© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Influence of postnatal-development on If occurrence and properties in neonatal rat ventricular myocytes
Department of Preclinical and Clinical Pharmacology, University of Firenze, Firenze, Italy
mugelli{at}pharm.unifi.it
* Corresponding author. Tel.: +39-055-427-1264; fax: +39-055-427-1285
Received 21 October 1998; accepted 10 December 1998
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: If is a hyperpolarization-activated current, which plays a key role in determining the spontaneous rate of cardiac pacemaker cells. We have previously shown that If is also expressed in left ventricular myocytes isolated from spontaneously hypertensive rats; in these cells, its occurrence and density is linearly related with the severity of myocardial hypertrophy. Since hypertrophy induces a re-expression of genes encoding fetal proteins, we investigated changes in If properties during post-natal development. Methods: Fresh ventricular myocytes were enzymatically isolated from the heart of 1–2- to 28-day-old Wistar rats. The whole-cell configuration of the patch-clamp technique was employed to record the action potential and If. Results: Membrane capacitance, an index of cell size, progressively increased from 13±1 pF at 1–2 days to 66±4 pF at 28 days of age (p<0.01). At 1–2 days, a cesium-sensitive hyperpolarization-activated inward current (If) was recorded in the majority of tested cells (n=51). The midpoint of the activation curve (V1/2) was –78±2 mV (n=32), and specific current conductance of fully activated If (gf,max) was 60±11 pS/pF. Reversal potential (Vrev) measured by tail-current analysis was –24±3 mV (n=8). Reduction of extracellular Na+ from 140 to 35 mM or extracellular K+ from 25 to 5.4 mM caused a shift of –12±1 mV (n=3) or –11±2 mV (n=5) of Vrev, respectively. Occurrence of If decreased with aging, being present in 64%, 48% and 32% of cells at 10, 15 and 28 days, respectively. When present, If density was significantly smaller than at 1–2 days (p<0.05), reaching a value of 8±2 pS/pF at 28 days. However, V1/2 did not change in the older rats, being –80±2, –83±4 and –85±3 mV at 10, 15 and 28 days, respectively. Vrev at 10 and 15 days was –27 and –28 mV, respectively, thus suggesting that channel selectivity did not change. Conclusions: The pacemaker current, If, is expressed in ventricular myocytes from neonatal rats and progressively disappears; when present, it shows electrophysiological properties similar to If re-expressed in hypertrophied adult rat ventricular myocytes. Thus, it is likely that the occurrence of If in ventricular myocytes of hypertrophied and failing hearts is due to the re-expression of a fetal gene.
KEYWORDS Cm, membrane capacitance; [K+]o, extracellular potassium concentration; (gf,max) gf, (maximal) specific conductance of If; [Na+]o, extracellular sodium concentration; V1/2, voltage of half maximal activation of If; Vrev, reversal potential of If.
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Cardiac hypertrophy and failure are associated with the development of cellular electrophysiological changes. Prolongation of action potential duration is the most common alteration found in almost all models of cardiac hypertrophy [1,2]. The underlying ionic mechanism appears to be a selective reduction in the repolarizing transient outward current Ito [1,2]. The cellular electrophysiological remodeling occurring in ventricular myocytes during hypertrophy due to pressure overload is not, however, limited to this change. In left ventricular myocytes, isolated from the hypertrophied left ventricle of spontaneously hypertensive rats (SHR), we have recently reported the expression of a current having the characteristics of the pacemaker current If [3]. Its occurrence and density in SHR are linearly related with the severity of myocardial hypertrophy [4]. Furthermore If has been found to be present in myocytes isolated from the failing human heart [5].
If is a nonselective cation current activated on hyperpolarization; it provides an inward current which might play a key role in determining the diastolic depolarization phase and the genesis of pacemaker activity in both primary and secondary pacemakers [6]. Its expression in ventricular cells from hypertrophied or failing hearts led us to suggest that If may represent an arrhythmogenic mechanism [4,7]. It is known that hypertrophy induces a re-expression of genes encoding fetal proteins [8]. Thus the possibility exists that hypertrophy may induce the re-expression of a current already present during the fetal life. In fact, an If-like current has been recorded in spontaneously beating embryonic or neonatal ventricular myocytes [9,10]. Developmental changes in neonatal rat ventricular cells are characterized by a significant increase in the density of the transient outward current Ito and by the hypertrophy of myocytes [8,11,12]. It has been recently shown that the developmental increase in Ito and postnatal cell hypertrophy of neonatal cardiomyocytes can be independently regulated by serum factors [13–15] and by thyroid hormone [16,17].
Thus a better understanding of the changes in the electrophysiological properties of If throughout postnatal development of ventricular myocytes which, in the adult stage, are physiologically quiescent and do not express If [3,4], appears to be important for a better understanding of the mechanisms and factors leading to and controlling its reappearance during disease (i.e. hypertrophy and failure).
For this reason, we have studied the changes in occurrence and properties of the pacemaker current If during postnatal development in freshly isolated rat ventricular cardiomyocytes.
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2 Methods |
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2.1 Cell isolation
The investigation conforms to the rules for The Care and Use of Laboratory Animals of the European Community (86/609/CEE).
Single ventricular myocytes were isolated from 1 to 28 day-old Wistar rats. After sacrifice of the rats, the hearts were rapidly removed and rinsed in cool low-calcium solution (LCS, see Section 2.3). Under a stereomicroscope, the aorta was identified and cannulated using the smoothed tip of a needle, inserted into a polyethylene tube (0.56 mm I.D.). The aorta was held tightly by the operator with a fine forceps and the heart was mounted on a micro-Langendorff apparatus and then perfused with LCS, prewarmed to 37°C and equilibrated with 100% O2, for 5 min. The solution was then quickly changed to LCS complemented with 0.1 mg/ml collagenase Type B (Boehringer) for 5 to 15 min, according to the age of the animal. Finally, the heart was rinsed with Kraft Brühe (KB) solution and the atria were discarded. The ventricular tissue was minced, gently stirred and the supernatant was resuspended in fresh KB solution and maintained at room temperature for 60 min. The cardiomyocytes that appeared in the supernatant were purified by centrifugation (5 min at 1000 rpm), resuspended and stored in control Tyrode’s solution (see Section 2.3) supplemented with 0.5 mM CaCl2 and 4% penicillin/streptomycin (Gibco BRL) and used within the day.
2.2 Electrophysiological recordings
The experimental approach is similar to that described elsewhere [3,4,18]. Cells were placed in an experimental bath on the platform of an inverted microscope (Nikon Diaphot TMD, Japan). The patch-clamp technique (whole cell recording) was used to measure the electrophysiological properties of the isolated myocytes. Experiments were performed using a patch amplifier (Axopatch-1B, Axon Instruments, CA, U.S.A) interfaced to a 486 personal computer by means of a DAC/ADC interface (Labmaster Tekmar, Scientific Solutions). Data were viewed on-line on an analogic oscilloscope and on a computer screen. Experimental control, data acquisition and preliminary analysis were performed by means of the integrated software package pClamp (Axon Instruments, CA, USA). Cells were superfused with normal Tyrode’s solution or with a modified Tyrode’s solution during measurements of the hyperpolarization-activated inward current (If) (see Section 2.3). Temperature was maintained in the range of 36–37°C. Patch-clamp pipettes, prepared from glass capillary tubes (Garner Glass, CA, USA) by means of a two-stage vertical puller (Hans Otchoski, Homburg, Germany), had a resistance of 3–4 M
when filled with the internal solution (see Section 2.3). The patch-clamped cell was superfused by means of a temperature-controlled micro-superfusor, which allowed rapid changes of the solution bathing the cell.
Action potentials were elicited at 0.2 Hz in the current-clamp mode and sampled at 2 kHz. If was evoked by hyperpolarizing steps to –50/–130 mV. To evaluate steady-state values of the hyperpolarization-activated current [3], data were fitted to an exponential decay. Current amplitudes were measured as the difference between the value at the steady state and that at the beginning of the test pulse, and normalized with respect to the membrane capacitance value (see below). Specific conductance was determined as a function of membrane potential according to the following equation:
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A Boltzmann model based on the partition theorem according to the general equation:
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Cell membrane capacitance (Cm) was measured by applying a ±10 mV pulse starting from a holding potential of –70 mV. The current transient following this clamp protocol was fitted with a mono-exponential model to compute the series resistance (Rs) and then Cm using the two equations given below:
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is the time constant of the exponential current decay. The membrane capacitance values obtained have been used to compute ionic current densities (If density in pA/pF).
2.3 Solutions
The composition of the solutions employed was as follows (in mM): Low Calcium Solution (LCS): NaCl 120, KCl 10, KH2PO41.2, MgCl2 1.2, D(+)-glucose 10, taurine 20, HEPES–NaOH, 10 (pH 7.0). Kraft Brühe (KB): KCl 40, KH2PO4 1.2, MgCl2 3, taurine 20, D(+)-glucose 10, glutamic acid 50, HEPES/KOH 10 (pH 7.2). Control Tyrode’s solution: NaCl 140; KCl 5.4; CaCl2 1.5; MgCl2 1.2; glucose 5.5; HEPES–NaOH 5 (pH 7.35). Modified Tyrode’s solution for hyperpolarization-activated inward current measurements: NaCl 140, KCl 25, CaCl2 1.5, MgCl2 1.2, BaCl2 2, MnCl2 2, 4-aminopyridine 0.5, glucose 10, HEPES–NaOH 5 (pH 7.35); this solution allowed for the reduction of interference from other currents, i.e., L-type calcium current, inward rectifier-like current and transient outward potassium current. In some of the experiments aimed to test the ionic selectivity of the f channel, the extracellular concentration of KCl was reduced to 5.4 mM or that of NaCl was reduced to 35 mM (replaced by equimolar TEA–Cl). Pipette solution: K-Aspartate 130, Na2–ATP 5, MgCl2 2, CaCl2 5, EGTA 11, HEPES–KOH 10 (pH 7.2; pCa 7.0).
2.4 Data analysis and statistics
Data analysis and fitting were performed by using the program ORIGIN 4.1 (MicroCal Software, MA, USA) running on a Pentium personal computer. For fitting functions, nonlinear models of convergence to solutions were used.
All data are expressed as mean±standard error of the mean (SEM). Statistical analysis was performed by means of the GRAPH PAD INSTAT program, using Student’s t test (grouped data) or ANOVA followed by Student–Neuman–Keuls multiple comparisons test. A probability value of less than 0.05 was considered significant.
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3 Results |
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3.1 Changes in Cm during development and presence of If
Fig. 1 shows the frequency histogram of membrane capacitance, a widely used index of cell size, measured in single myocytes isolated from the ventricles of the heart of rats at different age after birth. It appears that cell dimension increases progressively as a function of age, thus confirming that postnatal growth of the heart is associated with cell hypertrophy [11]. The mean cell capacitance in ventricular myocytes isolated from 1–2 day-old rats is 13.4±0.9 pF (n=75) and reaches a value of 66.1±4.1 pF in ventricular myocytes isolated from 28-day-old rats (n=38) (p<0.01). A typical recording of an action potential (AP) from 1-day-old rat ventricular myocytes is shown in Fig. 2 (panel A). The action potential duration is quite long as expected for a cell in which the repolarizing current Ito is almost absent [14]. The diastolic phase of the AP is however not flat, as it is in adult ventricular myocytes. A current activated on hyperpolarization could be consistently recorded in cells isolated from the heart of rat at 1–2 days of age. Panel B shows a typical recording of such a current, which, as the pacemaker current If we previously described in hypertrophied ventricular myocytes, increased in amplitude and become faster at more negative potentials (panel B and D) [3,4]. The I–V curve (panel C) clearly shows that the current begins to activate at potentials between –50 and –60 mV, and it is fully activated at –100 mV. Panel D shows the plot of the reciprocal of the time-constant of If activation obtained by fitting the current trace with an exponential decay (see Methods) versus membrane potential: it is evident that the kinetics of current activation is consistently faster at more negative potentials.
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3.2 Electrophysiological properties of If
We determined the electrophysiological characteristics of the current in 48 ventricular myocytes from 1–2 day-old hearts. As can be clearly seen (Fig. 3), the time-dependent inward current was completely abolished by superfusing the cell with a solution containing cesium ions (Cs+) at the concentration of 4 mM. The blocking action of Cs+ was confirmed in all of the tested cells, where the block was considered to be effective if no time-dependent inward current was left. The Cs+-block could be easily removed by washout. Steps in the range of –70 to +10 mV (Fig. 3B) elicited tail currents, following a hyperpolarizing step to –120 mV, which maximally activates If. In the presence of cesium, the negative region of the fully activated I–V relationship, obtained by plotting tail current amplitude (Itail) vs. the tail step potential, was characterized by a progressive reduction of the current, showing a clear-cut voltage-dependent blockade.
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) and presence (
) of 4 mM CsCl. Panel B: Plot of average tail current density (Itail) versus tail step potential. Each point represents the mean±SEM value, measured in eight cells superfused with control solution and five cells superfused with the same solution plus 4 mM CsCl.The measurement of tail current amplitude was also used to evaluate the reversal potential of If at different extracellular potassium concentrations ([K+]o). Current tracings in Fig. 4A were obtained in the same cell superfused with Tyrode’s solution containing either 25 or 5.4 mM [K+]o. The most evident effect caused by the reduction in [K+]o was a marked decrease in If amplitude. Fig. 4B shows the fully activated I–V relationship obtained from the same cell superfused with Tyrode’s solutions containing different [K+]o. With 25 mM [K+]o, best fit through data points gave a linear relationship, which intersected the x-axis (reversal potential of If) at –24.0±2.8 mV (n=8). With 5.4 mM [K+]o, the reversal potential was shifted to more negative potentials by 11.1±2.6 mV and the slope conductance was reduced to 33.7±5% of the control (n=5), in agreement with our previous results in hypertrophied rat myocytes [3]. Decreasing [Na+]o to 35 mM by replacement with equimolar TEA–Cl also shifted the fully activated I–V relationship toward more negative values (Fig. 4C,D), the average shift being 11.7±0.8 mV (n=3); however, as expected [20], [Na+]o decrease did not cause a reduction of slope conductance, which was similar (90.3±3.3%, n=3) to that measured in high [Na+]o (Fig. 4D).
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3.3 Occurrence, density, and properties of If during development
As previously stated, If was consistently recorded in ventricular myocytes isolated from 1–2-day-old rats. We considered If to be present in a given cell if a cesium-sensitive, time-dependent increasing inward current was detected. Using this criterion, 48 out of 51 ventricular myocytes showed If. As shown in Fig. 5 (panel A), the proportion of cells with If decreased progressively during development. If occurred in about 30% of ventricular myocytes at 28 days (in 10 out of 31 cells). This decrease was paralleled by a decrease in current density. In panel B of Fig. 5, If density is expressed as maximal current conductance, that is, the density of the fully activated current normalized with respect of the driving force (Vm–Vrev, see Methods). In the first 5 days after birth the current density was practically unchanged; than, starting from day 10, a progressive statistically significant decrease was observed, reaching a minimum at day 28. Specific current conductance decreased from 78.9±11.8 pS/pF at 5 days to 23.3±3.8 pS/pF and 7.8±2.3 pS/pF at 10 and 28 days, respectively. The reduction in current density was not only due to the increase in cell size, but also to a specific reduction in current amplitude, which was maximal at 5 days (160±36 pA, n=31) and, decreased to 58±10 pA and 49±14 pA at 10 and 28 days, respectively. While in 1–2 day-old myocytes If occurred in almost all the cells, at 10 days If occurred in approximately 50% of the cells (38 out of 59 tested cells). 1–2 day-old myocytes where If consistently occurred, had a action potential profile that can be defined as ‘immature’ type, i.e. characterized by the absence of a rapid repolarization and by a prolonged duration (see Fig. 2A). In order to assess if the occurrence of If was characteristic of the ‘immature’ type cells, action potential was measured in 10-day-old myocytes, in which If was present or absent. Fig. 6 shows representative recordings from two different ventricular myocytes, one in which If occurred and one in which it was absent. It appears that the myocytes which did not express If had a more ‘mature’ profile, i.e. similar to the action potential recorded in adult rat myocytes, characterized by a rapid phase of repolarization after the upstroke and by a shorter duration. The latter characteristics of the action potential in mature ventricular myocytes are the consequence of an increase in Ito expression [14]. Thus ventricular myocytes during the maturation process loose the capacity to synthesize the If channel. Despite the observed differences in occurrence and density, the characteristics of If did not change with development. This is shown in Fig. 7 in which two relevant properties of the current, the voltage of half maximal activation (V1/2) and the reversal potential (Vrev), are reported as a function of the myocytes age. V1/2 did not change in the different groups; due to the lower occurrence of If in myocytes isolated from 15- and 28-day-old rats, the number of cells in which the measurement could be done is less in these groups than in the others. However, the results clearly show that this property is not influenced by development. Also the reversal potential of If does not appear to be modified by development. This is clearly shown for the three younger age groups, including the group of 10-day-old myocytes, in which the current density and occurrence are significantly reduced. Measurements carried out in the few myocytes of 15 and 28 days of age, in which current density is usually too small to allow a correct measurement of the reversal potential, are in keeping with no change of the reversal potential during development. In fact, Vrev was –28 mV in two cells from 15-day-old rats.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The present results demonstrate that the pacemaker current If is expressed in ventricular myocytes isolated from newborn rats. Current occurrence and density are maximal at 1–5 days after birth and progressively decrease during development. A minority of myocytes isolated from the hearts of rats at 28 days of age express If, which, when present, has a small amplitude. Thus If is expressed in rat ventricular myocytes immediately after birth (present results; [9,10]) and likely during fetal life; it almost disappears with development (it occurs in a minority of adult ventricular myocytes [4]), and is re-expressed during severe hypertrophy [4] and failure [5,7]. In other words, the behavior of If is opposite during natural cell growth and during pathophysiological hypertrophy. Disappearance of If in ventricular myocytes during early development occurs while the cell size increases as postnatal cellular growth develops. During pathophysiological hypertrophy, both cell size and If density increase. Thus If is expressed independently of the cell dimensions as previously suggested by our results in old rats [4]. In fact, we showed that If amplitude is not related to the degree of cellular hypertrophy, i.e., a larger cell has not necessarily a larger current, rather its density (i.e. amplitude normalized to cell size, thus excluding the contribution of cellular hypertrophy) is directly related to the severity of cardiac hypertrophy caused by pressure overload. Our previous results suggest that cardiac hypertrophy as it occurs in the normal process of aging, is not a sufficient stimulus for the re-expression of the current [4]. Consequently, it appears that it is not the cellular growth per se which triggers this phenomenon, but other factors should be involved. This is not surprising, since the modification in the electrophysiological properties (i.e. changes in Ito) may be different during the hypertrophic process. During cell growth in neonatal cells, Ito increases [13,16,21] while during hypertrophy due to pressure overload [19] or following myocardial infarction [22] Ito decreases. Furthermore, cell growth and expression of Ito are independently regulated by serum factors and thyroid hormone [13–17]. In neonatal ventricular myocytes cultured in serum-free conditions, basic Fibroblast Growth Factor (bFGF) promotes Ito expression without a concomitant increase in cell size [13]. In the same cells, well known hypertrophic agents such as phenylephrine and endothelin-1, are able to induce a suppression of the expression of the Kv 4.2
-subunit, one of the proteins which largely accounts for Ito in the ‘mature’ ventricular rat cell and which is up-regulated during postnatal development [15], while producing a clear-cut increase of cell size [15]. On the whole, a variety of stimuli may specifically promote or inhibit the expression of genes encoding for channel proteins, this action being concomitant with or independent from the activation of cell growth. In this line, we recently observed [23] that angiotensin II plays a major role in controlling the expression of both Ito and If. Thus, it can been speculated that serum factors present during pathological hypertrophy may turn on the gene encoding for the If channel. The gene is turned off by some unknown mechanism during development. This interpretation is not in agreement with the results by Robinson et al. [9], who found that the pacemaker current If undergoes changes in its voltage-dependence during aging: in fact, they found a marked negative shift in If activation curve by comparing neonatal and adult rat ventricular myocytes. On the other hand, our results demonstrate that the voltage for half-maximal activation is not changed during early postnatal development. The reason for such a discrepancy is not obvious, since the experimental procedure is basically the same. The threshold for activation and the kinetics of If in neonatal cells are however comparable in the two studies: thus, the discrepancy is limited to If measured in myocytes from adult rats. Recent data [24] obtained in a different laboratory, show that in adult rat ventricular myocytes the threshold for activation is around –80 mV thus confirming our present and previous data. Taken together, our data suggest that a turning on/off of a gene encoding the If channel, rather than a shift in the activation voltage [9], is the mechanism by which If is regulated. The novel finding is that a current, which is physiologically present only in pacemaker tissues, is expressed in ventricular myocytes during early life or in diseased states. Such a current is likely to be involved in physiological pacemaking [6]; several data suggest that it may be important in generating spontaneous activity in hypertrophied and failing ventricular myocytes [3–5]. If in ventricular myocytes at physiologically relevant voltages (i.e. around the maximum diastolic potential) is of the order of 1 pA/pF in human and 1.5 to 2 pA/pF in old SHR ventricular myocytes [3–5]. The amplitude of If in physiological condition is obviously less, due to its dependence on extracellular potassium concentration: on average, If amplitude is reduced to 35% by a reduction of [K+]o from 25 to 5.4 mM. However, the amplitude of the outward component of IK1, which is also dependent on [K+]o, should be taken into account. In rats, the evidence that If can depolarize the cell only when it is large enough to overcome the stabilizing action of IK1 comes from the observation that a diastolic depolarization occurs in old, but not in young, rat ventricular multicellular preparations [25] and isolated cells [3]. Thus, even an If of small amplitude may be functionally important, if its depolarizing action is not counteracted by a small outward IK1 [26,27]. Interestingly, IK1 has been reported to be reduced in terminal heart failure [28,29]. Finally, β-adrenergic stimulation has opposite effects on these two currents: it activates If [4,30] and inhibits IK1 [31], thus enhancing the likelihood that If may act as an arrhythmogenic stimulus. If has been recently proved to be the inward current responsible for the anode break stimulation in isolated ventricular myocytes [24]. The experimental data were faithfully reproduced by an action potential model only including If activation and IK1 block/unblock. Furthermore, anode break responses were much more difficult to be elicited in cells from young (6 to 10 weeks old) than in old animals, and the authors suggest that this was due to the paucity of If in younger rats, as we have previously reported [4].
In conclusion, the understanding of the factors involved in the disappearance of If during the electrophysiological remodeling during development should help in the clarification of the mechanism leading to electrophysiological remodeling in disease.
Time for primary review 27 days.
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Acknowledgements |
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This study was partly supported by a grant from Telethon (Project no. 1092) by CNR (Project no. 98.03098.CT04) and by M.U.R.S.T.
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 X. Luo, H. Lin, Z. Pan, J. Xiao, Y. Zhang, Y. Lu, B. Yang, and Z. Wang Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart J. Biol. Chem., July 18, 2008; 283(29): 20045 - 20052. [Abstract] [Full Text] [PDF]
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 L. Sartiani, E. Cerbai, G. Lonardo, P. DePaoli, M. Tattoli, R. Cagiano, M. R. Carratu, V. Cuomo, and A. Mugelli Prenatal Exposure to Carbon Monoxide Affects Postnatal Cellular Electrophysiological Maturation of the Rat Heart: A Potential Substrate for Arrhythmogenesis in Infancy Circulation, January 27, 2004; 109(3): 419 - 423. [Abstract] [Full Text] [PDF]
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 S. Tanaka, N. Wu, C.-F. Hsaio, J. Turman Jr., and S. H. Chandler Development of Inward Rectification and Control of Membrane Excitability in Mesencephalic V Neurons J Neurophysiol, March 1, 2003; 89(3): 1288 - 1298. [Abstract] [Full Text] [PDF]
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 L. Sartiani, P. Bochet, E. Cerbai, A. Mugelli, and R. Fischmeister Functional expression of the hyperpolarization-activated, non-selective cation current If in immortalized HL-1 cardiomyocytes J. Physiol., November 15, 2002; 545(1): 81 - 92. [Abstract] [Full Text] [PDF]
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 K. S. Warren, K. Baker, and M. C. Fishman The slow mo mutation reduces pacemaker current and heart rate in adult zebrafish Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1711 - H1719. [Abstract] [Full Text] [PDF]
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 J. Qu, A. Barbuti, L. Protas, B. Santoro, I. S. Cohen, and R. B. Robinson HCN2 Overexpression in Newborn and Adult Ventricular Myocytes : Distinct Effects on Gating and Excitability Circ. Res., July 6, 2001; 89 (1): e8 - e14. [Abstract] [Full Text] [PDF]
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K. Yasui, W. Liu, T. Opthof, K. Kada, J.-K. Lee, K. Kamiya, and I. Kodama If Current and Spontaneous Activity in Mouse Embryonic Ventricular Myocytes Circ. Res., March 16, 2001; 88(5): 536 - 542. [Abstract] [Full Text] [PDF]
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D. Stilli, A. Sgoifo, E. Macchi, M. Zaniboni, S. De Iasio, E. Cerbai, A. Mugelli, C. Lagrasta, G. Olivetti, and E. Musso Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H142 - H150. [Abstract] [Full Text] [PDF]
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J. Qu, I. S Cohen, and R. B Robinson Sympathetic innervation alters activation of pacemaker current (If) in rat ventricle J. Physiol., August 1, 2000; 526(3): 561 - 569. [Abstract] [Full Text] [PDF]
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 E. Cerbai, A. Crucitti, L. Sartiani, P. De Paoli, R. Pino, M. L. Rodriguez, G. Gensini, and A. Mugelli Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes Cardiovasc Res, January 14, 2000; 45(2): 388 - 396. [Abstract] [Full Text] [PDF]
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S. Nattel, D. M. Roden, and D. Escande A spotlight on electrophysiological remodeling and the molecular biology of ion channels Cardiovasc Res, May 1, 1999; 42(2): 267 - 269. [Full Text] [PDF]
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