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K_Ca⁺ channels contribute to exercise-induced coronary vasodilation in swine

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands

Submitted 28 March 2006 ; accepted in final form 10 May 2006

	ABSTRACT

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Coronary blood flow is controlled via several vasoactive mediators that exert their effect on coronary resistance vessel tone through activation of K⁺ channels in vascular smooth muscle. Because Ca²⁺-activated K⁺ (K_Ca⁺) channels are the predominant K⁺ channels in the coronary vasculature, we hypothesized that K_Ca⁺ channel activation contributes to exercise-induced coronary vasodilation. In view of previous observations that ATP-sensitive K⁺ (K_ATP⁺) channels contribute, in particular, to resting coronary resistance vessel tone, we additionally investigated the integrated control of coronary tone by K_Ca⁺ and K_ATP⁺ channels. For this purpose, the effect of K_Ca⁺ blockade with tetraethylammonium (TEA, 20 mg/kg iv) on coronary vasomotor tone was assessed in the absence and presence of K_ATP⁺ channel blockade with glibenclamide (3 mg/kg iv) in chronically instrumented swine at rest and during treadmill exercise. During exercise, myocardial O₂ delivery increased commensurately with the increase in myocardial O₂ consumption, so that myocardial O₂ extraction and coronary venous PO₂ () were maintained constant. TEA (in a dose that had no effect on K_ATP⁺ channels) had a small effect on the myocardial O₂ balance at rest and blunted the exercise-induced increase in myocardial O₂ delivery, resulting in a progressive decrease of with increasing exercise intensity. Conversely, at rest glibenclamide caused a marked decrease in that waned at higher exercise levels. Combined K_Ca⁺ and K_ATP⁺ channel blockade resulted in coronary vasoconstriction at rest that was similar to that caused by glibenclamide alone and that was maintained during exercise, suggesting that K_Ca⁺ and K_ATP⁺ channels act in a linear additive fashion. In conclusion, K_Ca⁺ channel activation contributes to the metabolic coronary vasodilation that occurs during exercise. Furthermore, in swine K_Ca⁺ and K_ATP⁺ channels contribute to coronary resistance vessel control in a linear additive fashion.

coronary circulation; calcium-activated potassium channels; adenosine 5'-triphosphate-sensitive potassium channels

There are several subtypes of K⁺ channels present in vascular smooth muscle, including ATP-sensitive K⁺ (K_ATP⁺), Ca²⁺-activated K⁺ (K_Ca⁺), and voltage-dependent K⁺ (K_V⁺) channels. Although it has been proposed that K_ATP⁺ channels contribute to exercise-induced coronary vasodilation in dogs (8, 13), our laboratory (5, 20) has previously shown that in swine the contribution of these channels to regulation of coronary vasomotor tone is prominent under resting conditions but actually decreases during exercise in the porcine coronary vasculature. Thus it is likely that a different kind of K⁺ channels mediates the exercise-induced coronary vasodilation in swine. K_Ca⁺ channels are the predominant subtype of K⁺ channels on vascular smooth muscle (25, 30). Moreover, they have a very large conductance for K⁺ (25, 30), so that activation or inactivation of these channels can exert a large influence on vasomotor tone. Finally, activation of K_Ca⁺ channels can occur through various vasodilator pathways (NO, prostanoids, and -adrenoceptor activation) that are mediated via cAMP and/or cGMP, as well as through direct interaction with reactive O₂ species (25, 30, 33). In light of these considerations, we tested the hypothesis that K_Ca⁺ channels contribute to the exercise-induced vasodilation in the porcine coronary circulation. In addition, we investigated the integrated control of coronary resistance vessel tone by K_Ca⁺ and K_ATP⁺ channels.

	METHODS

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Studies were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals," as approved by the Council of the American Physiological Society, and with approval of the Animal Care Committee of the Erasmus Medical Center (Rotterdam, The Netherlands). Twelve crossbred Landrace x Yorkshire swine of either sex (2–3 mo old) were entered into the study.

Surgical Procedures

Twelve swine (21 ± 1 kg at the time of surgery) were sedated (20 mg/kg ketamine im), anesthetized (thiopental sodium, 10-15 mg/kg iv), intubated, and ventilated with a mixture of O₂ and N₂O (1:2) to which 0.2–1.0% (vol/vol) isoflurane was added (5, 6). Anesthesia was maintained with midazolam (2 mg/kg + 1 mg·kg^–1·h^–1 iv) and fentanyl (10 µg·kg^–1·h^–1 iv). Swine were instrumented under sterile conditions as previously described (5, 6). Briefly, a thoracotomy was performed in the fourth left intercostal space. Subsequently, a polyvinylchloride catheter was inserted into the aortic arch for the measurement of mean aortic pressure and blood sampling to determine of PO₂, PCO₂, pH (ABL 505, Radiometer), O₂ saturation, and hemoglobin concentration (OSM3, Radiometer). A fluid-filled catheter and a high-fidelity Konigsberg pressure transducer were inserted into the left ventricle via the apex. Fluid-filled catheters were also implanted into the left atrium for pressure measurements and in the pulmonary artery for infusion of drugs. A small angiocatheter was inserted into the anterior interventricular vein for coronary venous blood sampling. Finally, a transit-time flow probe (Transonic Systems) was placed around the left anterior descending coronary artery (LAD) for measurement of coronary blood flow.

Electrical wires and catheters were tunneled subcutaneously to the back, the chest was closed, and animals were allowed to recover. Animals received analgesia [buprenorphine (0.3 mg im) for 2 days] and antibiotic prophylaxis [amoxicillin (25 mg/kg iv) and gentamicin (5 mg/kg iv) for 5 days] (6, 17, 19).

Dose-Finding Study

In three animals, the K_Ca⁺ channel blocker tetraethylammonium (TEA) was infused intravenously in incremental dosages of 5, 10, and 20 mg/kg, and coronary vasoconstriction was assessed as the change in coronary venous PO₂ () and coronary venous O₂ saturation (). Assuming an extracellular volume of 0.2 l/kg body wt (31), a body weight of 25 kg and negligible plasma protein binding (9), we estimated the highest dose of TEA to result in a maximal final blood concentration of TEA (165 mol wt) of 0.6 mM.

Selectivity of TEA

At a dosage of 1 mM, TEA has been shown to predominantly block K_Ca⁺ channels (2). However, at higher dosages, TEA has been shown to inhibit K_ATP⁺ channels (6 mM) and K_V⁺ channels (10 mM) (2). Although it is unlikely that inhibition of K_ATP⁺ or K_V⁺ channels occurred with the estimated TEA concentration of 0.6 mM in the present study, we investigated whether the dose-response curve of the coronary vasodilator effect of bimakalim [37–225 ng·kg^–1·min^–1 iv (5)], a K_ATP⁺ channel opener, was affected by prior administration of TEA (20 mg/kg iv) in four swine.

Exercise Protocols

Studies were performed 1 to 3 wk after surgery. After hemodynamic measurements (lying and standing), blood samples (lying), and rectal temperature (standing) had been obtained, swine were subjected to a five-stage exercise protocol on a motor-driven treadmill (1–5 km/h). Hemodynamic variables were continuously recorded and blood samples collected during the last 60 s of each 3-min exercise stage, at a time when hemodynamics had reached a steady state (6, 17, 19).

Reproducibility of hemodynamic and metabolic responses to exercise. The reproducibility of two consecutive exercise protocols was investigated in seven swine. After completion of the first exercise protocol, animals were allowed to rest for 90 min. Animals then received physiological saline (30 ml iv) and 5 min later underwent a second exercise protocol (5–7).

K_Ca⁺ and K_ATP⁺ channels in exercise-induced coronary vasodilation. Three different protocols were performed to assess the role of of K_Ca⁺ and K_ATP⁺ channels, either alone or in combination, in the regulation of coronary vasomotor tone at rest and during exercise. These protocols were performed in random order on different days. To assess the role of K_Ca⁺ channels, TEA (20 mg/kg iv) was administered to 10 swine before the second exercise protocol, and the exercise protocol was repeated. To assess the role of K_ATP⁺ channels, glibenclamide (3 mg/kg iv) was administered to seven swine (5), and the exercise protocol was repeated. To assess the integrated coronary vasomotor control by K_Ca⁺ and K_ATP⁺ channels, the exercise protocol was repeated after combined administration of TEA (20 mg/kg iv) and glibenclamide (3 mg/kg iv) in five swine. The vasoconstrictor effect of combined intravenous administration of TEA and glibenclamide was compared with the effect of TEA alone and to glibenclamide alone.

Data Analysis

Digital recording and off-line analysis of hemodynamic data and computation of myocardial O₂ consumption (MO₂) have been described in detail elsewhere (6, 19). Coronary vascular conductance was calculated as the ratio of coronary blood flow and mean aortic pressure. Myocardial O₂ delivery (MDO₂) was computed as the product of LAD coronary blood flow and arterial blood O₂ content. MO₂ in the region of myocardium perfused by the LAD was calculated as the product of coronary blood flow and the difference in O₂ content between arterial and coronary venous blood. Myocardial O₂ extraction (MEO₂) was computed as the ratio of MO₂ and MDO₂.

Statistical Analysis

Statistical analysis of hemodynamic data was performed using two-way (drug treatment and exercise) ANOVA for repeated measures. When significant effects were detected, post hoc testing for the effects of exercise and drug treatment was performed using Scheffé's test and paired t-test. Similarly, two-way repeated-measures ANOVA was performed on dose-response curves to bimakalim in the presence and absence of TEA or glibenclamide. To test for the effects of drug treatment (TEA and/or glibenclamide) on the relationship between MO₂ and coronary venous O₂ tension () or saturation (), regression analysis was performed by using drug treatment and MO₂, as well as their interaction as independent variables, and by assigning a dummy variable to each animal. Statistical significance was accepted when P < 0.05 (two-tailed). Data are presented as means ± SE.

	RESULTS

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Dosage and Selectivity of K_Ca⁺ Channel Blockade

In three animals, the K_Ca⁺ channel blocker TEA was infused intravenously in cumulative dosages of 5, 10, and 20 mg/kg, and coronary vasoconstriction was assessed as the change in and . TEA had no significant effect at 5 or 10 mg/kg, whereas it induced modest coronary vasoconstriction at a dosage of 20 mg/kg (0.6 mM), as evidenced by a small but significant (P < 0.05) decrease in (2.2 ± 0.2 mmHg) and (5.5 ± 1.4%).

At a dosage of 1 mM, TEA has been shown to predominantly block K_Ca⁺ channels (2). However, at higher dosages, TEA has been shown to inhibit K_ATP⁺ channels (6 mM) and K_V⁺ channels (10 mM) (2). To investigate whether 20 mg/kg of TEA did block K_ATP⁺ channels, the dose-response curve of the coronary vasodilator effect of the K_ATP⁺ channel opener bimakalim [37–225 ng·kg^–1·min^–1 (5)] was compared before and after prior administration of TEA (20 mg/kg) in four swine. Administration of bimakalim had no effect on MO₂ either in the absence (275 ± 30 µmol/min at baseline and 311 ± 21 µmol/min during 225 ng·kg^–1·min^–1 bimakalim) or presence of TEA (237 ± 33 and 242 ± 30 µmol/min, respectively). Figure 1 shows that TEA induced modest coronary vasoconstriction as evidenced by the decrease in and at baseline. However, the bimakalim-induced increases in and were not affected by TEA. Furthermore, TEA had no effect on the bimakalim-induced increase in coronary vascular conductance (Fig. 2, left) in contrast to the K_ATP⁺ channel blocker glibenclamide, which significantly blunted the bimakalim-induced coronary vasodilation [Fig. 2,right (5)]. Taken together, these findings suggest that TEA at a dose of 20 mg/kg does not block K_ATP⁺ channels. Consequently, this dose of TEA was used in the subsequent exercise protocols.

View larger version (11K): [in this window] [in a new window]   Fig. 1. Dose-response curves of coronary venous O2 saturation (, left) and coronary venous PO2 (, right) as indexes of coronary vasomotor tone to intravenous administration of ATP-sensitive K+ (KATP+) channel opener bimakalim in the absence and presence of Ca2+-activated K+ (KCa+) channel blocker tetraethylammonium (TEA, 20 mg/kg iv) in 4 swine. TEA induced a decrease in and , whereas there was no significant difference in vasodilator response to bimakalim before and after administration of TEA. Data are means ± SE. *P < 0.05 vs. corresponding baseline (0 ng·kg–1·min–1 bimakalim).

View larger version (12K): [in this window] [in a new window]   Fig. 2. Dose-response curves of coronary vascular conductance (CVC) to intravenous administration of KATP+ channel opener bimakalim in the absence and presence of KCa+ channel blocker TEA (20 mg/kg iv; left) in 4 swine or KATP+ channel blocker glibenclamide (Glib, 3 mg/kg iv, right) in 5 swine [historic data from Duncker and colleagues (see Refs. 5 and 20)]. TEA had no effect on coronary vasodilation by bimakalim, whereas the latter was significantly blunted by Glib. Data are means ± SE. *P < 0.05 vs. corresponding baseline (0 ng·kg–1·min–1 bimakalim); P < 0.05 bimakalim after Glib vs. bimakalim under control conditions.

Under control conditions, the exercise-induced increase in the metabolic demand of the myocardium was accurately matched by an increase in coronary blood flow, so that ME_O2, , and were maintained constant (Table 1 and Fig. 3). Table 1 and Fig. 3 also illustrate the excellent reproducibility of the responses to consecutive bouts of exercise.

View larger version (10K): [in this window] [in a new window]   Fig. 3. Effect of 2 subsequent exercise protocols on relationship between myocardial O2 consumption (MO2) and (top) or (bottom) in saline (n = 7, first panels) and in the presence of KCa+ channel blockade with TEA (n = 9, second panels), KATP+ channel blockade with Glib (n = 8, third panels), or combined blockade of KCa+ and KATP+ channels (n = 6, fourth panels). Data are means ± SE. *P < 0.05 vs. corresponding control relation; P < 0.05, effect of TEA or Glib changes during exercise; P < 0.05, effect of TEA + Glib, different from effect of TEA alone; ¶P < 0.05, effect of TEA + Glib, different from effect of Glib alone.

	DISCUSSION

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Methodological Considerations

Myocardial O₂ balance. The myocardial O₂ balance provides the most sensitive way to assess changes in coronary vasomotor tone. The relationship between coronary venous O₂ levels and MO₂ reflects changes in resistance vessel tone corrected for changes in myocardial metabolism (4, 34). Thus, at a given level of MO₂, an increase in coronary vasomotor tone will decrease coronary blood flow and hence myocardial O₂ supply, thereby forcing the myocardium to increase its O₂ extraction to fulfill its O₂ demand and resulting in a lower coronary venous O₂ level. The coronary venous O₂ level thus represents an index of myocardial tissue oxygenation, i.e., the balance between myocardial O₂ supply and O₂ demand, which is determined by the coronary vasomotor tone. This way, changes in coronary vasomotor tone are assessed independently of the changes in myocardial O₂ demand.

A key point in the interpretation of the myocardial O₂ balance is the change in slope of the regression line between myocardial O₂ demand and coronary venous O₂ level induced by blocking a vasoactive mechanism (4, 34). A parallel decrease in the regression line upon blockade of a vasodilator mechanism reflects tonic vasoconstriction. Thus the vasoconstriction that occurs under resting conditions is not further altered during exercise, and the vasodilator pathway is not involved in metabolic regulation of coronary vasomotor tone. Such a parallel shift occurs, for example, in the porcine coronary circulation in response to blockade of adenosine receptors and NO synthesis (7, 17). In contrast, a small decrease in coronary venous O₂ level at rest in combination with divergence of the regression lines as occurs during -blockade (6) or administration of TEA (present study) reflects modest vasoconstriction at rest that increases with incremental exercise intensity, indicating that the contribution of the vasoactive pathway that is blocked increases during exercise and therefore is important in exercise-induced coronary vasodilation. Convergence of the regression lines, as occurs with glibenclamide (5, 17), indicates that the vasoconstriction that occurred at rest decreases with increasing exercise intensity.

Selectivity of TEA and glibenclamide. The importance of K_Ca⁺ and K_ATP⁺ channels in the regulation of coronary vasomotor tone of exercising swine was studied using TEA and glibenclamide. An inherent concern with pharmacological studies is the issue of efficacy and selectivity. Effective pharmacological blockade of K_Ca⁺ and K_ATP⁺ channels in the coronary circulation in vivo was confirmed by coronary vasoconstriction in response to TEA and glibenclamide, as evidenced by decreases in and (Fig. 3). Our laboratory (5) has previously shown that glibenclamide (3 mg/kg iv) attenuates the coronary vasodilator response to bimakalim (Fig. 2) but does not blunt the vasodilator response to nitroprusside, indicating that glibenclamide inhibits K_ATP⁺ channels but does not interfere with vascular smooth muscle responsiveness in a nonspecific manner. TEA has been reported to be a selective blocker of K_Ca⁺ channels at dosages up to 1 mM (2). In the present study, we performed a dose-response curve using incremental dosages (5, 10, and 20 mg/kg iv) of TEA. Assuming an extracellular volume of 0.2 l/kg body wt (31), a body weight of 25 kg and negligible plasma protein binding (9), we estimated the highest dose of TEA (20 mg/kg iv) to result in a maximal final blood concentration of TEA (165 mol wt) of 0.6 mM. Furthermore, it was the lowest dose that induced significant vasoconstriction in the present study under resting conditions. Data in the literature (2) suggest that TEA blocks K_ATP⁺ channels only at a dosage of 6.2 mM, and K_V⁺ channels, at a dosage of 10 mM. In agreement with this notion, we showed in the present study that the effect of the K_ATP⁺ channel opener bimakalim was not affected by TEA. Moreover, blocking K_ATP⁺ channels with glibenclamide demonstrated a markedly different vasoconstrictor profile that was most pronounced at rest and waned with increasing exercise intensity. Taken together, these data suggest that TEA (20 mg/kg iv) does not possess K_ATP⁺ channel blocking properties in swine. Because the effect of TEA on K_V⁺ channels occurs at higher dosage than its effect on K_ATP⁺ channels, it is also unlikely that the effect of TEA was mediated through K_V⁺ channels.

Role of K⁺ Channels in Regulation of Coronary Vasomotor Tone

There are several subtypes of K⁺ channels present on vascular smooth muscle: the K_ATP⁺, the K_Ca⁺, and the K_V⁺ channels. Activation of K⁺ channels leads to efflux of K⁺, membrane hyperpolarization, and closing of voltage-dependent Ca²⁺ channels, thereby decreasing Ca²⁺ influx and causing smooth muscle relaxation and vasodilation (25). Thus an increased opening of K⁺ channels during increased metabolic demand could contribute to coronary vasodilation as occurs during exercise. K_ATP⁺ channels appear to play an important role in exercise-induced coronary vasodilation in dogs (4, 8, 13) although this is not a ubiquitous finding (34). In contrast, the present study confirms our earlier observations that the contribution of K_ATP⁺ channels to regulation of coronary vasomotor tone actually decreases during exercise in swine (5, 20). Thus it is likely that a different kind of K⁺ channels mediates coronary vasodilation during exercise in swine. K_Ca⁺ channels are abundantly expressed in coronary vascular smooth muscle cells (10) and have a very large conductance for K⁺ (2, 25, 27, 30). Hence, small changes in opening probability of these channels have a significant effect on smooth muscle membrane potential and, thereby, on vasomotor tone (2, 25, 27, 30). Therefore, K_Ca⁺ channels are a likely candidate to mediate exercise-induced coronary vasodilation.

Membrane depolarization and increases in intracellular Ca²⁺ concentration are thought to be the main activators of the K_Ca⁺ channels, thereby constituting an important negative feedback mechanism for excess vasoconstriction (2, 25). In addition, various protein kinases have been shown to modulate the activity of the K_Ca⁺ channels (15, 28). K_Ca⁺ channels are activated by phosphorylation through cGMP-dependent protein kinase [PKG (32, 37)] and cAMP-dependent protein kinase [PKA (23, 29)], whereas protein kinase C (PKC) inhibits K_Ca⁺ channels (22). Many endogenous vasoactive substances exert their action through these protein kinases, thereby modulating K_Ca⁺ channel activity and hence altering coronary resistance vessel tone. In general, vasodilator substances, such as adenosine, EDHF, NO, norepinephrine, and H⁺, act through stimulation of PKA and PKG (2, 3, 15, 25), resulting in increased opening of K_Ca⁺ channels, whereas vasoconstrictor substances, such as endothelin and angiotensin II, activate PKC (11, 24) and decrease the opening of K_Ca⁺ channels. Hence, it is likely that many vasoactive substances acting in concert contribute to the exercise-induced opening of K_Ca⁺ channels.

Some factors that could potentially influence K_Ca⁺ channel opening, being adenosine, acidosis, angiotensin II, and EDHF, are either not present or do not increase their influence on vasomotor tone in the porcine coronary circulation during exercise. Thus acidosis, which induces K_Ca⁺ channel activation, does not occur as arterial and coronary venous pH increase rather than decrease during exercise. Adenosine exerts a tonic vasodilator influence on the coronary circulation of normal swine (7, 17), whereas preliminary data from our laboratory (18) indicate that angiotensin II exerts a tonic vasoconstrictor influence. Moreover, preliminary data from our laboratory (21) suggest that inhibition of cytochrome P-450 2C9, the enzyme that is thought to be responsible for the synthesis of EDHF in the coronary circulation, had no effect on coronary vasomotor tone in swine. Therefore, it is unlikely that acidosis, adenosine, angiotensin II, or EDHF is responsible for the increased opening of K_Ca⁺ channels during exercise.

Our laboratory (6) has previously shown that increased -adrenoceptor activation contributes to exercise-induced coronary vasodilation. Because activation of the -adrenoceptor has been shown to signal, at least in part, through the opening of the K_Ca⁺ channels (12, 29), it is likely that -adrenoceptor activation during exercise contributes to increased opening of K_Ca⁺ channels. Moreover, endothelin-receptor activation has been shown to inhibit opening of K_Ca⁺ channels (24, 26). Thus the progressive withdrawal of the endothelin-mediated vasoconstrictor influence on the coronary circulation, which we previously observed with incremental levels of exercise (16, 19), may also have contributed to the increased opening of K_Ca⁺ channels.

The effect of combined K_ATP⁺ and K_Ca⁺ channel blockade was not greater than the sum of the effects of K_ATP⁺ and K_Ca⁺ channel blockade alone, suggesting that these channels act in a linear additive, rather than a nonlinear redundant, fashion (4, 34). K_ATP⁺ channels are activated directly by increases in intracellular ADP (25), whereas vasodilators such as adenosine and prostacyclin are thought to principally exert their action via cAMP/PKA-mediated opening of K_ATP⁺ channels (1, 25, 36). In contrast, K_Ca⁺ channels are activated directly by membrane depolarization and Ca²⁺ (2, 14), whereas vasodilators like NO and atrial natriuretic peptide are considered to exert their action predominantly via cGMP/PKG-mediated opening of K_Ca⁺ channels (25, 32, 36). Although some overlap between the activation pathways appears to exists (2, 25), the separate intracellular signaling pathway involved in the activation of K_ATP⁺ and K_Ca⁺ channels may explain our observations that K_ATP⁺ and K_Ca⁺ channels act in an additive manner to the regulation of coronary resistance vessel tone during exercise.

In conclusion, increased opening of K_Ca⁺ channels during exercise contributes to exercise-induced metabolic coronary vasodilation. The exact mechanisms that induce the increased opening of K_Ca⁺ channels during exercise remain to be identified. Yet, the responsiveness of K_Ca⁺ channels to multiple extracellular and intracellular messengers puts these channels into a unique position to integrate multiple signals, local and global, vasodilator and vasoconstrictor, and thereby regulate coronary blood flow to match the O₂ demand of the myocardium (15).

	GRANTS

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D. Merkus is supported by a postdoctoral stipend from The Netherlands Heart Foundation (2000T042).

	ACKNOWLEDGMENTS

 
The authors gratefully acknowledge Margje van Schaik and Josephine Albertus for technical assistance.

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. Merkus, Experimental Cardiology, Thoraxcenter Erasmus MC, Univ. Medical Center Rotterdam, Box 1738, 3000DR Rotterdam, The Netherlands (e-mail: d.merkus{at}erasmusmc.nl)

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

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