolished in vitro by blockade of the K_ATP channel.⁶ Furthermore, Tomai and colleagues¹² attenuated preconditioning during clinical angioplasty in humans by administering the K_ATP channel inhibitor glibenclamide. We hypothesized that the increased cardiovascular mortality observed in the UDGP study is related to the inhibition of protective cardiac preconditioning by oral hypoglycemic agents. The purposes of this study were to determine whether myocardial preconditioning could be induced in human atrial trabeculae from patients who were not receiving oral hypoglycemic agents compared with trabeculae from diabetic patients treated with either oral hypoglycemic agents or insulin.

	Methods

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We have described our technique for isolated human myocardium studies previously.⁸ Briefly, right atrial appendages were obtained from patients undergoing coronary artery surgery with stable coronary artery disease. Patients were excluded from the study if they were hemodynamically unstable (mean arterial pressure <70 mm Hg), exhibited atrial dysrhythmias, experienced angina within 24 hours of surgery, or had right atrial pressures >10 mm Hg. All patients were taking nitrates (isosorbide) as antianginal therapy. In addition, 80% were using a calcium channel antagonist for either antianginal or antihypertensive treatment. The average duration of diabetes mellitus was not different in insulin-treated diabetics versus patients treated with oral hypoglycemic agents. Furthermore, the dose of glyburide was 5 mg twice daily in all patients on this agent and 10 mg daily for the one patient on glipizide. In this study, n represents the number of patients in each group.

Each appendage was placed in oxygenated modified Tyrode's solution, which was bubbled with 92.5% O₂/7.5% CO₂ at 37°C. Three atrial trabeculae were obtained from each appendage and suspended vertically in an organ bath. During the simulated ischemic period, the gas mixture was switched to 92.5% N₂/7.5% CO₂, which produced a PO₂ <50 mm Hg, and the organ baths were covered to prevent atmospheric gas exchange. Buffer was replaced at 20-minute intervals throughout experimentation except during the period of simulated ischemia.

Thirty minutes was allowed after appendage procurement for stabilization, after which time trabeculae were stretched to a resting force of 1 g. Field stimulation occurred through platinum electrodes at a frequency of 1 Hz. The indices of contractile function assessed were DF and resting force (in grams). Before the study, standards were established to discard trabeculae that failed to generate at least 0.5 g of DF during the initial equilibration period.

The modified Tyrode's solution was prepared daily with deionized distilled water and contained (in mmol/L) D-glucose 5, CaCl₂ 2, NaCl 118, KCl 4, MgSO₄ 1.2, NaHCO₃ 25, and NaH₂PO₄ 1.2. All reagents were from Sigma Chemical Co. In the substrate-free Tyrode's solution, choline chloride (7 mmol/L) was added to maintain constant osmolarity.

Trabeculae were subjected to a 90-minute equilibration period to allow for stabilization of DF, and subsequently all experiments were conducted for 180 minutes. All experimental groups were challenged with 45 minutes of simulated ischemia, which consisted of substrate-free, hypoxic modified Tyrode's solution with pacing at 3 Hz, followed by 120 minutes of reperfusion with normoxic modified Tyrode's solution with pacing at 1 Hz. In group 1 (n=16), simulated ischemia-reperfusion (control) trabeculae underwent 15 minutes of normoxic perfusion before simulated ischemic injury. In group 2 (n=5), simulated IPC trabeculae were subjected to 5 minutes in hypoxic, substrate-free, modified Tyrode's solution with pacing at 3 Hz, followed by 10 minutes in normoxic modified Tyrode's solution with pacing at 1 Hz before simulated ischemic injury. In group 3 (n=7), Oral Hypo+IPC trabeculae were treated identical to those from group 2; however, the trabeculae in this group were obtained from patients with diabetes mellitus who were taking long-term oral hypoglycemic agents. Group 4 (n=4) trabeculae were from patients taking insulin for diabetes mellitus (Ins+IPC) and were treated identical to those from group 2.

All data are presented as mean±SEM. All values were compared by ANOVA (Statview 4.1, Abacus Concepts) with application of a post hoc Bonferroni-Dunn's test. A value of P<.05 was accepted to represent a statistically significant difference between groups.

	Results

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Forty-eight atrial trabeculae were obtained from 16 patients with chronic ischemic heart disease. The mean time before surgery of the last dose of oral hypoglycemic agents was 17 hours. Ages and ejection fractions were comparable in all groups (Table 1). Six of the patients on oral hypoglycemic agents were using glibenclamide, and 1 was taking glipizide. Four patients were taking insulin therapy, and 5 had no evidence of carbohydrate intolerance. Six trabeculae were excluded from analysis because they failed to generate adequate DF. Each appendage was used in only one protocol, and a control trabecula was paired with each preconditioned trabecula. Baseline tissue characteristics, including DF, resting force, and tissue dimensions, are shown in Table 2. Because DF was similar among all experimental trabeculae at baseline, DF data will be presented as a percentage of baseline DF.

View this table: [in this window] [in a new window]   Table 1. Baseline Patient Characteristics

View this table: [in this window] [in a new window]   Table 2. Baseline DF and Tissue Characteristics

The effects of ischemic preconditioning on recovery of contractile function are shown in the Figure. The simulated ischemic preconditioning stimulus provoked a fall in DF to 42±6% of baseline after 5 minutes in all preconditioned trabeculae (P<.05 versus control). Upon initiation of 45 minutes of simulated ischemia, DF declined rapidly in all trabeculae, and after 45 minutes, all groups of trabeculae had a similar percent DF remaining. During reperfusion, the IPC trabeculae rapidly recovered a greater percentage of their DF compared with control trabeculae (33±4% versus 11±3% at 5 minutes of reperfusion, respectively, P<.05). At all time points measured during reperfusion, the IPC trabeculae maintained a greater recovery of baseline DF than control trabeculae. After 120 minutes of reperfusion, IPC trabeculae recovered 52±5% of their baseline DF (P<.05 versus control and Oral Hypo+IPC), whereas control and Oral Hypo+IPC trabeculae recovered only 28±4% and 27±3% of their respective baseline DF. Trabeculae (Ins+IPC) from patients on insulin therapy did not differ from the IPC trabeculae in their functional recovery and recovered 45±6% (P<.05 versus control) of DF.

View larger version (23K): [in this window] [in a new window]   Figure 1. Effects of ischemic preconditioning in trabeculae with and without long-term exposure to oral hypoglycemic agent. Preconditioned trabeculae from patients without oral hypoglycemic exposure (IPC, n=5) show increased recovery of DF relative to trabeculae not given preconditioning stimulus (CONT, n=16) after simulated ischemic injury. Conversely, trabeculae from patients with long-term Oral Hypo+IPC, n=7, are not functionally protected by ischemic preconditioning stimulus. Ins+IPC, n=4, does not inhibit protection by preconditioning. *P<.05 vs control.

	Discussion

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The findings of the present study indicate that human atrial trabeculae can be functionally protected by a preceding transient simulated ischemic preconditioning stimulus and that this protection is not evident in human myocardium from diabetic patients exposed to long-term oral hypoglycemic agents.

Our findings support the evidence suggesting that ischemic preconditioning in human myocardium is mediated by K_ATP channel activation. Tomai and colleagues¹² observed that during coronary angioplasty, the severity of ST-segment depression is lessened during a second balloon inflation relative to the first. When they administered glibenclamide 90 minutes before angioplasty, this cardioadaptive response was eliminated. Furthermore, Yellon's group⁶ used an in vitro isolated atrial trabecular model to study preconditioning in human myocardium. They observed that a preceding period of simulated ischemia functionally protected human myocardium against an ischemic injury and that when glibenclamide, an inhibitor of the K_ATP channel, was combined with the ischemic preconditioning stimulus in vitro, protection was eliminated. The present study suggests that doses of orally administered hypoglycemic agents used clinically are sufficient to block the protection of preconditioning in human myocardium.

Although the observations that excessive mortality occurs in patients taking oral hypoglycemic agents and that ischemic preconditioning provides tolerance to ischemia appear distinctly unrelated, investigations into the mechanisms of ischemic preconditioning may provide the explanation for the increased cardiovascular mortality observed in the UDGP study. An insightful hypothesis was recently offered by Engler and Yellon¹³ when they reviewed the mechanisms of ischemic preconditioning and the action of oral hypoglycemic agents. Ischemic preconditioning is thought to be mediated by opening of K_ATP channels in myocardium,¹⁴ and it is described that oral hypoglycemic agents antagonize these channels in myocardium.¹⁵ Inhibition of these channels abrogates the endogenous protection of preconditioning, which might exacerbate cardiovascular mortality in diabetic patients. Although the present study provides only an association between oral hypoglycemic agents and the inability to precondition human myocardium, this relationship may underlie the unexplained increased cardiovascular mortality in diabetic patients treated with oral hypoglycemic agents in the UDGP trial.

Others^{6 7} have previously used human atrium for the study of ischemic preconditioning. It is possible that our results are specific to atrial tissue. Although atrial and ventricular tissues differ, we have previously observed that explanted human ventricular tissue can be ischemically preconditioned.⁸ Another important consideration in the present study is whether the observed inability to precondition myocardium from patients receiving oral hypoglycemic agents is a result of K_ATP channel inhibition, is an effect of a confounding variable present in these patients, or is related to other described intracellular actions of these agents. Other mechanisms of action of sulfonylurea agents include their cleavage of certain membrane-based proteins, such as ecto-5'-nucleotidase, inhibition of other potassium currents at higher concentrations, and binding to the cystic fibrosis transmembrane regulator.¹³ Certainly, these other mechanisms could be operant. The basis for our observed lack of protection by ischemic preconditioning in the oral hypoglycemic agent group remains to be determined. The inability to induce preconditioning does not appear to be related to diabetes mellitus, in that functional protection was inducible in the trabeculae from patients on insulin. We attempted to measure tissue levels of the oral hypoglycemic agents in the specimens used for experimentation, but levels were undetectable in the small volume of tissue available. Furthermore, the average time since the last dose of the oral hypoglycemic agents in this study was 17 hours, which is considerably longer than the reported half-life of 3 to 10 hours for glyburide or glipizide. However, clinical pharmacological investigations of both glyburide and glipizide have revealed a duration of action for both of these agents of 18 to 24 hours after ingestion. Although preliminary, this study provides further evidence supporting the involvement of the K_ATP channel in ischemic preconditioning of human myocardium and is the first to report that long-term oral hypoglycemic intake abolishes ischemic preconditioning in human myocardium.

These observed results may have clinical relevance. At present, a majority of patients with diabetes mellitus are treated with oral hypoglycemic agents.¹³ Kloner and colleagues⁹ observed in the TIMI 4 trial that angina that precedes a myocardial infarction within 48 hours confers endogenous myocardial protection. We propose that angina before a myocardial infarction is a clinical analog for ischemic preconditioning. Diabetic patients receiving oral hypoglycemic agents suffer excess cardiovascular mortality compared with diabetics treated with diet alone¹ or insulin therapy.² Although it would be premature to incorporate these observations into clinical practice at present, we believe that these data may eventually prove to be important in designing optimal therapy for patients with diabetes mellitus.

	Selected Abbreviations and Acronyms

 

DF = developed force Ins+IPC = insulin+ischemic preconditioning IPC = ischemic preconditioned (trabeculae) KATP = ATP-sensitive potassium (channel) Oral Hypo+IPC = oral hypoglycemic agent+ischemic preconditioning UDGP = University Diabetes Group Project

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL-43696, HL-44186, and GM-08315.

Received April 2, 1997; revision received April 25, 1997; accepted May 8, 1997.

	References

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