AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 277: H1725-H1731, 1999;
0363-6135/99 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, J.-K.
Right arrow Articles by Toyama, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.-K.
Right arrow Articles by Toyama, J.
Vol. 277, Issue 5, H1725-H1731, November 1999

Downregulation of voltage-gated K+ channels in rat heart with right ventricular hypertrophy

Jong-Kook Lee1, Atsushi Nishiyama1, Fukushi Kambe2, Hisao Seo2, Susumu Takeuchi1, Kaichiro Kamiya1, Itsuo Kodama1, and Junji Toyama1

Departments of 1 Circulation and 2 Endocrinology and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan 464-8601


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The effects of myocardial hypertrophy on mRNA expression levels of voltage-gated K+ channels were investigated using monocrotaline (MCT)-induced pulmonary hypertensive rats. The ratio of right ventricle weight to left ventricle plus septum weight on day 28 was increased significantly compared with control rats [control vs. MCT: 0.27 ± 0.01 vs. 0.58 ± 0.03 ms (n = 8-13); P < 0.05]. Electrocardiograms showed that QRS duration [control vs. MCT: 26.4 ± 2.6 ms vs. 31.5 ± 5.8 ms (n = 6); P < 0.05], Q-T interval [control vs. MCT: 100.8 ± 8.9 ms vs. 110.0 ± 4.2 ms (n = 6); P < 0.05] and corrected Q-T interval [Q-Tc; control vs. MCT: 8.4 ± 0.7 ms vs. 10.2 ± 0.4 ms (n = 6); P < 0.05] were prolonged significantly on day 28. mRNA levels of Kv1.2, 1.5, 2.1, 4.2, and 4.3 for day 28 assessed by ribonuclease protection assays were decreased significantly from control by 60 ± 10, 76 ± 3, 58 ± 5, 81 ± 5, and 45 ± 12%, respectively (n = 3; P < 0.005), and Kv1.4 mRNA level for day 28 was unaffected [Kv1.4, control vs. MCT: 1.0 ± 0.28 vs. 0.88 ± 0.44 (arbitrary units) (n = 3); not significant (NS)]. On the other hand, there was no significant difference between control and MCT rats in mRNA levels of these Kv channels for day 14 [Kv1.2 (control vs. MCT): 1.0 ± 0.25 vs. 0.87 ± 0.18 (n = 3), NS; Kv1.4: 1.0 ± 0.22 vs. 1.27 ± 0.37 (n = 3), NS; Kv1.5: 1.0 ± 0.16 vs. 0.91 ± 0.28 (n = 3), NS; Kv2.1: 1.0 ± 0.26 vs. 0.99 ± 0.25 (n = 3), NS; Kv4.2: 1.0 ± 0.15 vs. 1.22 ± 0.28 (n = 3), NS; Kv4.3: 1.0 ± 0.20 vs. 1.21 ± 0.28 (n = 3), NS]. These findings suggest that altered ventricular repolarization at the advanced stage of hypertrophy may be the result of an inhibition of gene expression of multiple types of voltage-gated K+ channels.

ventricular hypertrophy; voltage-gated potassium channels; messenger ribonucleic acid expression


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

CLINICAL STUDIES have suggested that ventricular hypertrophy is associated with a greater risk of sudden cardiac death probably caused by lethal ventricular arrhythmias (18). Alterations of repolarization are often recognized in clinical electrocardiograms (ECGs) with the development of ventricular hypertrophy. Cellular electrophysiological studies have shown that these alterations in repolarization are caused by the prolongation of action potential duration (APD) (1). APD prolongation has been ascribed to a decrease of the transient outward K+ current (Ito) density or an increase of the L-type Ca2+ current (ICa) density in a variety of experimental models of cardiac hypertrophy in rats (5, 7, 15, 27, 31), cats (12, 16, 24), and guinea pigs (26). Comparable changes in Ito and ICa were also reported in human patients with an advanced stage of congestive heart failure (6).

In a recent study using rats with monocrotaline (MCT)-induced right ventricular (RV) hypertrophy, we reported (17) that hypertrophy was associated with stage-dependent changes in Ito and ICa; the APD prolongation in the early compensated stage of hypertrophy may be caused mainly by an increase of ICa density, whereas the APD prolongation in the advanced stage of hypertrophy may be the result of a reduction of Ito density. The decrease of Ito density at the late stage of hypertrophy is consistent with previous reports on other models of ventricular hypertrophy (5, 7, 31). In adult rat hearts, many voltage-gated K+ channel subunits have been cloned, which include Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, and Kv4.3. Kv4.2 and Kv4.3 of the Shal family are the most likely candidates for Ito (3, 9), whereas Kv1.2 and Kv1.5 of the Shaker family and Kv2.1 of the Shab family are considered as candidates for other delayed rectifier K+ channels sensitive to 4-aminopyridine (4-AP) or tetraethylammonium (TEA) (4, 8). It has been shown in several studies that the expression of these cloned K+ channels is affected in certain pathophysiological conditions including cardiac hypertrophy and hormonal abnormalities (20, 23, 29, 30). The molecular mechanisms for altered repolarization in cardiac hypertrophy are, however, still unsettled and controversial (20, 30).

In the present study, we investigated changes in voltage-gated K+ channel gene expression in hypertrophied rat hearts with MCT-induced pulmonary hypertension. mRNA levels of Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, and Kv4.3 alpha -subunits were measured by ribonuclease protection assay (RPA). The results have revealed that not only Kv4.2 and Kv4.3 but also Kv1.2, Kv1.5, and Kv2.1 mRNA are downregulated in the hypertrophied ventricle. Such alteration in multiple types of voltage-gated K+ channel gene expression may contribute to the repolarization delay in an advanced stage of ventricular hypertrophy.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. Five-week-old male Wistar rats weighing 170-190 g were treated with MCT (Sigma, St. Louis, MO) to produce pulmonary hypertension as described previously (14, 17, 22). In brief, a single dose of 60 mg/kg MCT, which was dissolved in 1 N HCl neutralized with 0.5 N NaOH and diluted with sterile distilled water to obtain a 2% solution, was injected subcutaneously into the interscapular region. In control rats of corresponding age and weight, saline was injected instead of MCT. The rats were allowed to eat freely from a supply of standard rat chow. The animals were killed under ether anesthesia on the day of MCT or saline injection (day 0) or 7, 14, 21, and 28 days after the injection. The hearts were removed quickly and used for estimation of RV hypertrophy as well as for cell isolation and mRNA measurements. RV hypertrophy was estimated by measuring the ratio of the RV free wall tissue weight to body weight (BW) and that of RV weight to left ventricular free wall plus septum (LV+S) weight.

Electrocardiograms. ECGs were recorded immediately before and on days 14 and 28 after the injection of MCT. Under anesthesia (20 mg/kg pentobarbital sodium ip), leads I and II were recorded. The signals were stored with a digital audio recording system (Sony, Tokyo, Japan), and the ECG parameters were analyzed using software (Softron, Tokyo, Japan) programmed for the analysis of ECG parameters in rodents.

Ribonuclease protection assay. For the RPA, rat Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, and Kv4.3 alpha -subunit cDNA fragments were amplified by RT-PCR. The nucleotide sequences of the primers and the amplified regions are described here. Nucleotide numbers for each primer correspond to those from the translation start site: Kv1.2: sense 5'-<UNL>AAGCTT</UNL>TAACTGATGTCTGATTGAAACCTA-3', antisense 5'-GATGCTGGCTCCATGGGTGAC-3', nucleotides 1,487-1,743 (21); Kv1.4: sense 5'-<UNL>AAGCTT</UNL>TCTACTTCTTCTT- CCCTGGGGGAC-3', antisense 5'-TGCATCACTTATTTG- ATATGC-3', nucleotides 1,801-2,132 (32); Kv1.5: sense 5'-CCGAGTATTTAAGCCCACCTG-3', antisense 5'-CTAAGCTTTTTAAAGTCAAATTTG-3', nucleotides 1,888-2,144 (28); Kv2.1: sense 5'-<UNL>AAGCTT</UNL>GCTCTGGTTTCTTCGTGGA- GAGTC-3', antisense 5'-CACGCTGTAGAGCAGCTGACC-3', nucleotides 1,931-2,295 (11); Kv4.2: sense 5'-TACCGCACGGGG<UNL>AAGCTT</UNL>CACTAT-3', antisense 5'-TGGAACTGTTTCCACCACATTCGC-3', nucleotides 295-624 (2); Kv4.3: sense 5'-<UNL>AAGCTT</UNL>GGCACCCCAGAAGAGGAGCATG-3', antisense 5'-GTTGGAGTTGGGCAGGTGCGTGGT-3', nucleotides 1,372- 1,626 (10). A Hind III site (AAGCTT) was introduced into the 5' end of the sense primers of the Kv1.2, Kv1.4, Kv2.1, and Kv4.3 (underlined). In Kv4.2, a Hind III site is present in the coding region (underlined). The amplified cDNA was cloned into pGEM-T vector using the TA cloning system (Promega, Madison, WI).

The plasmids containing cDNAs were linearized by digestion with an appropriate restriction enzyme (Hind III for Kv1.2, Kv1.4, Kv2.1, Kv4.2, and Kv4.3; NcoI present in pGEM-T vector for Kv1.5). Antisense cRNA probes were prepared using a MAXIscript kit (Ambion, Austin, TX) and [alpha -32P]UTP (Du Pont-New England Nuclear). The cyclophilin cRNA probe was also prepared from the cDNA purchased from Ambion (pTRI-cyclophilin-rat antisense control template, nucleotides 38-142) to detect cyclophilin mRNA as an internal control. RPA was performed using a HybSpeed RPA kit (Ambion) according to the manufacturer's protocol. Hybridization of the two probes [2 × 104 counts/min (cpm) Kv4.2 cRNA and 2 × 104 cpm cyclophilin cRNA] with 10 µg total RNA was carried out at 68°C for 10 min, followed by digestion with RNase A and RNase T1 at 37°C for 30 min. The reaction was terminated by addition of sodium dodecyl sulfate and proteinase K, followed by phenol-chloroform extraction and ethanol precipitation. The protected fragments were visualized by autoradiography after electrophoresis on a 5% polyacrylamide/8 M urea gel. Quantitative analysis was carried out using Fujix Bioimage Analyzer with which we measured the radioactivity of the bands in a selected area. Each mRNA level of Kv channels was normalized by the levels of cyclophilin. The mRNA of each lane in the gels is from different animals.

Statistics. Data are expressed as means ± SE. Statistical analyses were performed using one-way analysis of variance with multiple comparisons. Differences were considered significant at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Characteristics of experimental animals. Table 1 summarizes BW and heart, lung, liver, and kidney weight before and after the injection of MCT. There was no significant difference in BW between groups on days 0 and 14, but BW of MCT-treated rats were significantly decreased by 19.3% compared with those of control rats on day 28. The ratio of RV weight to BW and the ratio of RV weight to LV+S weight were both increased significantly on days 14 and 28, whereas the ratio of LV+S weight to BW was unaffected during the entire observation period. There was no significant difference in the ratio of kidney and liver weights to BW. On the other hand, there was a significant increase in the ratio of lung weight to BW in the MCT rats, probably because of the primary pathological effects of MCT on the lung. Eleven of twelve MCT rats showed the signs of right-sided heart failure during the following week, including tachypnea, ascites, pleural effusion, edematous extremities, and piloerection, and ten of twelve MCT rats died by day 35.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Body and organ weights in control and MCT-treated rats

Electrocardiograms. ECG leads I and II were recorded every week after MCT injection. Figure 1 shows the representative tracings of ECG lead II recorded in the same rats immediately before injection (day 0) and on days 14 and 28 after the injection. In the ECGs of the MCT rat, the T wave was flattened and the Q-T interval was prolonged on day 14 and the prolongation was remarkable on day 28, whereas the ECGs of the control rat remained unchanged over the entire observation period. Table 2 summarizes the ECG data obtained from control and MCT-treated rats on days 0, 14, and 28 after injection. The Q-T interval was significantly prolonged, on average, by 9.5 and 10.2% on days 14 and 28, respectively, and the interval corrected by the heart rate (Q-Tc) was also significantly prolonged by 6.9 and 13.7% on days 14 and 28. Although QRS duration did not show any difference on day 14, it was prolonged by 16.2% on day 28. P-R interval was unchanged over the observation period.


View larger version (31K):
[in this window]
[in a new window]
  		Fig. 1.   Body surface electrocardiograms (ECG) of extremity lead (II) before monocrotaline (MCT) and saline injection and on days 14 and 28 after injection. Top traces are records from a control rat, and bottom traces are from a MCT rat.


                              
View this table:
[in this window]
[in a new window]
  		Table 2.   ECG parameters recorded from control and MCT-treated rats

Gene expression of Kv channels. To examine the effects of cardiac hypertrophy on mRNA expression of cloned K+ channels, mRNA levels were measured with RPA, using the hearts obtained from control and MCT-treated rats killed on day 28. mRNA levels of three Shaker (Kv1.2, 1.4, 1.5), one Shab (Kv2.1), and two Shal (Kv4.2 and Kv4.3) channels were examined. These mRNAs were readily detected. Cyclophilin mRNA expression levels were used for the internal control.

Figure 2 shows the results for the Shaker family channels. The expression levels of Kv1.2 and Kv1.5 channels normalized to cyclophilin expression levels were significantly lower in the MCT-treated rats than in control rats [Kv1.2 (control vs. MCT): 1.0 ± 0.12 vs. 0.4 ± 0.13 (arbitrary units) (n = 3), P < 0.05; Kv1.5: 1.0 ± 0.05 vs. 0.24 ± 0.03 (n = 3), P < 0.01] (Fig. 2). Unlike Kv1.2 and Kv1.5, the expression levels of Kv1.4 mRNA did not show a significant difference between two groups [Kv1.4 (control vs. MCT): 1.0 ± 0.28 vs. 0.88 ± 0.44 (n = 3); not significant (NS)] (Fig. 2). The expression levels of Kv2.1 mRNA channels were significantly decreased in the MCT-treated rats compared with control rats [Kv2.1 (control vs. MCT): 1.0 ± 0.02 vs. 0.42 ± 0.05 (n = 3); P < 0.05] (Fig. 3). Figure 4 shows the expression levels of the Shal family channels. The expression levels of Kv4.2 were markedly decreased in the MCT rats [Kv4.2 (control vs. MCT): 1.0 ± 0.08 vs. 0.19 ± 0.05 (n = 3); P < 0.01]. In the meantime, Kv4.3 mRNA expression levels were also significantly decreased, but the extent of decrease was moderate compared with that of Kv4.2 [Kv4.3 (control vs. MCT): 1.0 ± 0.05 vs. 0.55 ± 0.12 (n = 3); P < 0.05].




View larger version (100K):
[in this window]
[in a new window]
  		Fig. 2.   Kv1 channel mRNA expression in control and hypertrophied right ventricles. Hypertrophied right ventricles were obtained from adult rats with pulmonary hypertension induced by a single injection of MCT. Total RNAs were extracted from right ventricles for ribonuclease protection assay on day 28 after MCT injection. A, C, and E: mRNA expression of Kv1.2, Kv1.4, and Kv1.5, respectively. Cyclo, cyclophilin mRNA as internal control; Cyclo#, mRNA of cyclophilin with less exposure. B, D, and F: average amounts of Kv1.2 (B), Kv1.4 (D) and Kv1.5 (F) mRNA are presented as ratio to internal control (n = 3). Significantly different from control: * P < 0.05, ** P < 0.01. NS, not significant.



View larger version (31K):
[in this window]
[in a new window]
  		Fig. 3.   Kv2.1 mRNA levels in right ventricles of control and MCT-treated rats on day 28 after injection. A: Kv2.1 mRNA measured by ribonuclease protection assay. Cyclo, cyclophilin mRNA as internal control; Cyclo#, mRNA of cyclophilin with less exposure. B: average amount of Kv2.1 mRNA is presented as ratio to internal control (n = 3). ** Significantly different from control at P < 0.01.




View larger version (73K):
[in this window]
[in a new window]
  		Fig. 4.   Kv4 mRNA expression in right ventricles of control and MCT-treated rats on day 28 after injection. A and C: Kv4.2 (A) and Kv4.3 (C) mRNA were measured by ribonuclease protection assay. Cyclo, cyclophilin mRNA as internal control; Cyclo#, mRNA of cyclophilin with less exposure. B and D: average amounts of Kv4.2 (B) and Kv4.3 (D) are presented as ratio to internal control (n = 3). Significantly different from control: * P < 0.05, ** P < 0.01.

mRNA levels of Kv channels on day 14 after injection were also measured to examine the effects of cardiac hypertrophy at the early stage. There was a slight increase in Kv1.4, Kv4.2, and Kv4.3 [Kv1.4 (control vs. MCT): 1.0 ± 0.22 vs. 1.27 ± 0.37 (n = 3), NS; Kv4.2: 1.0 ± 0.15 vs. 1.22 ± 0.28 (n = 3), NS; Kv4.3: 1.0 ± 0.20 vs. 1.21 ± 0.28 (n = 3), NS] and a slight decrease in Kv1.2 and Kv1.5 [Kv1.2 (control vs. MCT): 1.0 ± 0.25 vs. 0.87 ± 0.18 (n = 3), NS; Kv1.5: 1.0 ± 0.16 vs. 0.91 ± 0.28 (n = 3), NS], but these differences did not reach statistical significance. The mRNA level of Kv2.1 was identical between groups [1.0 ± 0.26 vs. 0.99 ± 0.25 (n = 3), NS].


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

MCT caused hypertrophy in RV. In the present study, we investigated the underlying molecular mechanisms of the altered repolarization in ventricular hypertrophy, using rats with RV hypertrophy secondary to MCT-induced pulmonary hypertension. MCT is known to cause pulmonary hypertension in rats through endothelial cell damage, medial thickening of the muscular pulmonary arteries, and neomuscularization of nonmuscular distal arteries. A single injection of MCT caused macroscopic RV hypertrophy without any morphological changes in the LV. An increase of the ratios of RV and lung weights to BW was observed in the MCT-treated rats, but the ratios of kidney and liver weights to BW were not affected by the treatment. Recent experimental studies have indicated that an increase of endogenous endothelin-1, a potent endothelium-derived vasoconstrictor peptide, is involved in the pathogenesis of MCT-induced pulmonary hypertension (22, 25). However, the lack of morphological change in the LV may suggest that the hypertrophy may not be the result of direct action of this compound on the heart but the result of pressure overload caused by pulmonary hypertension. The MCT rats on day 14 are considered to be in a compensated state of hypertrophy, because they showed normal growth and no physical signs of right-sided heart failure. On the other hand, the MCT rats on day 28 had more of the properties of heart failure, because they showed a significant decrease in BW and physical signs of right-sided heart failure, including tachypnea, ascites, pleural effusion, edematous extremities, and piloerection, in the following week.

Electrophysiological alterations in ventricular hypertrophy. In association with the development of hypertrophy, body surface electrocardiograms showed prolongation of Q-T and Q-Tc intervals and QRS duration, whereas P-R intervals were not affected (Table 2). In our previous electrophysiological experiments on single myocytes isolated from MCT-treated rats, cell membrane capacitance and APD of RV cells were increased progressively from day 14 to day 28, whereas other parameters of the action potential (resting membrane potential and action potential amplitude) were unaffected (17). The APD at 90% repolarization of the MCT-treated RV cells was increased to 192% of control (n = 10) on day 28 after the injection. As to the change of ionic currents responsible for the APD prolongation at the late stage of MCT-treated rats, we reported a significant reduction of Ito without any changes in its voltage dependence and inactivation kinetics (17). The changes in cell membrane capacitance and action potential configuration observed in our RV hypertrophy model are qualitatively similar to those in the reports by other investigators on the LV hypertrophy induced in rats by aortic banding and renovascular hypertension (4, 19, 32).

Molecular mechanisms of altered repolarization in ventricular hypertrophy. We have shown in the present study that mRNA levels of Kv4.2 and Kv4.3 are decreased in MCT-treated rats at the advanced stage of hypertrophy. Kv4.2 and Kv4.3 are supposed to be the most likely candidates for Ito in adult rat ventricles (3, 9). The reduction of Ito density at the advanced stage of RV hypertrophy in MCT-treated rats could be the result of downregulation of Kv4.2 and Kv4.3 gene expression. In experiments using renovascular hypertensive rats, Takimoto et al. (30) demonstrated significant reduction of mRNA levels for Kv4.2 and Kv4.3 in the LV in association with the progress of hypertrophy but no significant changes in mRNA levels for Shaker-related (Kv1.2, Kv1.4, Kv1.5), Shab-related (Kv2.1), and KvLQT1 channels.

In our experiments using MCT-treated rats, the mRNA levels for Kv1.2, Kv1.5, and Kv2.1 were also decreased significantly at the advanced stage of RV hypertrophy. Reasons for the discrepancy between our data and those reported by Takimoto et al. (30) are unclear; it might be related to different procedures used to produce hypertrophy.

The physiological and pathological roles of these cloned voltage-gated K+ channels in native cardiac cells are still unsettled (4, 8). Heterologous expression of Kv1.2, Kv1.5, and Kv2.1 in Xenopus oocytes has been shown to cause delayed-rectifier type current (IK) or rapidly activating sustained outward currents (Isus, Iss, or IKur), which are sensitive to 4-AP and TEA. In adult rat ventricular cells, the amplitude of these delayed-rectifier or sustained type outward currents is much less than that of Ito. This makes it difficult to detect the change of their current density in association with the progress of ventricular hypertrophy. Nevertheless, we cannot rule out some obligatory roles of the downregulation of Kv1.2, Kv1.5, and Kv2.1 gene expression in the APD prolongation in hypertrophied ventricular cells.

As for the early stage of hypertrophy, there was no significant difference in mRNA levels of these Kv channels. Thus there is a discrepancy between the increase of Ito density and the mRNA levels of the channels. At present, there is no clear interpretation for this discrepancy. There might be unknown subcellular factors that affect the protein synthesis or the availability of the channels in the pathological condition.

Limitation of study. Because the presence of mRNA does not necessarily mean the presence of the encoded proteins, studies measuring the mRNA levels have limitations for the understanding of the mechanism of the pathophysiological changes. To further elucidate the mechanism, studies measuring protein levels, including Western blot analysis and immunohistochemistry, will be required.


    FOOTNOTES

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: I. Kodama, Dept. of Circulation, Research Institute of Environmental Medicine, Nagoya Univ., Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan (E-mail: ikodama{at}riem.nagoya-u.ac.jp).

Received 10 September 1998; accepted in final form 10 June 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Aronson, R. S. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ. Res. 47: 443-454, 1980[Free Full Text].

2.   Baldwin, T. J., M. L. Tsaur, G. A. Lopez, Y. N. Jan, and L. Y. Jan. Characterization of a mammalian cDNA for an inactivating voltage-sensitive K+ channel. Neuron 7: 471-483, 1991[Medline].

3.   Barry, D. M., and J. M. Nerbonne. Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels? Circ. Res. 77: 361-369, 1995[Abstract/Free Full Text].

4.   Barry, D. M., and J. M. Nerbonne. Myocardial potassium channels: electrophysiological and molecular diversity. Annu. Rev. Physiol. 58: 363-394, 1996[Medline].

5.   Bénitah, J.-P., A. M. Gomezu, P. Bailly, J.-P. Da Ponte, G. Berson, C. Delgado, and P. Lorente. Heterogeneity of the early outward current in ventricular cells isolated from normal and hypertrophied rat heart. J. Physiol. (Lond.) 469: 111-138, 1993[Abstract/Free Full Text].

6.   Beuckelmann, D. J., M. Nabauer, and E. Erdmann. Alteration of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ. Res. 73: 379-385, 1993[Abstract/Free Full Text].

7.   Cerbai, E., M. Barbieri, Q. Li, and A. Mugelli. Ionic basis of action potential prolongation of hypertrophied myocytes isolated from hearts of spontaneously hypertensive rats of different ages. Cardiovasc. Res. 28: 1180-1187, 1994[Abstract/Free Full Text].

8.   Deal, K. K., S. K. England, and M. M. Tamkun. Molecular physiology of cardiac potassium channels. Physiol. Rev. 76: 49-67, 1996[Abstract/Free Full Text].

9.   Dixon, J. E., and D. McKinnon. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ. Res. 75: 252-260, 1994[Abstract/Free Full Text].

10.   Dixon, J. E., W. Shi, H.-S. Wang, C. McDonald, H. Yu, R. S. Wymore, I. S. Cohen, and D. McKinnon. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ. Res. 79: 659-668, 1996[Abstract/Free Full Text].

11.   Frech, G. C., A. M. VanDongen, G. Schuster, A. M. Brown, and R. H. Joho. A novel potassium channel with delayed rectifier properties isolated from rat brain by expression cloning. Nature 340: 642-645, 1989[Medline].

12.   Furukawa, T., R. J. Myerburg, N. Furukawa, S. Kimura, and A. L. Bassett. Metabolic inhibition of ICa,L and IK differs in feline left ventricular hypertrophy. Am. J. Physiol. 266 (Heart Circ. Physiol. 35): H1121-H1131, 1994[Abstract/Free Full Text].

14.   Hayashi, Y., J. F. Hussa, and J. Lalich. Cor pulmonale in rats. Lab. Invest. 16: 875-881, 1967[Medline].

15.   Keung, E. C. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium. Circ. Res. 64: 753-763, 1989[Abstract/Free Full Text].

16.   Kleiman, R. B., and S. R. Houser. Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H1434-H1442, 1988[Abstract/Free Full Text].

17.   Lee, J. K., I. Kodama, H. Honjo, T. Anno, K. Kamiya, and J. Toyama. Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2833-H2842, 1997[Abstract/Free Full Text].

18.   Levy, D., R. J. Garrison, D. D. Savage, W. B. Kannel, and W. P. Castelli. Prognostic implications of echocardiography determined left ventricular mass in the Framingham heart study. N. Engl. J. Med. 322: 1561-1566, 1990[Abstract].

19.   Li, Q., and E. C. Keung. Effects of myocardial hypertrophy on transient outward current. Am. J. Physiol. 266 (Heart Circ. Physiol. 35): H1738-H1745, 1994[Abstract/Free Full Text].

20.   Matsubara, H., J. Suzuki, and M. Inada. Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy. J. Clin. Invest. 92: 1659-1666, 1993.

21.   McKinnon, D. Isolation of a cDNA clone coding for putative second potassium channel indicates the existence of a gene family. J. Biol. Chem. 264: 8230-8236, 1989[Abstract/Free Full Text].

22.   Miyauchi, T., R. Yorikane, S. Sakai, T. Sakurai, M. Okada, M. Nishikibe, M. Yano, I. Yamaguchi, Y. Sugita, and K. Goto. Contribution of endogenous endothelin-1 to the progression of cardiopulmonary alterations in rats with monocrotaline-induced pulmonary hypertension. Circ. Res. 73: 887-897, 1993[Abstract/Free Full Text].

23.   Nishiyama, A., F. Kambe, K. Kamiya, S. Yamaguchi, Y. Murata, H. Seo, and J. Toyama. Effects of thyroid and glucocorticoid hormones on Kv1.5 potassium channel gene expression in the rat left ventricle. Biochem. Biophys. Res. Commun. 237: 521-526, 1997[Medline].

24.   Nuss, H. B., and S. R. Houser. Voltage dependence of contraction and calcium current in severely hypertrophied feline ventricular myocytes. J. Mol. Cell. Cardiol. 23: 717-726, 1991[Medline].

25.   Okada, M., C. Yamashita, M. Okada, and K. Okada. Role of endothelin-1 in beagles with dehydromonocrotaline-induced pulmonary hypertension. Circ. Res. 92: 114-119, 1995.

26.   Ryder, K. O., S. M. Bryant, and G. Hart. Membrane current changes in left ventricular myocytes isolated from guinea pigs after abdominal aortic coarctation. Cardiovasc. Res. 27: 1278-1287, 1993[Abstract/Free Full Text].

27.   Scamps, F., E. Mayoux, D. Charlemagne, and G. Vassort. Calcium current in single cells isolated from normal and hypertrophied rat heart. Effects of beta -adrenergic stimulation. Circ. Res. 67: 199-208, 1990[Abstract/Free Full Text].

28.   Swanson, R., J. Marshall, and J. S. Smith. Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain. Neuron 4: 929-939, 1990[Medline].

29.   Takimoto, K., and E. S. Levitan. Glucocorticoid induction of Kv1.5 K+ channel gene expression in ventricle of rat heart. Circ. Res. 75: 1006-1013, 1994[Abstract/Free Full Text].

30.   Takimoto, K., D. Li, K. M. Hershman, P. Li, E. K. Jackson, and E. S. Levitan. Decreased expression of Kv4.2 and novel Kv4.3 K+ channel subunit mRNAs in ventricles of renovascular hypertensive rats. Circ. Res. 81: 533-539, 1997[Abstract/Free Full Text].

31.   Tomita, F., A. L. Bassett, R. J. Myerburg, and S. Kimura. Diminished transient outward currents in rat hypertrophied ventricular myocytes. Circulation 75: 296-303, 1994.

32.   Tseng, C. J., G. N. Tseng, A. Schwartz, and M. A. Tanouye. Molecular cloning and functional expression of a potassium channel cDNA isolated from a rat cardiac library. FEBS Lett. 268: 63-68, 1990[Medline].

Am J Physiol Heart Circ Physiol 277(5):H1725-H1731
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
I. R. Henkens, K. T. B. Mouchaers, H. W. Vliegen, W. J. van der Laarse, C. A. Swenne, A. C. Maan, H. H. M. Draisma, I. Schalij, E. E. van der Wall, M. J. Schalij, et al.
Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography
Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1300 - H1307.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
X. Li, G. C. L. Bett, X. Jiang, V. E. Bondarenko, M. J. Morales, and R. L. Rasmusson
Regulation of N- and C-type inactivation of Kv1.4 by pHo and K+: evidence for transmembrane communication
Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H71 - H80.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. Kaprielian, R. Sah, T. Nguyen, A. D. Wickenden, and P. H. Backx
Myocardial infarction in rat eliminates regional heterogeneity of AP profiles, Ito K+ currents, and [Ca2+]i transients
Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1157 - H1168.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
T.-T. Zhang, K. Takimoto, A. F. R. Stewart, C. Zhu, and E. S. Levitan
Independent Regulation of Cardiac Kv4.3 Potassium Channel Expression by Angiotensin II and Phenylephrine
Circ. Res., March 16, 2001; 88(5): 476 - 482.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, J.-K.
Right arrow Articles by Toyama, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.-K.
Right arrow Articles by Toyama, J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online