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1 Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Alberta, Canada 2 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Alberta, Canada 3 Program in Human Molecular Biology and Genetics and Division of, Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, USA
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Abstract |
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(Received 22 September 2003;
accepted after revision 17 December 2003;
first published online 23 December 2003)
Corresponding author Y. Shimoni: Department of Physiology and Biophysics, Health Sciences Centre, 3330 Hospital Dr N.W., Calgary AB, Canada T2N 4N1. Email: shimoni{at}ucalgary.ca
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Introduction |
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Studies of electrophysiological abnormalities of the diabetic heart have mainly used the streptozotocin (STZ)-induced diabetic rat as a model of type 1 diabetes (Tomlinson et al. 1992). In this model, a substantial attenuation of transient and sustained potassium currents in cardiac ventricular cells has been reported (Magyar et al. 1992; Jourdon & Feuvray, 1993; Shimoni et al. 1994). These currents control repolarization of the action potential, and their attenuation prolongs the action potential and the QT interval. We showed (Shimoni, 2001) that an autocrine cardiac renin–angiotensin system, which is activated in diabetic conditions (Sechi et al. 1994; Fiordaliso et al. 2000; Frustaci et al. 2000), accounts for some of the changes in K+ currents in STZ-diabetic rats. Prolonged exposure to angiotensin II (ATII) attenuates the transient current (Yu et al. 2000), and our work demonstrated that in vitro incubation (>5 h) of myocytes from STZ-diabetic rats with an ATII receptor blocker or with an angiotensin-converting enzyme (ACE) inhibitor significantly augmented the depressed transient and sustained K+ currents (Shimoni, 2001). More recently we reported that the autocrine effects in STZ-diabetic rats were gender-selective. K+ currents were less attenuated in cells from female diabetic rats, and there was no effect of ACE inhibition (Shimoni & Liu, 2003).
The present study addresses changes in cardiac K+ currents in the db/db mouse, a model of type 2 diabetes exhibiting obesity and insulin resistance (Chua et al. 1996). Cardiac contractile function and metabolic parameters have been characterized in hearts from male and female db/db mice (Belke et al. 2000; Aasum et al. 2003). Both genders show similar significant weight gain by 6 weeks, with further increases by 12 weeks of age. Free fatty acids and insulin are also significantly increased at 6 weeks in both genders, although glucose elevation appears later in the females (details in Aasum et al. 2003). Mechanical dysfunction was identified at 12 but not at 6 weeks of age. This consisted of a reduction in cardiac output and cardiac power (Aasum et al. 2003).
Despite the increasing prevalence of type 2 diabetes, no detailed studies have addressed changes in electrical characteristics, as well as possible gender differences. In earlier work we found that outward K+ currents in ventricular cells from male db/db mice are significantly depressed at 12 weeks (Shimoni, 2001), as in the insulin-deficient STZ-diabetic rat (Shimoni et al. 1999). The attenuated currents were augmented by the angiotensin II receptor blocker valsartan. STZ-diabetic rats and db/db mice share the characteristics of hyperglycaemia and hyperlipidaemia. Although db/db mice and STZ-diabetic rats have high and low levels of plasma insulin, respectively, the action of insulin is effectively impaired in both models. Insulin augments attenuated K+ currents in myocytes isolated from STZ-diabetic male rats (Shimoni et al. 1999; Xu et al. 2002). However, STZ-induced diabetes leads to multiple changes in systemic and cardiac function (Tomlinson et al. 1992). The effects of insulin could thus interact with other long-term cellular changes. In order to determine the impact of insulin on K+ current density in isolation from other systemic changes, and to establish whether gender differences are due to differences in sensitivity to insulin, we have also measured these currents in mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO), described in detail previously (Belke et al. 2002). The present work addressed the following issues:
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Animals
Control male db/+ mice and db/db littermates (Jackson Laboratories) were used at 6 and 12 weeks of age. Female db/db and db/+ mice were used at 12 weeks of age. Other experiments were done on male and female mice with cardiac-specific deletion of the insulin receptor, described in detail previously (Belke et al. 2002). These CIRKO mice do not develop any of the symptoms of diabetes, since insulin secretion and function are normal in all other tissues. The bulk of experiments were done on 22- to 23-week-old CIRKO mice. A small number of experiments were also done on 12-week-old CIRKO mice (see Results).
Cell isolation
Mice were anaesthetized (pentobarbital, 100 mg kg-1, I.P.) and the heart was removed and placed in a calcium-free bicarbonate-based buffer at 4°C. The buffer composition was (mM): 120 NaCl; 5.4 KCl; 1.2 MgSO4; 1.2 Na2HPO4; 5.6 glucose; 20 NaHCO3; 10 2,3 butanedione monoxime (BDM); 5 taurine. The aorta was cannulated on a Langendorff apparatus and the heart perfused at 37°C for 4 min with the same buffer (bubbled with a 95% O2–5% CO2 mixture), followed with the same solution containing 25 µmol l-1 calcium chloride and 0.38 mg ml-1 collagenase (Worthington, 198 U mg-1). The coronary flow rate was 2.1 ml min-1. After 10–15 min, the free wall of the right ventricle was cut into small chunks, for further digestion in a shaking incubator (same solutions, containing 50 µM CaCl2 and 1% BSA, 37°C). Gentle trituration was used to assist cell dissociation. After 5–10 min the supernatant containing dispersed myocytes was filtered through a 250 µm mesh and gently centrifuged (500 r.p.m. for 1 min). The cell pellet was re-suspended in the same buffer, containing 100 µM CaCl2 and 5 mg ml-1 BSA. After settling of cells the supernatant was removed and the cells re-suspended in fresh solution. The viability (rod-shaped, calcium-tolerant cells) was typically 60–80%.
Current recording
Cells were placed in a 1 ml chamber on the stage of an inverted microscope and perfused with a solution containing (mM): 150 NaCl; 5.4 KCl; 1 CaCl2; 1 MgCl2; 5 Hepes; 5.5 glucose, brought to pH 7.4 with NaOH, and bubbled with 100% O2. Currents were recorded from single cells at 20–22°C, using the whole-cell voltage clamp method. The pipette solution contained (mM): 120 K-aspartate; 30 KCl, 5 Na2ATP; 5 Hepes; 1 MgCl2; 1 CaCl2; 10 EGTA, brought to pH 7.2 with KOH. Since currents in mouse ventricular cells are large (several nA), it was essential to minimize series resistance artifacts. This was done by using low resistance electrodes (2–4 M
) and by active electronic compensation (60–80%). Only well-polarized cells were used, with resting potentials of at least -65 mV. Action potentials were recorded in current clamp mode.
Mouse ventricle has a variety of outward K+ currents (Nerbonne, 2000). We measured peak outward current and the current at the end of a 500 ms pulse (defined as the sustained current, Isus), in response to voltage steps ranging from -110 to +50 mV (holding potential of -80 mV). The peak outward current (Ipeak) flows through channels encoded by Kv4.2 and Kv4.3 genes, whereas a mixture of channel proteins encoded by Kv1.2, Kv2.1 and Kv1.5 genes underlie the sustained current (Guo et al. 2000; Nerbonne, 2000). In the present experiments, Ipeak and Isus were used for comparison between groups, since they determine the repolarization of the cardiac action potential, which was the prime focus of this study. However, it is also important to establish if the transient current on its own is attenuated in type 2 diabetes. In the present work we separated the transient current component, using a prepulse to inactivate the transient component, with the difference current (with and without prepulse) giving the net transient current, as described by Trepanier-Boulay et al. (2001).
Cell size was represented by cell capacitance, measured by integrating currents obtained in response to 5 mV depolarizing steps from -80 mV. The mean cell capacitance in males was 92.4 ± 4.8 pF (n= 34) and 88.2 ± 3.1 pF (n= 70) for db/+ and db/db mice, respectively (P > 0.05). For females, the corresponding values were 71.1 ± 2.9 pF (n= 34) and 80.1 ± 2.1 pF (n= 96) (0.03 < P < 0.02). The reason for this difference is unknown. CIRKO mice showed a significant reduction in size (capacitance) for both genders, presumably due to the absence of insulin action (see Results).
Statistics
ANOVA and two-tailed Student's t test were used to compare between experimental groups, with the Student-Newman-Keuls test applied where appropriate. Results were considered significantly different for P < 0.05.
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Results |
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Earlier work had determined age-dependent changes in cardiac contractile function in db/db mice; at 6 weeks no differences were found in comparison to db/+ mice (Aasum et al. 2003). It was thus important to establish whether the outward K+ currents develop normally in db/db mice at 6 weeks, with subsequent attenuation at 12 weeks, and whether any parallels can be drawn between changes in current magnitude, metabolic parameters or contractile function.
We isolated cells from db/+ and db/db mice at 6 weeks of age and compared current densities. We found that current density in cells from diabetic mice at this age were not significantly (P > 0.05) different from currents obtained in cells from non-diabetic mice. Importantly, current densities were not significantly different at 6 and at 12 weeks in non-diabetic mice, suggesting that full development of current magnitude was attained by 6 weeks. Figure 2 shows these results. Panel A illustrates current traces from 2 cells, obtained from a control 6 week old db/+ mouse (left) and from a 6 week old diabetic db/db (right) mouse. Current–voltage relationships are plotted in panel B, showing no changes in either Ipeak (left) or Isus (right), across the whole range of membrane potentials. Note that current densities in control mice are similar at 6 and 12 weeks of age (shown in Fig. 1).
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The results presented so far suggest that the regulation of K+ current magnitude is altered between 6 and 12 weeks of age in the db/db mice. One of the mechanisms that may lead to K+ current changes was investigated in earlier work. This showed that a diabetes-related autocrine activation of the cardiac renin–angiotensin system (Sechi et al. 1994) is closely associated with attenuation of peak and sustained currents (Shimoni, 2001). Thus (in both STZ-diabetic rats and db/db mice) an ATII receptor blocker (valsartan) or (in the STZ-diabetic rat) the ACE inhibitor quinapril (Shimoni, 2001) augmented Ipeak and Isus. Since diabetic patients benefit from ACE inhibitors (Zuanetti et al. 1997), it was important to establish whether an ACE inhibitor also augments K+ currents in ventricular cells from a model of type 2 diabetes.
In the following series of experiments cells from db/db mice were incubated with 1 µM quinapril for 5–9 h. As in STZ-diabetic rats (Shimoni, 2001), quinapril significantly augmented both the peak and the sustained currents. Figure 3 shows mean current densities for Ipeak and Isus in the absence and presence of quinapril. Peak currents were significantly increased by quinapril (P < 0.03–0.05) between -20 and +50 mV. Isus values were significantly augmented (P < 0.03–0.05) between -10 and +50 mV. The transient currents, measured with the prepulse method, were 14.1 ± 1.8 and 22.3 ± 3.4 pA pF-1 (at +50 mV (P < 0.03) in the absence and presence of quinapril, respectively. Note that although currents were significantly augmented by quinapril, they did not attain densities measured in control db/+ mice. Mean peak current densities (at +50 mV) in cells from db/+ mice and from db/db mice in the absence of or following incubation (5–9 h) with 1 µM quinapril were 43.1 ± 2.4 pA pF-1 (n= 24), 21.2 ± 1.0 pA pF-1 (n= 38) and 30.6 ± 2.4 pA pF-1. The corresponding values for Isus were 26.8 ± 2.2, 12.7 ± 0.6 and 17.0 ± 1.2 pA pF-1. ANOVA (with Student-Newman-Keuls posthoc test) showed that the augmentation by quinapril was significant (P < 0.001 and P < 0.05 for Ipeak and Isus, respectively), but the densities were still significantly smaller than in control db/+ mice (P < 0.001 for both currents).
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The results so far demonstrate that the gender-selective changes in cardiac K+ currents observed earlier in diabetic rats are also present in the db/db mouse. These two models of diabetes share a variety of derangements, many of which could underlie the gender differences. In the present study, we addressed the possibility that the absence of insulin action may affect K+ currents only in males. These experiments were also designed to directly assess the role of insulin in regulating K+ current density. In our previous studies (Shimoni et al. 1999), effects of insulin were studied in cells obtained from diabetic animals. Thus, other diabetes-related changes (hyperglycaemia, hyperlipidaemia) were also present prior to cell isolation, possibly contributing to diminished current magnitude. For the present work, we isolated myocytes from cardiomyocyte-specific insulin receptor knock out (CIRKO) mice. These mice do have normal glucose homeostasis, and (the lack of) insulin action on cardiac K+ currents can be studied in isolation from other systemic changes. Several aspects of cardiac function have been studied in these mice (Belke et al. 2002), but no studies have addressed electrophysiological characteristics.
Interestingly, cell size, as estimated by capacitance measurements, was decreased in the CIRKO mice. In male CIRKO mice, the mean cell capacitance was 84.2 ± 3.7 pF (n= 39), which was significantly smaller (P < 0.02) than in heterozygous littermates, where the mean value was 98.1 ± 3.9 pF (n= 45).
In the first set of experiments, action potentials were recorded under current clamp conditions. At a stimulation rate of 1 Hz, action potential duration was significantly prolonged in cardiomyocytes from male CIRKO mice, as shown in Fig. 5. The increase in action potential duration in cells from CIRKO mice is very similar to results obtained with insulin-resistant db/db cells (Shimoni, 2001).
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Since the bulk of experiments with CIRKO mice were done at 22 weeks of age, whereas the experiments with db/db mice were done at 12 weeks of age, we examined whether the later age of the CIRKO mice (and a longer period without insulin action) could account for the lack of gender differences in this model. Cells were obtained from a small group of male and female CIRKO and control mice at 12 weeks of age. The results were identical to those obtained at 22 weeks. In female CIRKO and controls, mean Ipeak densities (at +50 mV) were 26.1 ± 3.0 pA pF-1 (n= 21) and 37.2 ± 4.6 pA pF-1 (n= 16, P < 0.05), respectively. The corresponding values for Isus were 14.2 ± 1.2 and 20.5 ± 2.0 pA pF-1 (P < 0.007). In males, the mean values of Ipeak (at +50 mV) were 47.3 ± 4.1 pA pF-1 (n= 15) and 34.3 ± 3.2 pA pF-1 (n= 12) in control and CIRKO mice, respectively (P < 0.025). The corresponding values for Isus were 28.9 ± 2.2 and 18.3 ± 1.8 pA pF-1 (P < 0.002). For both control and CIRKO male and female mice, Ipeak and Isus densities were not significantly different (P > 0.05) at 12 and at 22 weeks.
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Discussion |
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The results presented demonstrate several novel findings. Outward K+ currents in a mouse model of type 2 diabetes are attenuated at 12 weeks of age, whereas at the age of 6 weeks, currents are still comparable to those in control db/+ mice (Figs 1,2). This age-dependent pattern is similar to changes in contractile function and in glucose oxidation in db/db mice (Semeniuk et al. 2002; Aasum et al. 2003). The attenuated currents in cells from male db/db mice at 12 weeks of age are augmented by in vitro incubation with an ACE inhibitor (Fig. 3), suggesting autocrine regulation due to activation of a local renin–angiotensin system. These changes are restricted to cells from male db/db mice (Fig. 4). K+ currents are attenuated and action potentials prolonged in both male and female mice with cardiomyocyte-specific knockout of insulin receptors (Figs 5–7). The ACE inhibitor is without effect on these attenuated currents (Fig. 8).
Interpretation and significance
The attenuation of repolarizing currents in a model of type 2 diabetes has not been described in detail previously. Understanding the nature of current attenuation and underlying mechanisms is of vital importance. Abnormal repolarization, due in part to the reduction or elimination of the transient current by altering channel expression, has been demonstrated to be arrhythmogenic (Surawicz, 1997; Guo et al. 2000; Kuo et al. 2001). Our results in mouse models may apply to humans, since a prolongation of the QT interval, measured in the ECG of diabetic patients (Ewing et al. 1991; Veglio et al. 2002), reflects a longer action potential, as would occur if repolarizing currents were attenuated in the human ventricle.
Both male and female db/db mice develop contractile abnormalities by 12 weeks. These consist of a reduction in cardiac output and in cardiac power, expressed as the product of systolic pressure and cardiac output (Aasum et al. 2003). In males, there is a parallel between the development of contractile and electrical abnormalities, suggesting that these may be linked to common diabetes-related abnormalities.
Several mechanisms have been suggested to lead to attenuation of K+ currents in diabetic conditions. Insulin deficiency in type 1 diabetes was found to be of importance, and currents are indeed restored by in vivo or in vitro addition of insulin (Xu et al. 1996; Shimoni et al. 1999). Impaired cardiac metabolism has also been linked to altered electric function. Thus, stimulation of glucose metabolism and reducing oxidative stress were shown to augment the transient K+ current (Xu et al. 1996, 2002).
The incomplete restoration of current magnitudes by ACE inhibition in the present experiments (Fig. 3) suggests that multiple mechanisms regulate current magnitude. The augmentation of K+ currents by the ACE inhibitor can be interpreted as resulting from a removal of an inhibitory autocrine effect of angiotensin II, which is activated under diabetic conditions (Sechi et al. 1994). In female db/db mice, despite the changes in contractile function there was no attenuation in outward currents and no effect of quinapril (Fig. 4), as also found in female STZ-diabetic rats (Shimoni & Liu, 2003). These results suggest that autocrine mechanisms are not activated in the female diabetic heart, possibly due to suppression by oestrogen (Shimoni & Liu, 2003), which is known to suppress various components of the renin–angiotensin system (Brosnihan et al. 1997; Gallagher et al. 1999).
ACE inhibitors are of proven benefit to diabetics (Zuanetti et al. 1997; Torlone et al. 1993; Kontopoulos et al. 1997). Most of the benefits have been attributed to reduction of blood pressure, and improvement in insulin sensitivity. It is possible that some of the protection also derives from a reduction in arrhythmias. Direct effects of quinapril and ATII receptor blockers have been shown to reduce arrhythmias (Louch et al. 2000), although in the latter case this may be due to non-receptor-mediated actions (Thomas et al. 1995). The data relating to beneficial effects of ACE inhibitors does not differentiate between genders.
The results with CIRKO mice addressed one possible mechanism underlying gender differences. In STZ-diabetic rats and db/db mice, insulin action is compromised. Insulin had previously been shown to restore K+ current magnitude in cells from STZ-diabetic rats (Shimoni et al. 1999). However, cells in those experiments were isolated from hearts subject to elevation in glucose, free fatty acids and other diabetes-related systemic derangements. The present work with CIRKO mice shows directly that insulin regulates K+ current magnitude, in the absence of other confounding factors, and that this is similar in male and female hearts. Quinapril had no effect on the attenuated currents in cardiac cells from CIRKO mice, presumably because there was no activation of autocrine mechanisms in the absence of systemic diabetic stress. In summary, the present results suggest that gender differences in K+ current regulation derive from mechanisms that are related to the autocrine action of angiotensin II.
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), which significantly augmented both currents.
