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(Circulation Research. 2002;90:231.)
© 2002 American Heart Association, Inc.

Clinical Research

Effect of ATP-Sensitive Potassium Channel Inhibition on Resting Coronary Vascular Responses in Humans

H. M. Omar Farouque, Stephen G. Worthley, Ian T. Meredith, R. Andrew P. Skyrme-Jones, Michael J. Zhang

From the Centre for Heart and Chest Research, Monash Medical Centre and Monash University, Melbourne, Australia.

Correspondence to Assoc Prof Ian T. Meredith, Cardiovascular Research Centre, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, Victoria, 3168, Australia. E-mail ian.meredith{at}med.monash.edu.au

	Abstract

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Experimental data suggest that vascular ATP-sensitive potassium (K_ATP) channels regulate coronary blood flow (CBF), but their role in regulating human CBF is unclear. We sought to determine the contribution of K_ATP channels to resting conduit vessel and microvascular function in the human coronary circulation. Twenty-five patients (19 male/6 female, aged 56±12 years) were recruited. Systemic and coronary hemodynamics were assessed in 20 patients before and after K_ATP channel inhibition with graded intracoronary glibenclamide infusions (4, 16, and 40 µg/min), in an angiographically smooth or mildly stenosed coronary artery following successful elective percutaneous coronary intervention to another vessel. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. Adenosine-induced hyperemia was determined following bolus intracoronary adenosine injection (24 µg). Time control studies were undertaken in 5 patients. Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting conduit vessel diameter from 2.5±0.1 to 2.3±0.1 mm (P<0.01), resting CBF by 17% (P=0.05), and resting CBF corrected for rate pressure-product by 18% (P=0.01) in a dose-dependent manner. A corresponding 24% increase in coronary vascular resistance was noted at the highest dose (P<0.01). No alteration to resting CBF was noted in the time control studies. Glibenclamide reduced peak adenosine-induced hyperemia (P=0.01) but did not alter coronary flow reserve. Plasma insulin increased from 5.6±1.2 to 7.6±1.3 mU/L (P=0.02); however, plasma glucose was unchanged. Vascular K_ATP channels are involved in the maintenance of basal coronary tone but may not be essential to adenosine-induced coronary hyperemia in humans.

Key Words: blood flow • potassium channels • sulfonylurea • vasoconstriction • coronary flow reserve

	Introduction

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Membrane-bound adenosine triphosphate-sensitive potassium (K_ATP) channels were first identified by Noma in cardiac myocytes.¹ They have since been discovered in numerous cell types including pancreatic ß-cells,² vascular smooth muscle cells,³ and arterial endothelial cells.⁴ These channels are regulated by the cellular metabolic state and are selectively inhibited by sulfonylurea derivatives such as glibenclamide, which are widely used in the treatment of type 2 diabetes mellitus.

K_ATP channel activation results in membrane hyperpolarization, which in vascular smooth muscle cells leads to vasorelaxation.⁵ In mediating vascular smooth muscle cell membrane potential, K_ATP channels provide a means by which cellular metabolism can be linked to vascular tone. In the coronary circulation, local myocardial metabolism exerts the most important influence in regulating coronary blood flow (CBF). K_ATP channels in coronary resistance vessels appear to be an important intermediary in this process. Experimental studies in the coronary circulation of different animal species have indicated that K_ATP channels are involved in mediating basal tone,^6–9 reactive hyperemia,^6,10 hypoxic vasodilation,¹¹ and adenosine-induced vasodilation,^10–15 as reflected by the fact that these processes are inhibited by pretreatment with glibenclamide. Relatively little data are available on the role of K_ATP channels in human vasculature. Recent clinical studies suggest that K_ATP channels may contribute to peripheral blood flow regulation.^16–18 However, the role of K_ATP channels in regulating human CBF is not known. Thus, we examined the contribution of K_ATP channels to resting conduit vessel and microvascular function in the human coronary circulation.

	Materials and Methods

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Patient Selection
Patients undergoing elective percutaneous coronary intervention (PCI) were considered for the study. Suitable patients were required to have one angiographically smooth or mildly stenosed (<20% diameter stenosis) major epicardial coronary artery that had not previously been instrumented. All coronary flow studies were performed in a coronary artery fulfilling these criteria, after successful percutaneous single vessel intervention to an adjacent but unrelated vessel. Patients with unstable angina, valvular heart disease, left ventricular ejection fraction less than 50%, and renal or hepatic disease were excluded. Twenty-five patients were enrolled and their baseline characteristics are displayed in Table 1. Twenty patients received glibenclamide infusions, and 5 patients took part in time control experiments. The study was approved by the Human Research Ethics Committee of Monash Medical Center and written informed consent was obtained from all patients.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Study Population

Study Protocol
Vasoactive medication was discontinued at least 24 hours before the procedure. All patients received oral doses of aspirin (300 mg) and clopidogrel (300 mg) in preparation for PCI. Heparin (70 to 100 U/kg) was administered intravenously before coronary instrumentation. Following successful and uncomplicated PCI, a 0.014-inch Doppler guidewire (FloWire, Cardiometrics, EndoSonics) was advanced into the study artery and positioned in its proximal or mid-segment to obtain stable Doppler flow velocity signals. A 2.8F infusion catheter (Tracker, Target Therapeutics, Boston Scientific) for intracoronary drug administration was passed over the Doppler guidewire and positioned proximal to its tip. Resting blood flow velocity and coronary diameter as determined by quantitative coronary angiography were recorded after 5 minutes of vehicle infusion (0.9% saline). Quantitative coronary angiography was performed using a standardized automated power injection of contrast (Ultravist, Schering AG). Adenosine-induced coronary flow reserve (CFR) was then assessed and the time course of hyperemia recorded. In 20 subjects, 3 incremental doses of glibenclamide were then infused consecutively into the study vessel to establish a cumulative dose-response relationship. Resting coronary blood flow velocity, epicardial coronary diameter, and CFR were reassessed after 5 minutes of each infusion. Baseline coronary blood flow velocity was reestablished after each angiogram and adenosine bolus. Venous blood samples were taken at the beginning and end of the protocol for plasma glucose and insulin levels. In 5 additional subjects, the timing of infusions and study measurements were identical, except that saline and not glibenclamide was infused. These experiments were conducted to control for the effect of time.

Study Drugs
Glibenclamide lyophilisate (HB 419, Aventis Pharma Deutschland GmbH) was dissolved in 0.9% saline and infused at 4, 16, 40 µg/min into the study vessel by syringe pump (Terumo Corporation) at 0.8 mL/min. This preparation is suitable for parenteral human use and does not require the addition of an alkaline vehicle to ensure solubility. Assuming resting blood flow in a coronary artery is 80 mL/min,¹⁹ these infusion rates will result in estimated intracoronary blood concentrations of 50, 200, and 500 ng/mL, respectively. These concentrations are at the upper end of the range seen after administration of glibenclamide to patients with type 2 diabetes mellitus²⁰ and have been shown to block vascular K_ATP channels in humans.^21,22 Coronary flow reserve was assessed following a 24-µg bolus injection through the guiding catheter of the coronary vasodilator adenosine (Adenocor, Sanofi-Synthelabo).

Coronary Vascular and Hemodynamic Data
Epicardial coronary artery diameter was determined by digital coronary angiography. Images were analyzed off-line from end-diastolic frames using an automated edge-detection program (QCA-CMS version 4.1, MEDIS medical imaging systems) by an individual blinded to the study phase (S.G. Worthley). Mean coronary diameter was measured 5 mm distal to the tip of the Doppler guidewire over a 5-mm segment. Doppler indices, hemodynamic data (systemic blood pressure, heart rate), and the ECG were recorded continuously during the study and analyzed off-line as described previously.²³ Heart rate, blood pressure, and average peak velocity (APV) were obtained from a minimum of 10 cardiac cycles. Coronary blood flow (mL/min) was calculated using the formula · APV · 0.125 · coronary diameter.²⁴ The rate-pressure product (RPP, bpm · mm Hg), an index of myocardial workload, was computed by multiplying heart rate and systolic blood pressure. Coronary blood flow was corrected for RPP by dividing CBF by the RPP. The calculation of peak adenosine-induced hyperemia was based on the assumption that conduit vessel diameter does not alter significantly in the brief period taken before maximum vasodilation is achieved.²³ Coronary vascular resistance (CVR, mm Hg/mL/min) was calculated as the quotient of mean arterial blood pressure (MABP) and CBF.

Statistical Analysis
Baseline characteristics are presented as mean±SD; other values are reported as mean±SEM. Coronary vascular and hemodynamic data were tested for normality using the Kolmogorov-Smirnov test. Variables that were not normally distributed were transformed using the Box-Cox procedure.²⁵ Changes in coronary vascular responses and systemic variables within each group were analyzed using repeated measures analysis of variance followed by post hoc testing as appropriate. Humoral parameters were compared using the paired Student’s t test. Statistical significance was determined at a value of P<0.05.

	Results

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Safety and Systemic Effects of Glibenclamide
All coronary studies were completed without complication. The study vessel was the left anterior descending coronary artery in 10 patients, the circumflex coronary artery in 9 patients, and the right coronary artery in 1 patient. Intracoronary glibenclamide did not result in symptomatic or electrocardiographic evidence of myocardial ischemia. There was a small increase in MABP (P=0.008, Table 2) and an associated reduction in heart rate (P=0.03; Table 2) with increasing doses of glibenclamide. Compared with vehicle infusion, glibenclamide did not significantly alter RPP at any of the 3 doses used. Plasma insulin levels increased slightly (5.6±1.2 to 7.6±1.4 mU/L; P=0.02) during the study, but there was no change in plasma glucose (5.6±0.4 to 5.7±0.3 mmol/l; P=NS).

View this table: [in this window] [in a new window]   Table 2. Systemic Hemodynamic Parameters

Effect of Glibenclamide on Conduit Vessel Diameter
Glibenclamide infusions at 4, 16, and 40 µg/min elicited a vasoconstrictor response in the study vessel compared with vehicle infusion. A dose-response relationship was noted, with the highest glibenclamide dose having the greatest vasoconstrictor effect (2.50±0.10; 2.43±0.10; 2.40±0.11; and 2.32±0.11 mm; P=0.001, Figure 1). Compared with baseline, the percentage change in diameter at each glibenclamide dose was 2.8%, 4%, and 7.2%. The difference in epicardial diameter was due to a significant vasoconstrictor effect at each dose of glibenclamide (Figure 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Effect of glibenclamide on conduit vessel diameter. Glibenclamide decreased resting coronary diameter in a dose-dependent manner. Glib 1, 2, and 3 indicate intracoronary glibenclamide infusions at 4, 16, and 40 µg/min, respectively. *P<0.05 vs vehicle.

Effect of Glibenclamide on Coronary Microvascular Function
There was a strong trend to reduction in resting CBF with glibenclamide (32.9±5.3 versus 29.7±4.7 versus 28.4±3.8 versus 27.4±3.6 mL/min, P=0.05; Figure 2), which reached statistical significance when corrected for RPP (P=0.01; Figure 2). Glibenclamide also produced a graded increase in CVR (P=0.006, Figure 2), with the highest dose resulting in a 24% increase in CVR compared with vehicle infusion. Compared with vehicle, peak adenosine-induced CBF declined with glibenclamide infusion (P=0.01, Table 3). Baseline APV and maximal adenosine-induced APV were similar during vehicle infusion and after each of the glibenclamide doses used. Although peak adenosine-induced CBF was attenuated by glibenclamide, CFR did not decrease as basal CBF was proportionately reduced (Table 3). The duration of the vasodilator response was similar with vehicle or glibenclamide.

View larger version (14K): [in this window] [in a new window]   Figure 2. Effect of glibenclamide on resting coronary microvascular function. Glibenclamide reduced (A) coronary blood flow and (B) coronary blood flow corrected for rate pressure product Glibenclamide increased (C) coronary vascular resistance. Glib 1, 2, and 3 indicate intracoronary glibenclamide infusions at 4, 16, and 40 µg/min, respectively. *P<0.05 vs vehicle.

View this table: [in this window] [in a new window]   Table 3. Effect of Adenosine on Coronary Hemodynamics

Time Control Study
The study vessel was the left anterior descending coronary artery in 1 patient and circumflex coronary artery in 4 patients. In this group, MABP and RPP were unchanged during the time course of the study (P=NS). There was no alteration in epicardial diameter (2.62±0.21 versus 2.64±0.21 versus 2.61±0.18 versus 2.61±0.20 mm; P=NS), CBF (30.5±4.3 versus 31.2±4.3 versus 31.3±4.2 versus 30.7±3.7 mL/min; P=NS), or CVR (3.7±0.7 versus 3.6±0.6 versus 3.6±0.6 versus 3.6±0.6 mm Hg/mL/min; P=NS).

	Discussion

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To our knowledge, this is the first report to examine the effect of an intracoronary infusion of glibenclamide, an inhibitor of K_ATP channels, on human coronary vascular responses. We have demonstrated that under resting conditions, glibenclamide produces an incremental reduction in coronary conduit vessel diameter in a dose-dependent manner. Our findings also indicate that K_ATP channel inhibition has a moderate effect on coronary microvascular function as evidenced by a reduction in resting CBF and an increase in CVR. Furthermore, glibenclamide reduced peak adenosine-induced vasodilation but not CFR. These changes occurred in the absence of significant alteration to myocardial workload or clinical evidence of ischemia. The results suggest that K_ATP channels are active under resting conditions in the intact human coronary circulation and are involved in mediating basal coronary vascular responses but may not be essential to adenosine-induced coronary vasodilation.

K_ATP Channels and Basal Coronary Tone
There is good evidence from experimental studies that K_ATP channels contribute to basal coronary vascular tone. In the isolated perfused rabbit heart and anesthetized open-chest dogs, Samaha et al⁸ found that K_ATP channel inhibition caused a significant increase in basal CVR. In the open-chest dog model, intracoronary glibenclamide infusion at 16 to 64 µg/kg/min was used to inhibit K_ATP channels. The highest dose resulted in a 2-fold increase in CVR and a 50% reduction of CBF associated with evidence of myocardial ischemia, without altering heart rate and blood pressure.⁸ In a similar animal model, using doses of glibenclamide 0.5 to 50 µg/kg/min, Imamura et al⁷ confirmed these findings. Duncker et al⁶ studied regulation of basal coronary tone in chronically instrumented awake dogs. Intracoronary glibenclamide was infused at rates of 10 and 50 µg/kg/min and caused a 20% to 30% reduction in resting CBF. They also demonstrated that the glibenclamide-induced reduction in CBF was caused by selective inhibition of K_ATP channels as opposed to a nonspecific effect on vascular smooth muscle. A dose-response relationship was seen in these in vivo studies, with larger doses of glibenclamide (and therefore more pronounced K_ATP channel inhibition) having a greater effect on coronary vascular responses. It is evident that K_ATP channel inhibition results in impairment of resting coronary vascular responses using in vitro or in vivo experimental techniques across different animal species. Our findings in the human coronary circulation are consistent with the available experimental data.

Human data examining the role of vascular K_ATP channels in CBF regulation is limited. Nahser et al²⁶ studied coronary flow velocity reserve and metabolic coronary vasodilation induced by pacing in 24 patients with diabetes mellitus. Although the effect of K_ATP channel inhibitor therapy on coronary flow responses was not a major aim of the study, they subdivided their sample into patients receiving long-term oral sulfonylurea therapy for glycemic control and those not receiving these agents. No difference in coronary flow velocity reserve or metabolic vasodilation was noted between these subgroups. Of relevance to their findings, sulfonylurea medication was withheld on the study day. Thus, vascular K_ATP channels may not have been effectively inhibited at the time of catheterization.

Previous studies of vascular K_ATP channel function in human subjects have focused on the peripheral arterial circulation. Using the technique of forearm venous occlusion plethysmography, we²¹ and others^16–18 have infused K_ATP channel inhibitors into the brachial artery. These studies have been consistent in showing that resting forearm blood flow is not significantly altered using the sulfonylurea derivatives glibenclamide or tolbutamide. However, oral glibenclamide did reduce resting calf blood flow compared with placebo in another study.²⁷ Some of these studies have provided evidence for a modest contribution of K_ATP channels in reactive hyperemia induced by forearm^16–18 and calf²⁷ ischemia. The present study in the coronary circulation and those performed in the peripheral circulation suggest that K_ATP channels contribute to the regulation of human vascular tone to varying degrees, in different circulatory beds, and under a range of experimental conditions.

Adenosine-Induced Coronary Vasodilation
It has been postulated that adenosine is an important metabolic vasodilator in the coronary circulation, although it does not appear to play a prominent role in controlling resting blood flow. Most experimental studies suggest that its coronary vasodilator action may in part be mediated through K_ATP channels.^10–15 There is less evidence to support the alternate view that K_ATP channels are not involved in adenosine-induced vasodilation,²⁸ with the apparent inconsistency possibly due to methodological differences. Recent investigations have helped to clarify the basic mechanisms responsible for adenosine-induced coronary vasodilation. These studies suggest that adenosine may activate endothelial and smooth muscle K_ATP channels by binding to the adenosine A_2A receptor.^13,29

There is a paucity of data on the role of K_ATP channels in adenosine-induced vasodilation in the human circulation. A study in the forearm circulation found that adenosine-induced vasodilation was not attenuated by the K_ATP channel inhibitor, tolbutamide.¹⁸ In our study, coronary K_ATP channel inhibition resulted in a diminution of the peak vasodilator response to adenosine. However, the observation that CFR did not change significantly with glibenclamide infusion suggests that K_ATP channels are not critical to the vasodilator response to adenosine and that other mechanisms are involved. Taken together, these findings raise the possibility of species-related heterogeneity in the pathways responsible for adenosine-induced vasodilation.

Glibenclamide and K_ATP Channel Inhibition
It is well established that glibenclamide is a specific inhibitor of K_ATP channels.^3,6 This agent has been used extensively in animal studies to examine the role of K_ATP channels in controlling vascular tone.^{6–12,15,28,30,31} Although the doses of glibenclamide used in animal studies have in general been higher than in our study, there is evidence that lower concentrations may also result in significant inhibition of vascular K_ATP channels.^{12,21,22,32,33} Studies in the human forearm circulation have revealed that glibenclamide infused with the aim of attaining therapeutic regional concentrations, may attenuate the vasodilation induced by the K_ATP channel opener, diazoxide.^21,22 The doses of glibenclamide we used were chosen to achieve concentrations in the study vessel that were comparable with peak blood levels seen after oral administration of glibenclamide in type 2 diabetic subjects.²⁰ However, the actual intracoronary concentration of glibenclamide at each dose would have been higher than initial estimates, which were based on a CBF of 80 mL/min. We found that the average CBF was approximately 30 mL/min. Recirculation of glibenclamide over the duration of infusion may also have resulted in higher intracoronary glibenclamide concentrations. Furthermore, no change in conduit vessel diameter or CBF was seen in the subgroup of patients undergoing the time control studies, providing evidence that glibenclamide was having a specific effect on the coronary circulation. We documented a small rise in plasma insulin concentrations consistent with pancreatic ß-cell K_ATP channel blockade. Of note, experimental evidence suggests that K_ATP channels from pancreatic ß-cells and coronary resistance vessels may have similar sensitivity to inhibition by glibenclamide.³² Although it is possible that using higher glibenclamide doses may have achieved a greater degree of vascular K_ATP channel inhibition, this would have resulted in large alterations to insulin and glucose, thereby confounding coronary hemodynamic parameters.

Study Limitations
Ethical considerations preclude the invasive study of patients without coronary disease, thus all patients had atherosclerotic risk factors. The effect of these processes on K_ATP channel activity is unknown. It is conceivable that alteration of K_ATP channel function may occur in certain disease states as has been demonstrated in animal studies.^30,34 The coronary arteries studied were also likely to have been atherosclerotic with some degree of impaired endothelial vasodilator function. It is possible that a functional endothelium may have offset the vasoconstrictor response to K_ATP channel inhibition. In this study, all subjects received aspirin prior to catheterization. Although this agent can inhibit the production of vasodilator prostanoids and affect coronary hemodynamics, these effects are prominent at aspirin doses higher than were administered in this study.²³ Our study examined the effect of short-term K_ATP channel inhibition compared with long-term inhibition seen with prolonged oral therapy. The latter circumstance is more relevant to the clinical situation. There is evidence that long-term sulfonylurea therapy may lead to a reduction in the number of functional K_ATP channels in pancreatic ß-cells.³⁵ These findings raise the possibility that long-term K_ATP channel inhibition may also affect the function of vascular K_ATP channels.

Glibenclamide is a nonselective antagonist of K_ATP channels and in this sense not an ideal pharmacological modulator. This agent may interact with K_ATP channels at various sites including the inner mitochondrial membrane and sarcolemma. In theory, a primary effect of glibenclamide on mitochondrial respiration, by inhibition of mitochondrial K_ATP channels, could lead to secondary changes in coronary hemodynamics. However, a recent study has established that the reduction in CBF demonstrated with glibenclamide is due to primary vasoconstriction rather than a secondary effect related to a reduction in mitochondrial respiration.³⁶

Clinical Implications
K_ATP channel inhibition with sulfonylureas for glycemic control represents the mainstay of pharmacological therapy in patients with type 2 diabetes mellitus. It has been suggested that this class of drug may be associated with increased cardiovascular events in diabetic patients with coronary disease.^37–39 However, this remains a contentious issue with other studies refuting these claims.^40,41 At the present time, it is unclear if this class of drug is free of clinically significant cardiovascular effects. The available data indicates that activation of K_ATP channels leads to beneficial vascular effects and myocardial responses such as ischemic preconditioning. Inhibition of K_ATP channels in this setting may therefore be potentially disadvantageous.⁴² Our results suggest that K_ATP channel inhibition may affect coronary vascular responses in patients with underlying coronary disease. An understanding of the contribution of K_ATP channels in modulating blood flow may have important ramifications for the management of patients with acute or chronic myocardial ischemia.

	Conclusion

Top Abstract Introduction Materials and Methods Results Discussion Conclusion References

 
We provide evidence for the involvement of vascular K_ATP channels in regulating resting coronary tone in humans. This was manifest as a reduction in conduit vessel diameter, CBF, and an increase in CVR. Our results also suggest that K_ATP channels may not be essential to adenosine-induced coronary vasodilation. The role of these channels in human coronary metabolic vasodilation remains to be determined.

	Acknowledgments

 
Dr Farouque is supported by a National Heart Foundation of Australia Medical Postgraduate Research Scholarship (PM 98M 0006). Glibenclamide lyophilisate (HB 419) was kindly supplied by Aventis Pharma Deutschland GmbH, Frankfurt, Germany. The authors thank Kais Hamza, PhD, Dept of Mathematics and Statistics, Monash University, for performing the statistical analyses. We are grateful to Mauro Baldi, BSc, Jane Kealey, BSc, RN, Julie Plunket, RN, and the personnel of the Cardiac Catheterization Laboratories, Monash Medical Center for technical assistance.

	Footnotes

 
Presented in part at the 73rd Scientific Sessions of the American Heart Association, New Orleans, La, November 12–15, 2000, and published in abstract form (Circulation. 2000;102[suppl II]:II-706).

Received October 22, 2001; revision received December 3, 2001; accepted December 5, 2001.

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