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1 Institute of Biomedical and Life Science, University of Glasgow, University Avenue, Glasgow, G12 8QQ, Scotland, UK2 Section of Cardiology, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow Royal Infirmary, Scotland, UK
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(Received 17 October 2003;
accepted after revision 3 December 2003)
Corresponding author G. L. Smith: Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. E-mail: g.smith{at}bio.gla.ac.uk
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Introduction |
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2,3-butane-dione monoxime (BDM) is an inhibitor of myofibrillar ATPase (Blanchard et al. 1990), an action that prevents myocardial contraction despite an increase of intracellular [Ca2+]. BDM has therefore been widely used to eliminate motion in cardiac muscle preparations. However, this treatment is not without electrophysiological consequences. Transgenic mouse whole heart studies showed that 15 mmol l–1 BDM reduced conduction velocity (Verrecchia & Herve, 1997) and doubled action potential duration (Baker et al. 2000). In contrast, in swine (Lee et al. 2001) right ventricle, and in guinea pig and sheep (Liu et al. 1993) ventricle, demonstrated that 5-20 mmol l–1 BDM reduced APD90 in a dose dependent manner. BDM has also been shown to flatten the electrical restitution curve in swine (Lee et al. 2001) and canine (Riccio et al. 1999) ventricles. A recent study suggests that 20 mmol l–1 BDM flattens the restitution curve in rabbit (Banville & Gray, 2002), but the dose dependence of this effect has not been studied.
Cytochalasin-D (Cyto-D), an agent that impairs actin filament polymerization (Krucker et al. 2000), is also widely used. In isolated canine ventricular muscle, Biermann et al. (1998) demonstrated that Cyto-D at concentrations up to 80 µmol l–1 had no significant effect on cardiac repolarisation while having a profound, irreversible negative inotropic effect. Jalife et al. (1998) found that 20–80 µmol l–1 Cyto-D eliminated contraction in the mouse heart, although they also observed significant membrane hyperpolarisation and action potential prolongation. In one study that looked at the dynamics of ventricular fibrillation in the swine right ventricle, 10–40 µmol l–1 Cyto-D did not effect restitution (Lee et al. 2001), while in another study 10 µmol l–1 CytoD had minimal effects on restitution in isolated rabbit hearts (Banville & Gray, 2002).
The aim of this study was to investigate electrophysiological and mechanical effects of BDM and Cyto-D in the rabbit heart in an effort to develop a protocol to allow routine optical recording of action potentials from the epicardial surface of the heart.
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Methods |
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Male New Zealand White rabbits (2.5–3 kg) were sacrificed by intravenous administration of sodium pentobarbitone (100 mg kg–1) with 1000 IU heparin into the left marginal ear vein. The heart was rapidly excised and perfused in Langendorff mode with filtered (5 µm pore) modified, buffered, Tyrode's solution within 3 min of removal from the animal. The buffer solution consisted of (mmol l–1): 120.9 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 0.7 KH2PO4, 24.8 NaHCO3, and 11 glucose. The solution was equilibrated with 95% O2/5% CO2 and heated to 37°C. The heart was perfused at 40 ml min–1 using a Gilson Minipuls 3 peristaltic pump (Gilson, Inc., Middleton, WI, USA). Preliminary measurements confirmed the temperature (36–37°C) and pH (pH 7.35–7.45) of the Tyrode's solution emerging from the aortic cannula.
Experimental protocols
The right atrium was dissected from the heart to remove the sino-atrial node. The atrio-ventricular node was crushed to destroy its pacemaker activity. Under these circumstances, the intrinsic rate of the heart decreased to 
1 Hz. The heart was then paced at twice diastolic threshold and at a constant cycle length of 350 ms via a pair of bipolar pacing electrodes inserted at the base of the right ventricle. Intraventricular pressure was monitored with a fluid-filled latex balloon inserted into the apex of the left ventricle. The balloon was connected via a 6F cannula to a pressure transducer (Triton Technology Inc., San Diego, CA). The volume of the balloon was adjusted to give zero end diastolic pressure. To allow stabilisation, the hearts were perfused in standard Tyrode's solution for approximately 20 min. Perfusion pressure was monitored via a second transducer placed in series with the aortic cannula. Average perfusion pressure measured during diastole under control conditions ranged from 17–35 mmHg (mean value 27.4 ± 2.6; n= 8).
Perfusion protocols
Reduced extracellular [Ca2+]. Perfusion was initially with normal Tyrode's (containing 2.5 mmol l–1 Ca2+) solution for 5 min. Then a series of [Ca2+] changes were made to 0.7, 1.4 and 1.9 (mmol l–1). The heart was perfused for 10 min at each of these concentrations. Contractility was then restored by perfusion with normal Tyrode's solution for 20 min.
BDM. BDM (Sigma Aldrich, UK) was dissolved in normal Tyrode's solution prior to each experiment. Perfusion was initially with normal Tyrode's solution then BDM concentration was changed at 5-min intervals from (mmol l–1): 20, 10, 5, 3, 2, and 1. Finally the heart was perfused with Tyrode's solution for 15 min to monitor recovery. Preliminary investigations demonstrated that a reducing order of concentration of BDM avoided arrhythmias in the washout phase.
Cyto-D. Cyto-D was dissolved in DMSO to give a 10 mmol l–1 stock solution. The appropriate quantity of stock Cyto-D was added to normal Tyrode's solution prior to each experiment. Since Cyto-D is a photosensitive compound, these experiments were carried out in darkness. Perfusion solution containing Cyto-D was aerated and re-circulated for 20 min prior to recordings being taken. Perfusion was initially with normal Tyrode's solution for 5 min followed by a series of Cyto-D concentrations (µmol l–1): 1, 3, and 5. Washout was with normal Tyrode's solution for 60 min.
Monophasic action potential recordings
A Franz contact catheter electrode (non-polarisable Ag–AgCl electrode, 2 mm diameter, Boston Scientific/EP Technologies, San Jose, CA, USA) recorded monophasic action potentials (MAPs) from the basal region of the left ventricle. MAPs were digitised at a rate of 1 kHz and analysed off line using a locally developed computer programme. The time of the MAP upstroke was taken as the time of maximum rate of depolarisation (dV/dtmax). Measurements of conduction delay (CD) (time from stimulus artefact to the dV/dtmax of the MAP upstroke) and MAP duration (time between dV/dtmax and 90% repolarization, MAPD90) were made.
Restitution protocols
Electrical restitution was investigated in hearts perfused with Tyrode's solution (1.9 mmol l–1 Ca2+) with either 3 µmol l–1 Cyto-D or 20 mmol l–1 BDM. The heart was stimulated with a basic drive train of 16 stimuli at 350 ms intervals followed by an extra stimulus, S2. The S1–S2 interval was increased by 5 ms between 70 and 150 ms, 10 ms between 150 and 350 ms, and 50 ms between 350 and 600 ms. Graphs of MAPD90 of the S2-induced MAP against diastolic interval (DI) were fitted with an exponential restitution curve: MAPD90=
–ß* e–DI/
using Microcal Origin version 6.1 (OriginLab Corporation, MA, USA). The constants , ß and were measured from each dataset collected before and after perfusion with the experimental solutions. The maximum slopes of the restitution curves were obtained analytically by computing the derivative of the restitution fits to the above equation (Banville & Gray, 2002). The maximum MAPD90 (MAPD90max) values were taken from the mean of the MAPD90 values measured at 550 ms and 600 ms S1–S2 intervals.
Optical mapping
Membrane potential records were obtained using an optical mapping array. The heart was immobilised with a combination of 1.9 mmol l–1 Ca2+ Tyrode's and 3 µmol l–1 Cyto-D. The heart was placed in a custom-made perspex chamber. This further reduced motion artefact and allowed the temperature of the bathing solution to be controlled. The heart was loaded with 100 µl of the voltage sensitive dye RH-237 (Molecular Probes, Europe BV, Leiden, The Netherlands), dissolved in DMSO (1 mg ml–1) administered through the coronary perfusate, via a port in a bubble trap.
Light from a 150 W Xenon arc lamp (Cairn Research Ltd, Kent, UK) was passed through a 575 nm short-pass filter (Comar Instruments, Cambridge, UK) and shone on the surface of the heart. Light emitted from the stained preparation was collected with a camera lens (Nikon 85 mm, f1:1.4), passed through a 645 nm long-pass filter, and the image focused on a 16 x 16 photodiode array (C4675-102, Hamamatsu Photonics Corporation, NJ, USA). The four corner channels were reserved for other signals so optical signals were acquired from 252 of 256 diodes (see Fig. 7A). Digitised data samples were stored on hard disk and analysed using software written in IDL (Interactive Data Language, Research Systems Inc., CO, USA). Four optical action potentials from the basal region of the array were compared to a contact catheter obtained MAP from a comparable region of the same heart in n= 4 hearts (see Fig. 7).
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Recordings taken from the final 60 s of each perfusion period were analysed for MAPD90 and CD. Left ventricular developed pressure (LVDP) was represented as a percentage of the maximum control value. Repeated measures ANOVA was used to compare values of LVDP and of basic electrophysiological parameters (CD and MAPD90) and Student's t-test (paired data) for the restitution analysis. Data were expressed as the mean ± standard error.
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Results |
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Figure 1A shows an example of recordings of a MAP from a catheter electrode placed on the basal epicardium. Below the trace is the derivative of the voltage signal. As indicated, the MAPD90 value was derived from the time between the peak dV/dt signal and the time at which the MAP had decayed to 90% of its original value. The trace shown in Fig. 1B is a record of LVDP from the intraventricular balloon. The LVDP recorded in this study under the standard conditions (pacing cycle length of 350 ms, extracellular Ca2+ of 2.5 mmol l–1, end-diastolic pressure 0 mmHg) was 41.7 ± 6.7 mmHg (n= 7); similar values were reported for isolated Langendorff perfused rabbit hearts perfused under similar conditions (Ng et al. 1998). Mean MAPD90 under these conditions was 118.2 ± 2.1 ms (n= 7).
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As shown in Fig. 2, decreasing extracellular [Ca2+] from 2.5 mmol l–1 to less than 1.4 mmol l–1 caused a marked prolongation of the MAPD90, but only a small decrease in CD. At 0.7 mmol l–1 Ca2+, significant depression of LVDP to 74.0 ± 6.1% (n= 6) of control level occurred along with an increase in MAPD90 (mean value 162.8 ± 7.2 ms n= 6) Subsequent perfusion of the heart with normal Tyrode's solution (2.5 mmol l–1 Ca2+) resulted in recovery of electrical and mechanical activity. The relationship between extracellular [Ca2+] and these baseline electrical parameters suggests that 1.9 mmol l–1 is approximately the lowest extracellular [Ca2+] that can be used without marked electrophysiological effects.
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Figure 3A illustrates the effect of both BDM and Cyto-D on LVDP. The steady-state values and the degree of recovery after removal of either agent are summarised in Fig. 3B. BDM (3-20 mmol l–1) causes a significant dose-dependant depression of LVDP. 3 µmol l–1 Cyto-D reduced LVDP to 20.1 ± 5.3% of control values.
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Under these conditions, the highest BDM concentration (20 mmol l–1) increased the CD (normally 33.3 ± 1.0 ms, n= 16) to 132.7 ± 10.52% (n= 6) of control value. The effects of BDM on MAPD90 were variable and not statistically significant at any concentration studied (Fig. 4). Cyto-D increased MAPD90 at higher concentrations (5 µmol l–1). At this concentration CD was also significantly increased to 118.7 ± 9% of control value, as shown in Fig. 4B.
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Effects of BDM and Cyto-D on electrical restitution
The measurements of electrical restitution were made in the presence of 1.9 mmol l–1 Ca2+ using a dose of BDM (20 mmol l–1) or Cyto-D (3 µmol l–1) that the earlier data had indicated would be the best compromise between maximal inhibition of LVDP and minimal effects on MAPD90 and CD. Electrical restitution was assessed using an extra stimulus (S2) as indicated in Fig. 5A at varying times during diastole. An example of the restitution data for 20 mmol l–1 BDM is shown in Fig. 5B, and for 3 µmol l–1 Cyto-D in 5C. These data illustrate the monotonic relationship between MAPD90 and the preceding diastolic interval. The data were fitted by an exponential curve with parameters , and ß (see Methods). The maximum slope was derived from the restitution curve fits. As shown in Fig. 5B, BDM (20 mmol l–1) increased , i.e. reduced the maximum slope of the restitution curve, a result that confirms the findings of earlier studies (Banville & Gray, 2002; Riccio et al. 1999), and reduced the MAPD90max. The average data shown in Fig. 6A(i) and B(i) indicate a significant reduction in maximum slope and increase in by 20 mmol l–1 BDM. Figure 6C(i) indicates that MAPD90max was not significantly different. Figure 6A(ii), B(ii) and C(ii) summarise the effects of Cyto-D on electrical restitution, as with BDM, the maximum slope was decreased and increased, but there was no significant effect on MAPD90max.
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MAPs recorded from a catheter electrode were compared with those recorded from optical measurements in n= 4 hearts. Figure 7A shows optical signals recorded from the basal-epicardial surface of the left ventricle. Movement artefacts were minimised by perfusion with a combination of 1.9 mmol l–1 Ca2+ Tyrode's and 3 µmol l–1 Cyto-D. Highlighted within the array are 4 adjacent basal pixels, the individual signals are shown in detail in Fig. 7B. Measurement of action potential duration (APD) was made at 50% and 75% repolarisation to avoid artefact as a result of minor movement artefacts contaminating the final 10-15% of the repolarisation (Fig. 7B). Then a single MAP recording was made using the catheter electrode at the same site on the epicardial surface from which optical recordings were recorded. As shown in Fig. 7B, the time course of these two recordings is very similar. On average, APD50, APD75 and APD90 recorded using optical techniques were very close to those recorded using a catheter MAP electrode (106 ± 6.0%, 105 ± 2.4% and 109 ± 2.1% respectively). Paired t-test applied to the data at each point in the repolarisation phase revealed that only the APD90 values by the optical methods were significantly longer than the comparable MAP recording. These data indicate that MAP duration and APD values recorded with optically agree well over the majority of the repolarisation phase. The significant difference emerging at APD90 may be due to residual movement artefact.
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Discussion |
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Electrical and mechanical effects of lowered [Ca2+]
Reduction of extracellular Ca2+ to 1.9 mmol l–1 i.e. 76% of control levels (2.5 mmol l–1) had no significant effect on systolic LVDP, CD or MAPD90. A significant reduction in systolic LVDP was observed at the non-physiological Ca2+ concentration of 0.7 mmol l–1, accompanied by dramatic changes in electrophysiological parameters. These results suggest that lowering extracellular [Ca2+] to 1.9 mmol l–1 can be achieved with relatively minor effects on whole heart electrophysiology or LVDP. Further reductions of [Ca2+] decrease LVDP but also have dramatic effects on MAPD90 and CD. This range of electrophysiological effects is not surprising given the essential role of extracellular Ca2+ for the function of cardiac muscle cells, Purkinje cells of the cardiac conduction system and nodal cells of the atrio-ventricular node. The prolongation of APD90 observed on lowering extracellular [Ca2+] is due to a combination of reduced Ca2+ influx via L-type Ca2+ channels and effects on a range of Ca2+ sensitive currents involved in the later phases of the action potential. These currents include the Na+/Ca2+ exchanger (Eisner & Lederer, 1989), the Ca2+ sensitive Cl– current (Hiraoka et al. 1998), Ca2+ sensitive non-selective current (Mubagwa et al. 1997), the transient outward current (Nitta et al. 1994) and the Ca2+ sensitive component of the delayed rectifier (Barrett et al. 1982). Lowering extracellular [Ca2+] to 45% had little effect on contractility but a profound effect on MAPD and CD. Therefore reducing extracellular [Ca2+] alone is a poor method for uncoupling electrical activity and contraction. The lowest extracellular [Ca2+] studied that can be used without effects on cardiac electrophysiology is 1.9 mmol l–1.
Electrical and mechanical effects of BDM
The concentration dependence of the depressive effects of BDM on LVDP is similar to that reported in a number of cardiac preparations including human myocardium (Blanchard et al. 1990; Schwinger et al. 1993; Wiggins et al. 1980). In this study however, there were no effects of BDM on MAPD90 at the standard cycle length (350 ms). Previous reports on canine myocardium reported pronounced action potential shortening with 10 and 20 mmol l–1 BDM (Riccio et al. 1999). A separate study indicated that the ability of BDM to shorten APD was small and dependent on cycle length (Liu et al. 1993). At cycle lengths close to physiological, concentrations of BDM up to 15 mmol l–1 had no effect on guinea pig APD. This is in agreement with the absence of a significant effect of BDM observed in this study at a pacing cycle length close to physiological resting heart rate. As shown in Fig. 5, BDM reduced (flattened) the slope of the restitution relation. The average of the exponentially fitted restitution curves was significantly increased by 20 mmol l–1 BDM and the maximum slope was significantly reduced. Similar results with BDM were reported in swine (Lee et al. 2001), rabbit (Banville & Gray, 2002) and canine myocardium (Riccio et al. 1999). This study by Riccio et al. went on to show that drugs that reduce the slope of the restitution curve play a role in the prevention of ventricular fibrillation and the conversion of fibrillation to ventricular tachycardia. Clearly this has implications for the use of BDM as a motion artefact inhibitor. BDM has been reported to affect a number of ion channels, pumps and exchangers in cardiac tissue. Inhibition of L-type Ca2+ channels (Ferreira et al. 1997), Na+/Ca2+ exchanger (Watanabe et al. 2001), and transient outward K+ channel (Coulombe et al. 1989) have been reported. BDM also has actions on intracellular targets including the SR Ca2+ release channel (Eisner & Lederer, 1989) and Ca2+ pump (Steele & Smith, 1993).
Some or all of these actions may account for the effects of BDM on the ventricular myocytes and may play a role in the ability of BDM to increase CD. A study on isolated tissue reported a decrease in A-V node conduction delay by 10 mmol l–1 BDM (Cheng et al. 1997). This suggests that the increased CD observed in this study may be a result of an effect of BDM on the ventricular conduction system. Further work is needed to distinguish the source of the delayed conduction with BDM.
Mechanical and electrical effects of cytochalasin-D
Cyto-D substantially depressed LVDP at concentrations as low as 3 µmol l–1, which were much lower than used previously. Previous studies have used concentrations as high as 10–40 µmol l–1 in swine (Lee et al. 2001) and 60–80 µmol l–1 in canine myocardium (Biermann et al. 1998). In both of these studies, Cyto-D was reported to have negligible effects on action potential duration and myocardial conduction velocity. These results are in contrast to the current study where significant prolongation of MAPD90 and CD were observed in 5 µmol l–1 Cyto-D, a result supported by a recent independent study in the rabbit (Hayashi et al. 2003). These effects limit the concentration of Cyto-D that can routinely be used to uncouple contraction from electrical activity in rabbit myocardium to 1–3 µmol l–1. At these concentrations Cyto-D does not eliminate contraction but has minimal electrophysiological effects. The observed effect of Cyto-D on the electrical restitution curve is in contrast to previous reports. An initial study suggested that Cyto-D had no significant effects on the slope of the restitution curve (Lee et al. 2001). However, subsequent reports indicate that the maximum slope is increased by Cyto-D in the rabbit (Banville & Gray, 2002; Hayashi et al. 2003). In the current study, Cyto-D flattened the restitution curve (decreased maximum slope). The reason for the disparity with recent work is unknown; the stimulus protocols used in these different published studies to uncover the restitution curve differ from each other and from the current study. Alternatively, the current study used exclusively male rabbits whilst Hayashi et al. (2003) used female rabbits. It is recognised that there are differences in the repolarisation characteristics of male and female mammals (Smetana et al. 2002).
Regardless of the form of the effect, changes in the restitution curve due to BDM or Cyto-D indicate that these agents are not suitable for investigations of restitution parameters in the rabbit. Furthermore, changes in the shape of the restitution curve have marked effects on the ability of the myocardium to convert ventricular fibrillation to tachycardia. Therefore studies of re-entrant arrhythmias in rabbit myocardium in the presence of these agents must be interpreted with caution.
Optical mapping validation study
A limited validation study was performed to verify that the action potential duration measured using MAP recordings coincided with those recorded from RH 237 fluorescence. As shown in Fig. 7 and the accompanying data, recordings from both techniques showed remarkable agreement. Comparisons of the APD50 and APD75 values from a series of hearts were not significantly different. Measurements of APD90 from optical recordings were significantly longer than the corresponding values measured by MAP recording. Assuming that these latter recordings are less susceptible to artefacts, the data suggest that the remaining movement artefact and poorer signal-to-noise ratio of optical recordings reduce the reliability of the APD90 measurements from optical data.
Summary
From this study Cyto-D (3 µmol l–1) and BDM (20 mmol l–1) are effective agents at reducing contractility in whole rabbit hearts. Cyto-D was the preferred since at 3 µmol l–1, the effects on MAPD90 and conduction delay were minimal, whereas 20 mmol l–1 BDM significantly delayed conduction. At these concentrations, neither agent affected action potential duration at physiological cycle lengths (350 ms). However, both agents affected electrical restitution, and so caution must be exercised when using these agents to study phenomena where restitution parameters are critical.
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Footnotes |
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References |
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