HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 287/1/H408    most recent 00049.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Rundell, V. L. M. Articles by de Tombe, P. P. Search for Related Content PubMed PubMed Citation Articles by Rundell, V. L. M. Articles by de Tombe, P. P.

Depressed cardiac tension cost in experimental diabetes is due to altered myosin heavy chain isoform expression

Center for Cardiovascular Research,Physiology, Biophysics and Medicine, University of Illinois at Chicago, Chicago, Illinois 60612

Submitted 21 January 2004 ; accepted in final form 2 March 2004

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Cardiac disease in diabetes presents as impaired left ventricular contraction and relaxation; however, the mechanisms underlying contractile protein dysfunction during the progression of disease are unknown. Accordingly, we assessed Ca²⁺-dependent tension development and tension-dependent ATP consumption (tension cost) in a rat model early (6 wk) and late (12 wk) after the onset of diabetes (50 mg/kg iv streptozotocin) using mechanical force- and enzyme-coupled UV absorbance measurements. Myofilament Ca²⁺ sensitivity and maximal tension were unchanged between groups at either time point. Cross-bridge cycling rate was significantly decreased in diabetes, as indexed by tension cost (early control 5.4 ± 0.4 and early diabetes 4.2 ± 0.3; and late control 6.0 ± 0.2 and late diabetes 4.2 ± 0.2; P < 0.05). Because rodent models of cardiac disease are confounded by altered myosin isoform distribution, myosin content was determined by SDS-PAGE and densitometry. The cardiac content of -myosin in diabetes was decreased to 41% ± 4.1 at 6 wk and 32.5% ± 2.9 at 12 wk of diabetes (early control 77.8% ± 3.3 and late control 73.6% ± 2.5). Separate control experiments demonstrated a linear decrease in tension cost with decreased -myosin content. Given this, the depression of tension cost in this rodent model of diabetes could be fully explained by the altered myosin isoform distribution.

cross-bridge cycling; cardiac energetics

Accordingly, models of experimental diabetes have been generated to explore the molecular alterations that occur in diabetic CM. In brief, excitation-contraction coupling and the kinetics of shortening and relaxation are generally depressed in these preparations, regardless of peak shortening defects (17, 23, 24). In terms of the energetics of contraction, cross-bridge cycling and Ca²⁺ sensitivity of Ca²⁺-dependent actin-activated MgATPase have been reported to be altered in diabetes (17, 18). Alterations in maximal tension development have not been described; however, controversy exists with regard to Ca²⁺ sensitivity of myofilaments in multicellular preparations (1, 17). Likewise, in isolated single cell preparations there have been reports of normal (17, 24), increased (28), and decreased peak shortening (23). Thus diabetic myocardium is generally recognized to have impaired relaxation and contraction kinetics and cross-bridge cycling kinetics, whereas alterations in cell shortening, Ca²⁺ sensitivity, and tension development are still controversial.

Experimental models of diabetic CM often employ rodents, which introduces the confounding problem of isoform switching. A particularly problematic issue when one is examining the energetics (20) and power of contraction (14) is that of myosin heavy chain (MHC) isoform content. It has been long recognized that rodent hearts synthesize less -MHC (faster cycling) isoform when exposed to a pathological stimulus (21). This is true in diabetes as well, where hyperglycemia is known to reduce the -MHC content and promote the presence of -MHC (9). It is clear that there are deficits in cardiac energetics in rodent models of experimental diabetes; however, it is not known whether MHC isoform switching is the sole cause of these deficits or whether there is further underlying contractile dysfunction. Accordingly, the primary goal of this study was to fully characterize the rodent model of diabetic CM in terms of contractile protein isoform content, myofilament function, and cross-bridge cycling kinetics.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Experimental models. All subjects were treated and housed in accordance with the Animal Care and Use Committee guidelines at the University of Illinois at Chicago. This study was designed to evaluate possible mechanisms of progressive cardiac disease in a model of rodent diabetes. Therefore, 4- to 6-wk-old male Lewis-Brown Norway rats were administered a 50 mg/kg dose of streptozotocin (STZ) intravenously to cause experimental insulin-dependent (Type 1) diabetes mellitus. Blood glucose levels were uncontrolled throughout the disease development period because we did not administer supplemental insulin. Age-matched controls were housed alongside the experimental groups and all were allowed food and water ad libitum. To investigate the possible progressive effects of uncontrolled diabetes, animals were euthanized at two time points: 6- and 12-wk post-STZ treatment. To control for the MHC isoform shifts known to confound the study of rat cardiac tissue, a separate group of young animals that express 100% -MHC was treated for short periods of time (0, 6, 11, 16, 21, and 42 days) with propylthiouracil (PTU; 0.8 g/l in the drinking water) to induce various amounts of -MHC protein expression. Right ventricular trabeculae from these hearts were used experimentally to define the relationship between -MHC protein expression, tension cost, and force development.

Mechanical experiments. The animals were anesthetized after intraperitoneal injection of pentobarbital (50 mg), and hearts were rapidly excised. Serum glucose and body and heart weight were obtained at the time of death. Right ventricular trabeculae were dissected free and incubated overnight at 4°C in low-Ca²⁺ "skinning" solution containing 1% Triton X-100 to allow for chemical permeablization of extracellular membranes (skinning solution) composed of (in mM) 20 EGTA, 10 creatine phosphate, 100 N,N-bis[2-hydroxyethyl]-2-aminoethane sulfonic acid (BES), 5.93 ATP, 6.6 MgCl, and 20.7 potassium proprionate, pH 7.0. After permeabilization, the trabeculae were attached to hooks mounted on a force transducer (model AE 801 SensoNor) and a motor arm (Cambridge) in the experimental apparatus by way of aluminum T-clips, as previously described (7). Sarcomere length (SL) was set to 2.3 µm by laser diffraction. The trabeculae were then exposed to a range of Ca²⁺ solutions obtained by proportional mixing of activating and relaxing solutions, and the force generated and ATP consumed were measured simultaneously during contraction. ATP consumption was measured as previously described using a UV-coupled optical absorbance method (7). Individual examples are depicted in Fig. 1A. Briefly, the consumption of ATP is stoichiometrically coupled to NADH consumption. UV absorbance is depicted in the top panels and the matched force trace is shown in the bottom panels. NADH absorbs UV light, whereas its reduced form, NAD+, does not. It is clear that UV absorbance decreases immediately on incubation of the trabecula in activating levels of Ca²⁺ (50 µM) and halts on removal of the trabecula from the bath. A series of calibration steps is performed with every record by stepwise injection of 250 pmol of ADP (indicated by arrows). The activating solution contained (in mM) 20 Ca-EGTA, 1.55 potassium proprionate, 6.59 MgCl, 100 BES, 5 sodium azide, 1 DTT, 10 phosphoenolpyruvate, 0.01 leupeptin, 0.001 pepstatin, 0.01 oligomycin, 0.01 PMSF, and 0.01 A₂P₅. The relaxing solution was identical, except it contained (in mM) 20 EGTA, 21.2 potassium proprionate, and 7.11 MgCl. Preactivating solution contained (in mM) 0.5 EGTA, 19.5 HDTA (Fluka), and 21.8 potassium proprionate. All solutions contained 0.5 mg/ml pyruvate kinase (386 U/mg) and 0.05 mg/ml lactate dehydrogenase (880 U/mg) (Sigma; St. Louis, MO). All solutions had an ionic strength of 200 mM, 5 mM free ATP, and 1 mM free magnesium, as determined by using the methods of Fabiato and Fabiato (10), assuming an apparent stability constant of the Ca²⁺-EGTA complex of 10^6.58 (7). All measurements were made at 20°C. After each experiment, trabeculae were stored in 1% SDS solution and frozen at –20°C for later analysis by SDS-PAGE.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Data acquisition and analysis. A: original NADH and force traces from right ventricular trabeculae of control and diabetic rats. Top, NADH signals recorded from 1 control and 1 diabetes trabecula from the 12-wk study group and maximum activating Ca2+ (50 µM). Bottom, matched force traces for each trabecula. As the trabecula is incubated in Ca2+, force is generated and the NADH signal declines. ATP consumption is stoichiometrically coupled to NADH consumption by the actions of the enzymes pyruvate kinase and lactate dehydrogenase; thus the slope of the NADH trace is proportional to ATP consumption. When the trabecula is removed to a relaxing solution, force drops to preactivation levels, and NADH consumption, and therefore ATP consumption, essentially stops. A series of ADP injections (250 pmol), indicated by arrows, are made into the measuring chamber for calibration of the NADH signal. B: Ca2+-dependent tension relationships plotted after a series of activations of the trabeculae as shown in A. Force has been normalized to trabecular cross-sectional area. The data has been fit to a modified Hill equation. Maximum tension development and Ca2+ sensitivity are not different between the two trabeculae. C: tension-dependent ATP consumption for the trabeculae reflected in A and B. ATP consumption has been normalized to trabecular volume. It is apparent that the slope of the linear fit is lower in the diabetic trabecula (control 6.95, R = 0.99; diabetes 3.8, R = 0.99).

Data analysis. The results of the mechanical experiments were fit to a modified Hill equation

(1)

where F is peak steady-state force (skinned); F_max is the maximum saturated value F can attain; EC₅₀ is the [Ca²⁺] at which F is 50% of F_max, and H is the Hill coefficient that represents the slope of the force-[Ca²⁺] relation at EC₅₀. The results from each experiment were fit individually as is shown in Fig. 1B. The fit parameters from each trabecula were pooled and the mean values are reported. Consumption of ATP was normalized to trabecula volume and plotted versus the force/cross sectional area attained during each contraction. Linear regression was used to fit this relationship (cf. Fig. 1C), the slope of each experimental line fit was pooled, and the mean value is reported as tension cost. Individual fits were pooled to generate the mean value reported. For the 6-wk study, group sizes were n = 11 for both control and diabetic groups. In the 12-wk study, the control group was n = 14, and the diabetic group was n = 11. One trabecula per heart was used for mechanical experiments. Analysis of data was by two-way ANOVA to evaluate the separate and combined effects of diabetes and time using SPSS version 10.0 software, with the exception of the heart weight-to-tibial length ratio in the late diabetes cohort, which was analyzed by Student's t-test. The data are reported as means ± SE. Significant values are reported at P < 0.05.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Evaluation of model. Characteristics of the animals treated with STZ are summarized in Table 1. Circulating glucose levels, measured at time of death, were increased threefold over controls (P < 0.001). Total body weight was lower in diabetes groups at 6 wk (17%) and further decreased (25–45%) at the 12-wk time point. In acknowledgement of the decrease in body weight, the ratio of wet heart weight to tibial length was determined in the 12-wk study. This comparison documented no change in relative heart size in the late diabetes group, and thus there was no hypertrophy present in diabetes.

View larger version (20K): [in this window] [in a new window]   Fig. 2. Ca2+-dependent tension development is unchanged in diabetes. Hill fits of the mean data are summarized in Table 2. There are no significant alterations in the shape or position of the Ca2+-dependent force relationships in diabetes.

View larger version (13K): [in this window] [in a new window]   Fig. 3. SDS-PAGE illustrating the separation between - and -myosin heavy chain (MHC). Example of MHC separation from early and late controls and diabetes. Each trabecula used in mechanical experiments was reserved and subjected to SDS-PAGE. The top -MHC band can be clearly resolved from the lower -band by densitometry.

View larger version (24K): [in this window] [in a new window]   Fig. 4. Relationship between -MHC and tension cost is linear in diabetic cardiomyopathy. The mean tension cost is plotted vs. -MHC content for each trabecula. All points are fit to a common regression line (R = 0.70). It is clear that the control groups cluster near the top left and the diabetes groups cluster near the bottom right. PTU, propylthiouracil.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

Myofilament function was not depressed, as indexed by maximal tension development, in either early or late diabetes. The present findings of no alteration in maximal isometric tension development are consistent with other reports in diabetes (1, 11, 15). Likewise, it is consistent with the unchanged peak shortening of beating isolated cardiac myocytes from diabetic animals reported previously (17). There is a paucity of experiments that demonstrate changes in maximal isometric tension development in skinned fiber preparations. The majority of experiments demonstrate no change in maximal tension development but report a slowing in the kinetics of contraction, namely time to peak shortening and relaxation parameters, in diabetes (11). In intact, working heart preparations there are reports of decreased left ventricular peak pressure development in diabetes that is exacerbated by hypertension (6, 25). Ren and Bode (23) and Davidoff and Ren (5) report a slight decrease in peak shortening of unloaded intact myocytes from the spontaneously diabetic BioBreed rat model and the STZ-induced diabetes model, respectively; however, this was not recapitulated in other experiments (28). Thus, whereas there is still variation in the literature, in this study we report no deleterious effects of experimental diabetes on the maximal myofilament force-generating capability of small rodent myocardium.

The myofilament Ca²⁺ sensitivity was unchanged in this study. Akella and colleagues (1) reported decreased Ca²⁺ sensitivity at short SL between control and diabetic subjects, although those measurements were made at a shorter SL (1.9 µm) than reported here (2.3 µm). However, it is unlikely that that factor alone can explain the difference because other investigators have measured the tension-Ca²⁺ relationship in diabetes in skinned trabecula preparations and found no difference in sensitivity at SL 1.9 µm (17). Myofilament force-Ca²⁺ relations measured in intact, nonskinned isolated cardiac muscle by this same group also demonstrated no alteration in Ca²⁺ sensitivity. Hofmann and colleagues (15) also reported decreased Ca²⁺ sensitivity in diabetes; however, in their study, the control myocytes had an average SL of 2.45 µm in full-activating solution, whereas diabetes myocytes attained an average SL of 2.37 µm; therefore the EC₅₀ may have been artificially decreased as a result of poor SL control, thereby magnifying a possible effect of diabetes. In addition, Akella and colleagues (1) demonstrated an enhanced length dependency in diabetes. In our study, a small subset of trabeculae were studied at short SL (2.0 µm) to investigate length-dependent activation. In early diabetes there was a nonsignificant trend toward decreased length-dependent activation, which is in contrast to that reported previously. In late diabetes, there was neither an increase in EC₅₀ or myofilament length-dependent activation; thus, whatever the mechanism of increased Ca²⁺ sensitivity in diabetes, this was transient and may well have been an early adaptation to hyperglycemia and not a defining property of established diabetic cardiomyopathy. Nevertheless, the reasons for differences between earlier findings and those reported here are not entirely clear.

In terms of cross-bridge cycling kinetics, there was a significant decrease in maximal ATP consumption rate and tension cost that was present in early and late diabetes. Decreases in cross-bridge cycling kinetics have been reported previously (13, 17, 18). That these decreases correlated with decreasing -MHC content in these hearts leads us to conclude that the depression of cross-bridge cycling kinetics was directly related to diabetes-induced expression of -MHC in rat myocardium. It has been reported that there is an increase in -skeletal actin mRNA expression in rodent models of diabetes (8). No published studies have indicated an increase in -skeletal actin protein in myocardium as a result of diabetes, although there are reports of such increases in human cardiac disease (27). Recent investigations on the impact of -enteric actin on tension cost in our laboratory have found a depressed tension cost with expression of the -enteric actin that could not be explained solely by the concomitant increased expression of -MHC in those animals (20). However, we did not find a depressed tension cost that could not be accounted for by increased -MHC expression in the present study, supporting the notion that increased -skeletal actin protein expression did not occur in our study, nor contributed to the alteration in cross-bridge cycling rate. Nevertheless, we cannot fully exclude this possibility because the concentration of -skeletal actin protein was not investigated directly in this study.

Diabetic cardiomyopathy is manifest as altered contraction and relaxation, which is generally associated with altered Ca²⁺ handling ability of the myocyte and most likely the myofilaments. Electrophysiological data has demonstrated a lengthening of the Ca²⁺ transient in diabetes, as well as defects in sarcoplasmic reticulum Ca²⁺ handling (2, 4, 17). This altered Ca²⁺ handling and relaxation rate can be seen nearly immediately, within days of onset of diabetes and even in normal cells cultured in media containing high glucose and low insulin (6, 24). Thus the immediate effects of diabetes are very clearly detrimental, and yet the myocardium adapts so that it can function in the face of this homeostatic alteration. Transcription of -MHC begins very early in disease development; however, due to a long half-life for MHC significant protein replacement takes weeks to appear (8). Thus it appears that in the face of reduced energy supply, as a result of hypoinsulinemia in this model of diabetes, the rat cardiomyocyte attempts to become as economical as possible while still producing enough force to meet the constant demand for oxygenated blood from the tissues. Accordingly, MHC isoform expression shifts to preferentially -MHC and cross-bridge cycling kinetics are likewise depressed.

Although the data demonstrated in this study clearly establish the primacy of the myosin isoform shifting in rodent models of disease, the relevance of this to diabetic cardiomyopathy in larger animals and in humans, where myosin isoform shifting is not prominent, is less clear. Hence, caution should be exercised to extrapolate our present results obtained in rats to diabetes in larger mammals, such as humans. Moreover, the present study evaluated a model of Type I diabetes (hypoinsulinemia), and it is similarly unclear whether hyperglycemia and insulin excess would have similar effects on muscle mechanics. It is quite possible that alternate adaptational mechanisms, perhaps related to posttranslational modification of thin filament proteins by activated PKC (19), might provide a mechanism for myofilament desensitization to Ca²⁺ and reduction of the energy costs of contraction in these alternate circumstances. Confirmation of this awaits analogous studies in larger animal models as well as rodent models of Type II diabetes.

	GRANTS

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This work was supported by National Heart, Lung, and Blood Institute Grants HL/DK-R01-63704 and HL-P01-62426 (to P. P. de Tombe and P. M. Buttrick). V. L. M. Rundell received National Institutes of Health Institutional Training Grant 32-HL-07692.

	ACKNOWLEDGMENTS

 
We thank Brent Reiger and Beth Reid for assistance with generating and maintaining the animals. We also thank Vlasios Manaves for assistance with the MHC gels.

	FOOTNOTES

 

Address for reprint requests and other correspondence: P. P. de Tombe, Dept. of Physiology and Biophysics, Univ. of Illinois at Chicago, 835 S. Wolcott (M/C 901), Chicago, IL 60612 (E-mail: pdetombe{at}uic.edu).

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

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Akella AB, Ding XL, Cheng R, and Gulati J. Diminished Ca²⁺ sensitivity of skinned cardiac muscle contractility coincident with troponin T-band shifts in the diabetic rat. Circ Res 76: 600–606, 1995.[Abstract/Free Full Text]
2. Bouchard RA and Bose D. Influence of experimental diabetes on sarcoplasmic reticulum function in rat ventricular muscle. Am J Physiol Heart Circ Physiol 260: H341–H354, 1991.[Abstract/Free Full Text]
3. Brenner B. Effect of Ca²⁺ on cross-bridge turnover kinetics in skinned single rabbit psoas fibers: implications for regulation of muscle contraction. Proc Natl Acad Sci USA 85: 3265–3269, 1988.[Abstract/Free Full Text]
4. Choi KM, Zhong Y, Hoit BD, Grupp IL, Hahn H, Dilly KW, Guatimosim S, Lederer WJ, and Matlib MA. Defective intracellular Ca²⁺ signaling contributes to cardiomyopathy in Type 1 diabetic rats. Am J Physiol Heart Circ Physiol 283: H1398–H1408, 2002.[Abstract/Free Full Text]
5. Davidoff AJ and Ren J. Low insulin and high glucose induce abnormal relaxation in cultured adult ventricular myocytes. Am J Physiol Heart Circ Physiol 272: H159–H167, 1997.[Abstract/Free Full Text]
6. Davidoff AJ and Rodgers RL. Insulin, thyroid hormone, and heart function of diabetic spontaneously hypertensive rat. Hypertension 15: 633–642, 1990.[Abstract/Free Full Text]
7. De Tombe PP and Stienen GJ. Protein kinase A does not alter economy of force maintenance in skinned rat cardiac trabeculae. Circ Res 76: 734–741, 1995.[Abstract/Free Full Text]
8. Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, Davies PJ, and Taegtmeyer H. Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J Mol Cell Cardiol 32: 985–996, 2000.[CrossRef][ISI][Medline]
9. Dillmann WH. Diabetes mellitus induces changes in cardiac myosin of the rat. Diabetes 29: 579–582, 1980.[ISI][Medline]
10. Fabiato A and Fabiato F. Calculator programs for computing the composition of the solutions containing multiple metals and ligands used for experiments in skinned muscle cells. J Physiol 75: 463–505, 1979.
11. Fein FS, Kornstein LB, Strobeck JE, Capasso JM, and Sonnenblick EH. Altered myocardial mechanics in diabetic rats. Circ Res 47: 922–933, 1980.[Abstract/Free Full Text]
12. Fein FS, Strobeck JE, Malhotra A, Scheuer J, and Sonnenblick E. Reversibility of diabetic cardiomyopathy with insulin in rats. Circ Res 49: 1251–1261, 1981.[Abstract/Free Full Text]
13. Fein FS, Zola B, Malhotra A, Cho S, Factor S, Scheuer J, and Sonnenblick E. Hypertensive cardiomyopathy in rats. Am J Physiol Heart Circ Physiol 258: H793–H805, 1990.[Abstract/Free Full Text]
14. Herron TJ, Korte FS, and McDonald KS. Loaded shortening and power output in cardiac myocytes are dependent on myosin heavy chain isoform expression. Am J Physiol Heart Circ Physiol 281: H1217–H1222, 2001.[Abstract/Free Full Text]
15. Hofmann PA, Menon V, and Gannaway KF. Effects of diabetes on isometric tension as a function of [Ca²⁺] and pH in rat skinned cardiac myocytes. Am J Physiol Heart Circ Physiol 269: H1656–H1663, 1995.[Abstract/Free Full Text]
16. Huxley AF. Muscle structure and theories of contraction. Prog Biophys Biophys Chem 7: 255–318, 1957.[Medline]
17. Ishikawa T, Kajiwara H, and Kurihara S. Alterations in contractile properties and Ca²⁺ handling in streptozotocin-induced diabetic rat myocardium. Am J Physiol Heart Circ Physiol 277: H2185–H2194, 1999.[Abstract/Free Full Text]
18. Malhotra A, Lopez MC, and Nakouzi A. Troponin subunits contribute to altered myosin ATPase activity in diabetic cardiomyopathy. Mol Cell Biochem 151: 165–172, 1995.[CrossRef][ISI][Medline]
19. Malhotra A, Nakouzi A, Bowman J, and Buttrick P. Expression and regulation of mutant forms of cardiac TnI in a reconstituted actomyosin system: role of kinase dependent phosphorylation. Mol Cell Biochem 170: 99–107, 1997.[CrossRef][ISI][Medline]
20. Martin AF, Phillips RM, Kumar A, Crawford K, Abbas Z, Lessard JL, de Tombe P, and Solaro RJ. Ca²⁺ activation and tension cost in myofilaments from mouse hearts ectopically expressing enteric -actin. Am J Physiol Heart Circ Physiol 283: H642–H649, 2002.[Abstract/Free Full Text]
21. Mercadier JJ, Lompre AM, Wisnewsky C, Samuel JL, Bercovici J, Swynghedauw B, and Schwartz K. Myosin isoenzymic changes in several models of rat cardiac hypertrophy. Circ Res 49: 525–532, 1981.[Abstract/Free Full Text]
22. Penpargkul S, Schaible T, Yipintsoi T, and Scheuer J. The effects of diabetes on performance and metabolism of rat hearts. Circ Res 47: 911–921, 1980.[Abstract/Free Full Text]
23. Ren J and Bode AM. Altered cardiac excitation-contraction coupling in ventricular myocytes from spontaneously diabetic BB rats. Am J Physiol Heart Circ Physiol 279: H238–H244, 2000.[Abstract/Free Full Text]
24. Ren J and Davidoff AJ. Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes. Am J Physiol Heart Circ Physiol 272: H148–H158, 1997.[Abstract/Free Full Text]
25. Rodgers RL. Depressor effect of diabetes in the spontaneously hypertensive rat: associated changes in heart performance. Can J Physiol Pharmacol 64: 1177–1184, 1986.[ISI][Medline]
26. Rubler S, Sajadi RM, Araoye MA, and Holford FD. Noninvasive estimation of myocardial performance in patients with diabetes. Effects of alcohol administration. Diabetes 27: 127–134, 1978.[ISI][Medline]
27. Suurmeijer AJ, Clement S, Francesconi A, Bocchi L, Angelini A, Van Veldhuisen DJ, Spagnoli LG, Gabbiani G, and Orlandi A. -Actin isoform distribution in normal and failing human heart: a morphological, morphometric, and biochemical study. J Pathol 199: 387–397, 2003.[CrossRef][ISI][Medline]
28. Wold LE, Relling DP, Colligan PB, Scott GI, Hintz KK, Ren BH, Epstein PN, and Ren J. Characterization of contractile function in diabetic cardiomyopathy in adult rat ventricular myocytes. J Mol Cell Cardiol 33: 1719–1726, 2001.[CrossRef][ISI][Medline]

This article has been cited by other articles:

				J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]

				N. Hamdani, V. Kooij, S. van Dijk, D. Merkus, W. J. Paulus, C. d. Remedios, D. J. Duncker, G. J.M. Stienen, and J. van der Velden Sarcomeric dysfunction in heart failure Cardiovasc Res, March 1, 2008; 77(4): 649 - 658. [Abstract] [Full Text] [PDF]

				M. C. G. Daniels, T. Naya, V. L. M. Rundell, and P. P. de Tombe Development of contractile dysfunction in rat heart failure: hierarchy of cellular events Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R284 - R292. [Abstract] [Full Text] [PDF]

				J. Giger, A. X. Qin, P. W. Bodell, K. M. Baldwin, and F. Haddad Activity of the beta-myosin heavy chain antisense promoter responds to diabetes and hypothyroidism Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3065 - H3071. [Abstract] [Full Text] [PDF]

				T. J. Herron, R. Vandenboom, E. Fomicheva, L. Mundada, T. Edwards, and J. M. Metzger Calcium-Independent Negative Inotropy by {beta}-Myosin Heavy Chain Gene Transfer in Cardiac Myocytes Circ. Res., April 27, 2007; 100(8): 1182 - 1190. [Abstract] [Full Text] [PDF]

				A. C. Hinken and R. J. Solaro A Dominant Role of Cardiac Molecular Motors in the Intrinsic Regulation of Ventricular Ejection and Relaxation Physiology, April 1, 2007; 22(2): 73 - 80. [Abstract] [Full Text] [PDF]

				J. E. Stelzer, S. L. Brickson, M. R. Locher, and R. L. Moss Role of myosin heavy chain composition in the stretch activation response of rat myocardium J. Physiol., February 15, 2007; 579(1): 161 - 173. [Abstract] [Full Text] [PDF]

				D. E. Montgomery, V. L. M. Rundell, P. H. Goldspink, D. Urboniene, D. L. Geenen, P. P. de Tombe, and P. M. Buttrick Protein kinase C{varepsilon} induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1881 - H1888. [Abstract] [Full Text] [PDF]

				F. S. Korte, T. J. Herron, M. J. Rovetto, and K. S. McDonald Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H801 - H812. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 287/1/H408    most recent 00049.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Rundell, V. L. M. Articles by de Tombe, P. P. Search for Related Content PubMed PubMed Citation Articles by Rundell, V. L. M. Articles by de Tombe, P. P.