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(Circulation. 1995;92:511-517.)
© 1995 American Heart Association, Inc.

Articles

Glibenclamide, a Selective Inhibitor of ATP-Sensitive K⁺ Channels, Attenuates Metabolic Coronary Vasodilatation Induced by Pacing Tachycardia in Dogs

Yousuke Katsuda, MD; Kensuke Egashira, MD; Hideki Ueno, MD; Yutaka Akatsuka, MD; Takahiro Narishige, MD; Yukinori Arai, PhD; Tsuneo Takayanagi, BS; Hiroaki Shimokawa, MD; Akira Takeshita, MD

From the Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.

Correspondence to Kensuke Egashira, MD, PhD, The Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812, Japan.

	Abstract

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Background We previously reported that glibenclamide (a selective inhibitor of ATP-sensitive K⁺ channels [K⁺_ATP channels]) inhibited metabolic coronary vasodilatation induced by ß₁-adrenoceptor stimulation. However, the role of K⁺_ATP channels in metabolic coronary vasodilatation induced by tachycardia is still unknown. This study aimed to determine whether glibenclamide attenuates metabolic coronary vasodilatation induced by pacing-induced tachycardia.

Methods and Results In anesthetized dogs, increasing heart rate from 103±1 to 160 beats per minute with atrial pacing increased coronary blood flow without altering arterial pressure and left ventricular pressure. Intracoronary infusion of glibenclamide at 1.5 and 5.0 µg · kg^-1 · min^-1 did not alter basal coronary blood flow but significantly attenuated (P<.01) the tachycardia-induced coronary vasodilatation without altering the tachycardia-induced increase in myocardial oxygen consumption (MO₂). In conscious dogs, intracoronary glibenclamide at 5.0 µg · kg^-1 · min^-1 attenuated (P<.05) coronary vasodilatation induced by ventricular pacing from 85±6 to 150 beats per minute. Glibenclamide markedly attenuated coronary vasodilatation evoked with the K⁺_ATP channel opener pinacidil.

Conclusions These data indicate that blockade of coronary vascular K⁺_ATP channels with glibenclamide inhibited metabolic coronary vasodilatation induced by pacing tachycardia in dogs, suggesting that K⁺_ATP channels are involved in the mechanism mediating metabolic coronary vasodilatation associated with pacing tachycardia.

Key Words: adenosine • potassium • circulation • glibenclamide • vasodilation

	Introduction

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It is generally assumed that coronary perfusion in physiological conditions is regulated predominantly by myocardial metabolic state (for reviews see References 1 through 3). For a local mediator of metabolic control of coronary blood flow, adenosine was previously considered because myocardial concentration of adenosine correlated with changes in myocardial tissue metabolism.^{1 2 3 4 5 6} However, it appears that adenosine does not play a primary role in metabolic control of coronary blood flow, since adenosine receptor antagonists had no or only a modest effect on the change in coronary blood flow due to increase in myocardial metabolism.^{7 8 9}

Recent studies have suggested that changes in myocardial oxygen tension may contribute to local control of coronary blood flow during the increase in myocardial metabolism¹⁰ and during reductions in coronary perfusion pressure.^{6 11 12} Broten et al¹⁰ showed that there is a negative correlation between coronary venous oxygen tension and the degrees of metabolic coronary vasodilatation induced by pacing tachycardia. In their study, changes in myocardial oxygen tension accounted for 40% of the changes in coronary blood flow during changes in myocardial oxygen consumption (MO₂) induced by pacing tachycardia. However, it is not definitely established whether metabolic coronary vasodilatation is mediated by changes in tissue oxygen tension per se or by some factors such as ATP-sensitive potassium channels (K⁺_ATP channels) that may be altered by changes in tissue oxygen tension.

K⁺_ATP channels have been reported to exist in a variety of cell types, including vascular smooth muscle cells.¹³ The channels open when the intracellular ATP concentration falls below 1 mmol/L.^{13 14 15} Opening of the channels causes membrane hyperpolarization and subsequent vasorelaxation.¹³ Recent studies have suggested that K⁺_ATP channels may be involved importantly in local control of coronary blood flow; hypoxic coronary vasodilatation,¹⁶ coronary reactive hyperemia after brief coronary occlusion,¹⁷ autoregulatory coronary vasodilatation during reduction in perfusion pressure,¹⁸ and ß-adrenoceptor-mediated coronary vasodilatation¹⁹ were significantly attenuated by intracoronary infusion of glibenclamide, a specific blocker of K⁺_ATP channels. However, whether the channels are also involved in metabolic coronary vasodilatation induced by other means such as tachycardia has not been elucidated.

The aim of this study was to determine whether intracoronary glibenclamide inhibits metabolic coronary vasodilatation associated with the increase in MO₂ induced by pacing tachycardia in anesthetized dogs as well as in conscious dogs.

	Methods

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Animal Preparation
This study was done in anesthetized dogs with short-term placement of instruments as well as conscious dogs instrumented with long-term implanted devices, as we previously described.^{18 19 20} All animals were treated in accordance with the guidelines of the American Physiological Society.

Anesthetized Dog Preparations
Adult mongrel dogs (15 to 24 kg) were anesthetized with sodium pentobarbital (25 mg/kg IV) and ventilated with a respirator. A left thoracotomy was performed in the fourth intercostal space, and the heart was suspended in a pericardial cradle. A heating pad was used to maintain body (rectal) temperature of animals within the range from 36.0°C to 37.0°C.

A transit-time ultrasonic flow probe of an appropriate size (Transonic Inc) was placed at the midportion of the left anterior descending coronary artery (LAD). A pneumatic cuff occluder was also placed distal to the flow probe. A heparin-filled miniature polyethylene cannula (OD, 1 mm) was inserted into the LAD just distal to the flow probe for drug infusion. A polyethylene cannula (OD, 0.8 mm) was inserted into the great cardiac vein and was advanced into the anterior interventricular coronary vein for venous blood sampling. A 6F polyethylene catheter was inserted into the aortic arch through the left carotid artery for the measurement of aortic pressure. A 7F catheter-tip pressure transducer (Millar Instruments Inc) was inserted into the left ventricular (LV) cavity through the left atrial appendage for measurement of LV pressure. A pacing wire was attached to the left atrial appendage.

Conscious Dog Preparations
Dogs (20 to 30 kg) were anesthetized with sodium pentobarbital (25 mg/kg). Under sterile surgical conditions, a left thoracotomy was performed. A 6F polyethylene catheter was placed in the ascending aorta. A transit-time ultrasonic flow probe was placed in the proximal region of the left circumflex coronary artery (LCx). A heparin-filled polyethylene cannula was inserted into the LCx just distal or proximal to the flow probe for drug infusion. A pair of pacing wires was attached to the right ventricle. After the chest was closed, these dogs were allowed to recover. Seven to 10 days later, when the dogs were afebrile and had recovered from the surgery, the experiments were performed in the conscious state.

Measurements
In conscious dogs, aortic pressure (Aop) was measured with a strain-gauge transducer (Statham P23Db, Statham Instruments Inc). Heart rate (HR) was calculated by a cardiotachometer triggered by aortic pressure. Coronary blood flow (CBF) was measured with an ultrasonic flowmeter (T201, Transonic Inc). Coronary vascular resistance (CVR, mean arterial pressure/CBF) was estimated.

In anesthetized dogs, in addition to Aop, HR, and CBF, the following variables were measured. Left ventricular pressure (LVP) was measured with a catheter-tip pressure transducer (PC 350, Millar Instruments), and the positive first derivative of LVP (LV dP/dt) was obtained by electronic differentiation. All variables were continuously monitored and recorded with a polygraph system (Polygraph 360 system, NEC San-Ei). The ultrasonic flow-measurement system was calibrated by perfusing blood at known flow rates through a coronary artery branch with the flow probe.

To determine MO₂, oxygen saturation of arterial and anterior interventricular coronary venous blood was measured, because CBF of the myocardium perfused via the LAD drains exclusively to the anterior interventricular coronary vein.²¹ Oxygen saturation of paired blood samples from the aortic arch and the coronary vein was measured by a calibrated oxygen analyzer (Oxymeter type PWA-200S, ERMA Inc). The hemoglobin content in each venous blood sample was measured.

MO₂ (mL/min) was calculated by the following formula: MO₂={CBF(mL/min)x0.013xHb(g/dL)x[SaO₂(%)- SVO₂(%)]}/100, where Hb is hemoglobin content and SaO₂ and SvO₂ indicate oxygen saturation of coronary arterial and venous blood, respectively.

PO₂, PCO₂, and pH in arterial and coronary venous blood were also measured by a gas analyzer (pH blood gas analyzer, type 238, Ciba-Corning Inc).

Drugs
Glibenclamide, sodium nitroprusside (Sigma Chemical Co), acetylcholine (Dai-ichi Pharmaceutical Co), pinacidil (Shionogi Pharmaceutical Co), and UL-FS 49 (Dr Karl Thomae, Biberach GmbH) were used. Glibenclamide was dissolved in 4% glucose solution containing 0.01N NaOH. Pinacidil was dissolved in 0.01N HCl and neutralized by addition of equimolar NaOH. Other drugs were dissolved in normal saline.

Experimental Protocol
The inclusion criteria for anesthetized dog experiments were (1) peak reactive hyperemic response of CBF (peak CBF/basal CBFx100) >300%; (2) coronary venous PO₂ <30 mm Hg; and (3) hemoglobin concentration >10 g/dL.

The following protocols were performed in anesthetized dogs (protocols 1, 2, and 3) and conscious dogs (protocol 4).

Protocol 1
After completion of surgical preparations, a selective bradycardiac agent, UL-FS 49,^{22 23} at a dose of 0.25 mg/kg IV was administered to decrease the basal heart rate. Thirty minutes after administration of UL-FS 49, when all hemodynamic variables became stable, the following experiments were performed in 10 dogs. The averaged coronary blood flow per myocardium perfused via the LAD in these dogs was 8.4 mL · min^-1 · 100 g^-1 (the size of myocardium was determined by use of Evans blue dye). After baseline hemodynamics were recorded for 2 minutes, atrial pacing was repeated three times before (during intracoronary infusion of vehicle [1 mL/min]) and during low and high doses of intracoronary glibenclamide (1.5 and 5.0 µg · kg^-1 · min^-1) while CBF at the LAD, Aop, HR, LVP, and LV dP/dt were recorded. In each pacing protocol, HR was increased in a stepwise fashion from the basal HR to 120, 140, and 160 beats per minute. CBF and other hemodynamic variables were allowed to stabilize for at least 2 minutes before pacing rate was increased to the next level. To determine MO₂, oxygen saturation of arterial and coronary venous blood was measured at baseline conditions and during pacing at 160 beats per minute. Then, the animals were allowed to recover for 30 minutes before addition of glibenclamide. In the experiments with glibenclamide, pacing was started 2 minutes after the onset of glibenclamide at each dose.

Protocol 2
In four dogs, to examine the possibility of the time-related changes in hemodynamic responses to pacing, we repeated the atrial pacing protocol three times at 30-minute intervals while CBF of the LAD, Aop, LVP, LV dP/dt, and HR were recorded. MO₂ was also determined at baseline and during pacing at 160 beats per minute. These experiments were done after intravenous administration of UL-FS 49.

Protocol 3
In four dogs that were treated with UL-FS 49, to examine the efficacy of glibenclamide, acetylcholine (3 µg/min), sodium nitroprusside (30 µg/min), and pinacidil (3 and 10 µg/min), a selective K⁺_ATP channel opener, were administered into the LAD before and after simultaneous intracoronary infusion of glibenclamide at 1.5 and 5.0 µg · kg^-1 · min^-1, while CBF at the LAD, Aop, and HR were continuously monitored and recorded.

Protocol 4
In eight chronically instrumented conscious dogs that were lying quietly in a dimly lighted room without restraint, ventricular pacing was performed before (during intracoronary infusion of vehicle) and after intracoronary infusion of glibenclamide at a dose of 5.0 µg · kg^-1 · min^-1, while CBF of the LCx, Aop, and HR were continuously monitored and recorded.

Statistical Analysis
Data are presented as mean±SEM. For comparison of paired or unpaired data, Student's t tests were used. For serial changes in hemodynamic variables in response to changes in pacing rate, one-way ANOVA followed by Bonferroni's multiple comparison tests was used. When pacing-induced changes in hemodynamic variables were compared before and after glibenclamide, two-way ANOVA of repeated measures was applied. A probability of P<.05 was considered statistically significant.

	Results

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Effects of Glibenclamide on Coronary Vasodilatation Induced by Pacing Tachycardia (Protocols 1 and 4)
Basal arterial and coronary venous PO₂, PCO₂, and pH are indicated in Table 1 (n=10), all of which were similar during vehicle and glibenclamide infusion. Reactive hyperemic responses to a 20-second coronary occlusion were preserved during vehicle infusion but were significantly attenuated during intracoronary glibenclamide at 5.0 µg · kg^-1 · min^-1 (Table 1), as reported previously.¹⁷

View this table: [in this window] [in a new window]   Table 1. Blood Gas Data and Reactive Hyperemia

In anesthetized dogs, intravenous administration of UL-FS 49 decreased basal HR and CBF (Table 2). Hemodynamic parameters before UL-FS 49 at an HR of 143±4 beats per minute were comparable to those after UL-FS 49 at an HR of 140 beats per minute, indicating that UL-FS 49 selectively decreased basal HR without altering other hemodynamic variables. During vehicle infusion (after UL-FS 49), stepwise increases in HR with atrial pacing increased CBF and decreased CVR in a rate-dependent fashion (P<.05 by one-way ANOVA) without altering Aop, LV end-diastolic pressure (EDP), and LV dP/dt (Table 2, Fig 1). Intracoronary infusion of glibenclamide at 1.5 and 5.0 µg · kg^-1 · min^-1 did not change basal CBF, CVR, and other hemodynamic variables. Glibenclamide significantly attenuated the tachycardia-induced increase in CBF (P<.01 by two-way ANOVA) and the decrease in CVR (P<.05 by two-way ANOVA), while glibenclamide did not alter tachycardia-induced changes in Aop, LVEDP, and LV dP/dt.

View this table: [in this window] [in a new window]   Table 2. Effect of Glibenclamide on Tachycardia-Induced Coronary Vasodilatation in Anesthetized Dogs

View larger version (21K): [in this window] [in a new window]   Figure 1. Graphs showing effects of intracoronary glibenclamide on the percent changes in coronary blood flow (CBF) (A), coronary vascular resistance (B), and the ratio of the percent increase in CBF to that in myocardial oxygen consumption (MO2) (C) in response to pacing tachycardia. Data are mean±SEM (n=10). HR indicates heart rate; bpm, beats per minute.

During vehicle infusion, the tachycardia-induced increase in CBF was associated with a similar increase in calculated MO₂ (P<.05), and thus, the ratio of CBF to MO₂ was comparable at baseline conditions and during pacing at 160 beats per minute (Table 2). Intracoronary glibenclamide increased myocardial oxygen extraction (arteriovenous O₂ difference) during pacing (P<.05), so that the tachycardia-induced increase in MO₂ was comparable during vehicle infusion and during glibenclamide (Table 2). Intracoronary glibenclamide at 1.5 and 5.0 µg · kg^-1 · min^-1 significantly decreased the CBF/MO₂ ratio during tachycardia (Table 2). The ratio of the increase in CBF to that in MO₂ during glibenclamide at 5.0 µg · kg^-1 · min^-1 was significantly lower than that during vehicle infusion (Fig 1, Table 2). There was no significant correlation (P>.1) between the percent inhibition of tachycardia-induced increase in CBF and basal oxygen contents in the coronary vein (data not shown).

In conscious dogs, glibenclamide at 5.0 µg · kg^-1 · min^-1 significantly attenuated the increase in CBF and the decrease in CVR with ventricular pacing tachycardia but did not alter the tachycardia-induced changes in Aop and the pressure-rate products (systolic arterial pressurexHR) (Table 3, Fig 2).

View this table: [in this window] [in a new window]   Table 3. Effects of Glibenclamide on Tachycardia-Induced Coronary Vasodilatation in Conscious Dogs

View larger version (11K): [in this window] [in a new window]   Figure 2. Bar graphs showing effect of intracoronary glibenclamide on percent increase in coronary blood flow (CBF) (A) and pressure-rate product (PRP) (B) in response to pacing tachycardia in conscious dogs. Data are mean±SEM (n=8).

Reproducibility of Pacing-Induced Coronary Vasodilatation (Protocol 2)
In the time-control experiments (Table 4), in which responses to pacing tachycardia were studied three times in a similar time sequence, responses of CBF, CVR, MO₂, and other variables to pacing tachycardia were comparable among the first, second, and third experiments.

View this table: [in this window] [in a new window]   Table 4. Time Course of Tachycardia-Induced Coronary Vasodilatation in Anesthetized Dogs

Effects of Glibenclamide on Pinacidil-Induced Coronary Vasodilatation (Protocol 3)
Intracoronary administration of pinacidil, acetylcholine, and sodium nitroprusside did not alter Aop, LVEDP, and HR (data not shown) but did increase CBF. The percent increases in CBF by pinacidil at 3 and 10 µg/min were 37±10% and 102±14%, respectively, during vehicle infusion, 3±2% and 42±9% during infusion of glibenclamide at 1.5 µg · kg^-1 · min^-1 (P<.01 for each by ANOVA plus multiple comparison tests), and 5±4% and 6±2% during glibenclamide at 5.0 µg · kg^-1 · min^-1 (P<.01 by ANOVA plus multiple comparison test). Glibenclamide did not affect the percent increases in CBF by acetylcholine (266±20% during vehicle, 264±44% during glibenclamide at 1.5 µg · kg^-1 · min^-1, and 244±19% during glibenclamide at 5.0 µg · kg^-1 · min^-1 [P=NS]) and sodium nitroprusside (169±28% during vehicle, 142±27% during glibenclamide at 1.5 µg · kg^-1 · min^-1, and 133±18% during glibenclamide at 5.0 µg · kg^-1 · min^-1 [P=NS]).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major new findings of this study are that glibenclamide, a selective inhibitor of K⁺_ATP channels, inhibited coronary vasodilatation associated with pacing tachycardia without altering the tachycardia-induced increase in myocardial oxygen consumption in dogs.

In the present study, we used glibenclamide as a selective inhibitor of K⁺_ATP channels as in previous studies.^{16 17 18 19 24 25} However, it is reported that glibenclamide at higher doses decreases CBF,^{24 25} modulates calcium-activated K⁺ channels,²⁶ and activates the endogenous vasodilatory substances such as adenosine.²⁵ Coronary vasodilatation evoked by adenosine may be mediated in part by opening of K⁺_ATP channels.^{17 27} Therefore, the use of glibenclamide at higher doses might be inappropriate for studying a specific effect of K⁺_ATP channels on tachycardia-induced metabolic coronary vasodilatation. In this study, intracoronary glibenclamide at 5 µg · kg^-1 · min^-1 did not alter basal hemodynamic variables but nearly abolished coronary vasodilatation evoked with pinacidil, a specific K⁺_ATP channel opener. Glibenclamide did not affect coronary vasodilatation evoked with acetylcholine or sodium nitroprusside. Therefore, it is reasonable to assume that the doses of glibenclamide used in this study were sufficient and specific to block opening of coronary vascular K⁺_ATP channels.

In anesthetized dogs, the pacing-induced tachycardia caused coronary vasodilatation without altering other hemodynamic parameters during vehicle infusion. The tachycardia-induced increase in CBF was associated with a similar increase in MO₂, and thus, the CBF/MO₂ ratio was comparable at baseline conditions and during tachycardia. These findings are consistent with a previous suggestion that pacing tachycardia causes coronary vasodilatation proportional to the increase in MO₂.^{1 2 3}

An important finding of this study is that intracoronary glibenclamide significantly inhibited the tachycardia-induced coronary vasodilatation in anesthetized dogs (Table 2, Fig 1A and 1B) and conscious dogs (Table 3, Fig 2). In anesthetized dogs, glibenclamide did not alter tachycardia-induced changes in MO₂; the CBF/MO₂ ratio and the ratio of the increase in CBF to that in MO₂ were significantly less after than before glibenclamide. In conscious dogs, glibenclamide did not affect the tachycardia-induced increases in the pressure-rate product. These results suggest that the inhibitory effect of intracoronary glibenclamide on tachycardia-induced coronary vasodilatation did not result from changes in tachycardia-induced increase in MO₂. It is unlikely that changes in Aop, LVEDP, and LV dP/dt during tachycardia accounted for the effect of glibenclamide, because tachycardia-induced changes in these hemodynamic parameters during infusion of glibenclamide did not differ from those during vehicle infusion. Furthermore, in the time-control study, tachycardia-induced coronary vasodilatation was comparable among the first, second, and third experiments, indicating that the effect of glibenclamide was not time-related nonspecific changes.

It should be noted that the coronary venous oxygen contents were somewhat high in our open-chest dogs, which might possibly account for the effect of glibenclamide. However, a similar inhibitory effect of glibenclamide on tachycardia-induced coronary vasodilatation was noted in conscious dogs, in which coronary venous oxygen content should not be high. Furthermore, in anesthetized dogs, there was no correlation between the inhibitory effects of glibenclamide and basal oxygen content in the coronary vein. Therefore, these results suggest that the effect of glibenclamide on tachycardia-induced coronary vasodilatation was not related to the high oxygen content in the coronary vein in anesthetized dogs.

Therefore, our results strongly suggest that metabolic coronary vasodilatation associated with the increase in myocardial metabolism induced by pacing tachycardia is mediated by opening of coronary vascular K⁺_ATP channels. However, the degree to which K⁺_ATP channels are involved in metabolic coronary vasodilatation associated with pacing tachycardia appears to be partial, in that the magnitudes of attenuation of the ratio of the increase in CBF to the increase in MO₂ by glibenclamide at 5.0 µg · kg^-1 · min^-1 were approximately 46%. Intracoronary glibenclamide at 5.0 µg · kg^-1 · min^-1 abolished coronary vasodilatation evoked with pinacidil at 3 µg/min (percent increase in CBF, 37±10%), which was comparable to coronary vasodilatation associated with pacing at 160 beats per minute in anesthetized dogs. Therefore, incomplete inhibition of tachycardia-induced coronary vasodilatation by glibenclamide may not be explained by inadequate blockade of K⁺_ATP channels with glibenclamide. Since the degree of coronary vasodilatation was relatively modest in this study, we cannot exclude the possibility that the inhibitory effect of glibenclamide might be more evident if experiments with a greater increase in HR were performed.

Recent studies have examined the role of K⁺_ATP channels in metabolic coronary vasodilatation induced by exercise,²⁸ ß-adrenoceptor stimulation,¹⁹ and pacing tachycardia (this study). It is interesting to note that the magnitudes of attenuation of metabolic coronary vasodilatation by glibenclamide differed depending on stimuli for increasing myocardial metabolism. Namely, we previously showed that metabolic coronary vasodilatation associated with ß₁-adrenoceptor stimulation was nearly abolished by intracoronary glibenclamide at 1.5 or 5.0 µg · kg^-1 · min^-1,¹⁹ whereas Duncker et al²⁸ demonstrated that metabolic coronary vasodilatation associated with exercise was not affected by intracoronary glibenclamide at 10 and 50 µg · kg^-1 · min^-1. This study demonstrated that metabolic coronary vasodilatation associated with pacing tachycardia was partly inhibited by intracoronary glibenclamide at 1.5 and 5.0 µg · kg^-1 · min^-1. Previous studies have reported that opening of K⁺_ATP channels is facilitated by ß-adrenoceptor stimulation,^{29 30} which might have accounted for the greater inhibitory effect of glibenclamide on metabolic coronary vasodilatation induced by ß-adrenoceptor stimulation.¹⁹ The reason for the difference between our studies and the study by Duncker et al²⁸ is not clear, but it may be related to the doses of glibenclamide. In the study by Duncker et al,²⁸ it is possible that the decrease in basal CBF and myocardial function by glibenclamide at higher doses might have activated the endogenous vasodilatory mechanisms and thus blunted the effect of glibenclamide. Nevertheless, the results of previous studies and this study may suggest that metabolic coronary vasodilatation induced by exercise, ß-adrenoceptor stimulation, and tachycardia may be mediated by the different mechanisms. Further studies are needed to elucidate more precise roles of K⁺_ATP channels in metabolic coronary vasodilatation.

Since intracellular concentrations of ATP may not fall below 1 mmol/L during the increase in MO₂ without ischemia or hypoxia, opening of K⁺_ATP channels that might occur during metabolic coronary vasodilatation cannot be explained by a fall in global intracellular ATP concentrations per se. It is possible that increased myocardial metabolism would reduce oxygen tension in the region of metabolically compromised myocardium, so that local concentrations of ATP could decrease.³¹ A subsequent decrease in ATP concentrations in the vicinity of K⁺_ATP channels with no measurable change in global intracellular ATP concentrations (ie, intracellular compartmentation of ATP) would activate opening of K⁺_ATP channels at the cell membrane of vascular smooth muscle cells. Further studies are needed to prove this speculative hypothesis.

In summary, we have shown that glibenclamide significantly attenuated metabolic coronary vasodilatation induced by pacing tachycardia in dogs. These results suggest that K⁺_ATP channels may be partly involved in the mechanisms mediating metabolic coronary vasodilatation associated with increased MO₂ during pacing tachycardia. The results also suggest that currently unknown mechanisms other than K⁺_ATP channels may play a relatively large part in metabolic coronary vasodilatation.

	Acknowledgments

 
This study was supported by Grants-in-Aid for General Scientific Research 05670617, 05857085, and 06670725 from the Ministry of Education, Science, and Culture, Tokyo, and by grants from the Japan Cardiovascular Research Foundation, Osaka, the Japan Heart Foundation, Tokyo, and the Naito Memorial Foundation, Tokyo, Japan.

Received December 19, 1994; accepted January 24, 1995.

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