Cardiovascular Research

Cardiovascular Research 1997 34(1):41-47; doi:10.1016/S0008-6363(97)00010-2
© 1997 by European Society of Cardiology

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Pierce, G. N Articles by Russell, J. C Search for Related Content PubMed PubMed Citation Articles by Pierce, G. N Articles by Russell, J. C Social Bookmarking          What's this?

Copyright © 1997, European Society of Cardiology

Regulation of intracellular Ca²⁺ in the heart during diabetes

Grant N Pierce^a,* and James C Russell^b

^aInstitute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and the Department of Physiology, University of Manitoba, Winnipeg, MB, Canada
^bDepartment of Surgery, University of Alberta, Edmonton, Alta., Canada

^* Corresponding author. Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, 351 Tache Ave., Winnipeg, MB, Canada R2H 2A6. Tel. +1 204 235-3414; Fax +1 204 233-6723; E-mail: pierce@sbrc.umanitoba.ca

Received 13 August 1996; accepted 5 December 1996

	Abstract

Top Abstract 1 Introduction 2 The regulation of... 3 Conclusions References

 
Cardiovascular disease is a significant medical problem. The diabetic population is even more susceptible to cardiovascular complications and heart failure than non-diabetic patients. Atherosclerotic complications, a neuropathy and microvascular lesions have all been implicated causally in the accelerated cardiovascular disease during diabetes. However, one mechanism which may participate in the abnormalities in heart performance demonstrated during diabetes and may also contribute to heart failure in the diabetic is a derangement in the capacity of the myocardial cell to regulate its [Ca²⁺]. The purpose of this treatise is to identify the current controversies and conclusions available regarding the specific defects in Ca²⁺ flux thought to contribute to these cardiac defects during diabetes mellitus.

KEYWORDS Diabetes; Calcium, intracellular concentration; Cardiomyopathy; Calcium fluxes; Contractile function

	1 Introduction

Top Abstract 1 Introduction 2 The regulation of... 3 Conclusions References

 
It was approximately two decades ago that a defect in cardiac contractile performance was first identified in diabetic animals in the absence of vascular injury. Three studies, one from the lab of Timothy Regan [1], another from James Scheuer's group [2]and the third from Edmund Sonnenblick's lab [3], were critical in providing comprehensive descriptions of the contractile abnormalities which were present in a chemically-induced diabetic animal model. These studies provided the framework and rationale for a large number of studies which subsequently confirmed and extended these original observations. These three investigations were important because they changed the direction of our understanding of cardiovascular disease in the diabetic population. Instead of cardiovascular disease and cardiac failure in diabetes being thought of as primarily a vascular problem [4], these studies [1–3]documented the presence of a cardiomyopathy in animals. This diabetic cardiomyopathy has been extended over time to include a number of species including the human (see Refs. [5]and [6]for reviews on the topic). The original conclusion from these three seminal works remains valid: chronic diabetes mellitus induces cardiac performance defects which can occur in the absence of vascular complications. The data did not refute the presence of vascular defects or their importance in cardiovascular disease and morbidity. They simply identified the possibility that some of the cardiac failure and dysfunction associated with diabetes was due to problems inherent within the myocardium itself. Although the mechanisms responsible for the diabetic cardiomyopathy remain unresolved (see several reviews [6–9]), a disturbance in intracellular Ca²⁺ homeostasis was immediately proposed by several labs [10–12]as an important contributory factor. The purpose of the present article is to review and update this information in order to further our understanding of the significance of Ca²⁺ in the diabetic cardiomyopathy.

	2 The regulation of Ca2+ by the diabetic heart

Top Abstract 1 Introduction 2 The regulation of... 3 Conclusions References

 
2.1 Relationship of Ca²⁺ to the contractile response of the diabetic myocardium
The contractile defects identified in hearts from insulin-deficient diabetic animals by a number of laboratories include: slower shortening and relaxation kinetics, diminished peak tension or pressure, elevated end-diastolic pressure, and lower values for stroke volume, cardiac work, cardiac output and resting heart rate [6]. The vast majority of these data originate from chemically-induced rat models of diabetes. However, animals of other species with chemically-induced diabetes exhibit similar cardiac dysfunction [1, 13]. Furthermore, strains of animals with genetic insulin-dependent diabetes also display similar defects in cardiac performance [14, 15]. Thus, the problem is not limited to a particular animal species or mechanism leading to an insulin-deficient diabetic condition. The defect in cardiac function is clearly associated with an aspect of the diabetic state.

Cardiac function in diabetic animal models which are insulin-resistant, not insulin-deficient, has received far less research attention. One chemically-induced model of insulin resistance [16], a diet-induced model of glucose intolerance [17]and three genetic models of diabetes which are not insulin-deficient [18–20]have all shown evidence (although some is indirect) of cardiac contractile dysfunction. It is presently unclear if another model of diabetes (the JCR:LA-cp rat) which is glucose-intolerant in the presence of high circulating levels of insulin displays contractile performance abnormalities at rest or only under stressful stimuli [21, 22]. Further work is obviously required to determine if cardiac performance is compromised in both insulin-deficient and hyperinsulinemic diabetic states. These studies would not be trivial because it would identify if insulin or glucose abnormalities were central to the functional integrity of the heart.

Regulation of the intracellular [Ca²⁺] in the myocardium is a critical determinant of contractile performance. The contractile defects described above, therefore, may involve a change in the ability of the myocardium to regulate its [Ca²⁺] during diabetes. If the diabetic myocardium has a compromised ability to regulate Ca²⁺, then one might hypothesize that the Ca²⁺ content or concentration of the diabetic heart would be altered. This concept has lead to controversial results. An increase in ventricular calcium content in both insulin-deficient and insulin-resistant diabetic animals has been reported [20, 23, 24]. However, others have found that the net influx of Ca²⁺ was reduced in hearts from insulin-deficient rats [25]. The study of isolated single cells from the heart instead of whole tissue preparations has not resolved the matter. In single cardiomyocytes from diabetic animals, an increased resting [Ca²⁺] [26], no change in [Ca²⁺]_i [27, 28], a decreased resting [Ca²⁺]_i [29], and a decreased calcium content [30]have been reported. It is impossible to make reliable conclusions from such a confusion of varying results. However, one might hypothesize that insulin status may be a factor since all of the studies which used an insulin-resistant diabetic animal model reported an increase in cell or tissue [Ca²⁺] [20, 24, 26]. However, this issue will require further study.

Although we cannot make firm conclusions as to whether the resting diabetic heart exists in a Ca²⁺-deficient or a Ca²⁺-overloaded state, it is clear that its response to stimuli which alter the [Ca²⁺]_i is defective. At a tissue level, a hypersensitive response to plasma [Ca²⁺] has been documented in insulin-deficient and insulin-resistant diabetic rat hearts [21, 30–35]. This is probably the simplest way to demonstrate a defect in the capacity of the myocardium to regulate its [Ca²⁺]_i. However, other studies corroborate these initial conclusions. Diabetic hearts exhibit a supersensitivity to drugs which modify [Ca²⁺]_i. These include BAYK 8644 [33, 36], CoCl₂ [37], Cd [31], verapamil [33], and ryanodine [37, 38]. These data suggest that Ca²⁺ movements and their regulatory processes are altered in the diabetic myocardium. Other studies have employed varying stimulation frequencies and patterns to identify potential changes in Ca²⁺ flux within the myocardium. For example, post-rest contractions [38, 39]and rapid cooling contractures [39]were depressed in diabetic hearts in comparison to control, suggesting a defect in Ca²⁺ release from the sarcoplasmic reticulum. Post-stimulation potentiation was also attenuated in the diabetic myocardium [38], again suggestive of changes in cellular Ca²⁺ flux.

2.2 Alterations in the Ca²⁺ transport pathways
Ca²⁺ movements and the [Ca²⁺] in the myocardium are regulated in two manners: (1) in an active fashion by various enzymatic processes and, (2) passively by cellular buffering systems. Both appear affected by the diabetic condition.

Among the first subcellular organelles studied in the myocardium as a function of chronic diabetes were the contractile proteins. It is very clear that the Ca²⁺-ATPase activity of the myosin protein is depressed during diabetes [12, 40–44]. This depression is thought to contribute to the depressed force generation of the diabetic heart. Changes in contractile protein phosphorylation capacities may contribute to the altered ATPase activities and contractile protein function [45, 46]. The issue which remains unresolved is the involvement of the myofibrillar components in the change in sensitivity of the myocardium to Ca²⁺. Two studies have indirectly implicated the myofibrillar proteins as responsible for the change in sensitivity of the diabetic myocardium to Ca²⁺ [32, 34]. However, the initial work on isolated myofibrils directly demonstrated that the Ca²⁺ sensitivity of the myofibrillar complex was not altered during diabetes [12]. This has been corroborated by two other studies from different laboratories [30, 43].

Another subcellular system involved in the regulation of Ca²⁺ and, therefore, tension in the heart is the sarcoplasmic reticulum (SR). The uptake of Ca²⁺ into the SR is depressed in the diabetic heart [11, 47, 48]. The SR Ca²⁺ pump is defective as well [11, 47, 48]. This does not appear to be as a result of a decrease in the pump density [49]. Instead, other factors like the SR membrane phospholipid environment [47], fatty acid profile [50, 51], carnitine metabolism [48, 51]and calmodulin activity [52]have been suggested to contribute to the SR defect. Insulin treatment of insulin-deficient animals will normalize SR activity [47, 48]but correcting the thyroid status of the diabetic animals will not restore SR function [47]. Ca²⁺ release from the SR is also attenuated due to a depletion of SR Ca²⁺ stores [39](Fig. 1).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Dysfunction in the sarcoplasmic reticulum during diabetes mellitus and its significance for cardiac performance.

 
The change in SR function may have two implications for cardiac performance. The depression in SR Ca²⁺ uptake may cause a slower rate of relaxation by the diabetic heart. The poor release of Ca²⁺ from the SR would result in less Ca²⁺ available for force generation and may partly explain the lower indices of tension generation in the diabetic hearts.

Transsarcolemmal Ca²⁺ flux pathways have received a great deal of research attention recently. The action potential duration is significantly prolonged in the hearts from insulin-deficient and insulin-resistant diabetic animals [18, 31, 37, 53]. This is due to a decrease in the transient outward current and the steady-state outward current [54–56]. Several studies have documented no change in the L-type Ca²⁺ current in diabetic hearts [18, 54, 55]. A recent study found that longer durations of diabetes induce a decrease in this channel [56]. Biochemical investigations have found that Ca²⁺ channel density was decreased but the affinity of the channel for Ca²⁺ antagonist drugs was increased [57]. The former alteration may explain the depressed contractile force in the diabetic hearts whereas the latter may contribute to the increased sensitivity of the diabetic myocardium to Ca²⁺. It is noteworthy that the Ca²⁺ current was not altered in hearts from insulin-resistant diabetic animals [18].

Several other proteins important in Ca²⁺ homeostasis in the heart have been shown to be altered functionally during diabetes. Activities of the sarcolemmal Ca²⁺ pump [58, 59], the Na⁺/Ca²⁺ exchanger [58, 60], the Na⁺,K⁺-ATPase [61]and the Na⁺/H⁺ exchanger [60]are all depressed during insulin-deficient diabetes. These proteins will have direct or indirect effects on cellular [Ca²⁺] and, ultimately, cardiac performance. For example, the decreased Na⁺/Ca²⁺ exchanger activity may contribute to the slower rates of relaxation in the diabetic heart. The depressed Na⁺/H⁺ exchange will compromise the ability of the diabetic heart to recover from an acidic load [62]. Lower intracellular pH would be expected to result in poor force generation. The passive Ca²⁺ binding capacity of the sarcolemmal membrane is also decreased during diabetes [63]. If the sarcolemmal bound Ca²⁺ represents a pool of Ca²⁺ important in force generation, then this may also contribute to the depression in cardiac contractile performance.

2.3 The association of calcium with cell injury and death
The diabetic myocardium, as described above, is hypersensitive to Ca²⁺ and possesses defects in the function of many of the systems responsible for the regulation of intracellular Ca²⁺ in a normal physiological state. It is possible, therefore, that in pathological conditions where one would expect a stimulation of Ca²⁺ entry, defects in the Ca²⁺ regulatory systems may become accentuated. This may result in an inability to prevent excessive Ca²⁺ entry which could lead to serious injury to the myocardium. Intracellular Ca²⁺ overload has been associated with cell damage and death during pathological conditions like ischemia, hypoxia and exposure to free radicals [64, 65].

Is the diabetic myocardium, therefore, hypersensitive to injury from pathological stimuli? The answer to this question appears to be dependent upon the type of stimulus, the duration of diabetes and the type of diabetes. For example, metabolic inhibition of diabetic rat myocytes induced hypercontracture and rounding up of the cells at lower intracellular Ca²⁺ concentrations than in control preparations [29]. KCl depolarization induced a greater accumulation of Ca²⁺ in diabetic myocytes than was observed in controls [26]. The diabetic heart may be hypersensitive to ischemic challenge as well; however, the duration of diabetes may be an important factor. At 3 months of age, insulin-resistant diabetic rats were less affected by an ischemic challenge [22]. However, hearts from rats which were 6 months of age or older were hypersensitive to ischemic reperfusion injury [22]. These results are consistent with findings in insulin-deficient diabetic rats which demonstrated a resistance to ischemic injury 2 weeks after the induction of a diabetic state followed by a deterioration of postischemic function after 8 weeks of diabetes [66].

There is evidence that calcium is involved in the damage to the diabetic heart. Long-term treatment with the calcium channel antagonists, nifedipine [67]and nisoldipine [68], are protective against myocardial ischemic damage in older rats with long-standing diabetes. These hearts were also more sensitive to the cardioprotective effects of a Ca²⁺ antagonist applied during the ischemic challenge [69, 70]. Indeed, Ca²⁺ antagonists have also been shown to be beneficial against the cardiac dysfunction exhibited under control conditions in insulin-deficient diabetic rats [71]. The data suggest that the diabetic heart allows the entry of an excessive amount of Ca²⁺. The diabetic myocardium may also have less of a capacity to buffer this abnormally high [Ca²⁺]_i. Mitochondrial Ca²⁺ uptake, which is thought to serve as a cytoplasmic buffering system during conditions of high [Ca²⁺]_i, is depressed in the diabetic heart [72].

It is important to recognize that the duration of diabetes may not be the only factor which may influence the susceptibility of the heart to ischemic insult. Although older insulin-resistant rat hearts were hypersensitive to ischemic challenge, many studies in insulin-deficient diabetic rats have found that these hearts were more resistant to ischemic challenge than control hearts [73–78]. The protective mechanism in this case may again involve Ca²⁺ but in an indirect manner. Activation of the Na⁺/H⁺ exchange pathway is thought to play a central role in ischemic injury to the heart [64, 79–84]. The acidic cell interior (which is generated by the ischemic insult) stimulates the Na⁺/H⁺ exchanger to remove H⁺ from the cell in exchange for extracellular Na⁺. The accumulation of intracellular Na⁺ is known to activate the Na⁺/Ca²⁺ exchanger, which will result in excessive entry of Ca²⁺ into the cell. The diabetic heart exhibits a defective Na⁺/H⁺ exchanger [60, 74, 85]and a defective Na⁺/Ca²⁺ exchanger [58, 60]. The depressed Na⁺/H⁺ exchange activity will protect the diabetic heart from ischemic insult and result in less damage and dysfunction [74, 85, 86].

	3 Conclusions

Top Abstract 1 Introduction 2 The regulation of... 3 Conclusions References

 
Although it is unclear if the resting levels of cardiac calcium are altered, changes in Ca²⁺_i in response to a variety of stimuli are disturbed during diabetes. For example, cardiac contractile performance is abnormal in the presence of varying perfusate Ca²⁺ concentrations. The diabetic heart also responds differently to agents which alter [Ca²⁺]_i. Proteins which actively regulate [Ca²⁺]_i in a direct or an indirect manner are defective. Passive buffering of [Ca²⁺]_i is also depressed in the diabetic heart. These changes have important implications for cardiac performance not only during normal physiological states but also during pathological challenges like ischemia (Fig. 2). The dysfunctional regulation of Ca²⁺ in the myocardial cell (directly or indirectly), therefore, may be a prime determinant of injury to the heart in the presence of diabetes. Future studies should be designed with the objective of improving the regulation of [Ca²⁺]_i in the diabetic heart and understanding the mechanism responsible for the defect. Temporal data would suggest that the sarcolemmal membrane may be a critical site for study [87]. Although the SR has an important influence on cardiac function [88], several dissociations of SR function from contractile performance in the diabetic heart would suggest that it may not be the primary defect [48, 89, 90]. Furthermore, changes in protein expression may not always be the primary cause for the dysfunctional activities of the Ca²⁺ regulatory proteins [49, 91, 92]. Instead, lipid abnormalities accompanying the diabetic state may provide promising mechanistic answers to the study of Ca²⁺ homeostasis in the diabetic myocardium [8, 47, 48, 50, 51, 61, 63, 93]. Interventions which lower circulating lipid levels improve cardiac performance in diabetic animals [8, 94, 95]. These treatments have also improved the function of many of the subcellular organelles thought to contribute to the abnormal contractile performance of the diabetic heart [50, 51, 96]. In addition to lipids, insulin also remains as an attractive suspect for three reasons. Firstly, as discussed above, there are important differences in cardiac function and integrity between diabetic models which are insulin-deficient and those which have normal or elevated insulin levels. Secondly, insulin has the capacity to directly influence Ca²⁺ movements in the myocardium [97, 98]. Finally, the presence of insulin has also been shown to affect the severity of ischemic injury in the heart [99]. Specific experimental tests to identify the etiology of diabetic heart dysfunction and abnormal Ca²⁺ regulation are now possible and should provide new insight and strategies for the prevention of myocardial damage.

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Schematic representation of the importance of calcium homeostasis in the heart during diabetes mellitus.

 
Time for primary review 42 days.

	Acknowledgements

 
This work was supported by the Heart and Stroke Foundations of Manitoba and Alberta. G.N. Pierce is a Scientist of the Medical Research Council of Canada.

	References

Top Abstract 1 Introduction 2 The regulation of... 3 Conclusions References

 

1. Regan TJ, Ettinger PO, Khan MI, et al. Altered myocardial function and metabolism in chronic diabetes mellitus without ischemia in dogs. Circ Res 1974;35;222–237.
2. Penpargkul S, Schaible T, Yipintsoi T, Scheuer J. The effects of diabetes on performance and metabolism of rat hearts. Circ Res 1980;47:911–924.
3. Fein FS, Kornstein LB, Strobeck JE, Capasso JM, Sonnenblick EH. Altered myocardial mechanics in diabetic rats. Circ Res 1980;47:922–933.
4. Scott RC. Diabetes and the heart. Am Heart J 1975;90:283–289.
5. Regan TJ. Congestive heart failure in the diabetic. Annu Rev Med 1983;34:161–168.
6. Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Prog. Cardiovasc Dis 1985;27:255–270.
7. Pierce GN, Beamish RE, Dhalla NS. Heart Dysfunction in Diabetes, Boca Raton, FL: CRC Press, 1988:1–245.
8. Rodrigues B, McNeill JH. The diabetic heart: metabolic causes for the development of a cardiomyopathy. Cardiovasc Res 1992;26:913–922.
9. Dhalla NS, Pierce GN, Innes IR, Beamish RE. Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol 1985;1:263–281.
10. Dillmann, WH. Diabetes mellitus induces changes in cardiac myosin of the rat. Diabetes 1980;29:579–582.
11. Penpargkul S, Fein F, Sonnenblick EH, Scheuer J. Depressed cardiac sarcoplasmic reticular function from diabetic rats. J Mol Cell Cardiol 1981;13:303–309.
12. Pierce GN, Dhalla, NS. Cardiac myofibrillar ATPase activity in diabetic rats. J Mol Cell Cardiol 1981;13:1063–1069.
13. Fein FS, Miller-Green B, Sonnenblick EH. Altered myocardial mechanics in diabetic rabbits. Am J Physiol 1985;248:H729–H736.
14. Malhotra A, Mordes JP, McDermott L, Schaible TF. Abnormal cardiac biochemistry in spontaneously diabetic Bio-Breeding/Worcester rat. Am J Physiol 1985;249:H1051–H1059.
15. Rodrigues B, McNeill JH. Cardiac dysfunction in isolated perfused hearts from spontaneously diabetic BB rats. Can J Physiol Pharmacol 1990;68:514–518.
16. Schaffer SW, Tan BH, Wilson GL. Development of a cardiomyopathy in a model of noninsulin-dependent diabetes. Am J Physiol 1985;248:H179–H185.
17. Pierce GN, Lockwood MK, Eckhert CD. Cardiac contractile protein ATPase activity in a diet induced model of noninsulin dependent diabetes mellitus. Can J Cardiol 1989;5:117–120.
18. Tsuchida K, Watajima H, Otomo S. Calcium current in rat diabetic ventricular myocytes. Am J Physiol 1994;267:H2280–H2289.
19. Saito K, Nishi S, Kashima T, Tamaka H. Histologic and ultrastructural studies on the myocardium in spontaneously diabetic KK mice: a new animal model of cardiomyopathy. Am J Cardiol 1984;53:320–330.
20. Nakagawa M, Kobayashi S, Kimura I, Kimura M. Diabetic state-induced modification of Ca, Mg, Fe and Zn content of skeletal, cardiac and smooth muscles. Endocrinol Jpn 1989;36:795–807.
21. Lopaschuk GD, Russell JC. Myocardial function and energy substrate metabolism in the insulin-resistant JCR:LA corpulent rat. J Appl Physiol 1991;71:1302–1308.
22. Maddaford TG, Russell JC, Pierce GN. Post-ischemic cardiac performance in the insulin-resistant JCR:LA corpulent rat. Am J Physiol; under revision.
23. Regan TJ, Wu CF, Yeh CK, Oldewurtel HA, Haider B. Myocardial composition and function in diabetes: the effects of chronic insulin use. Circ Res 1981;49:1268–1280.
24. Schaffer SW, Mozaffari MS, Artman M, Wilson GL. Basis for myocardial mechanical defects associated with non-insulin-dependent diabetes. Am J Physiol 1989;256:E25–E30.
25. Bergh CH, Hjalmarson A, Sjogren KG, Jacobsson B. The effects of diabetes on phosphatidylinositol turnover and calcium influx in myocardium. Horm Metab Res 1988;20:381–386.
26. Allo SN, Lincoln TM, Wilson GL, Green FJ, Watanabe AM, Schaffer SW. Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation. Am J Physiol 1991;260:C1165–C1171.
27. Eckel J, Gerlach-Eskuchen E, Reinauer H. Alpha-adrenoceptor-mediated increase in cytosolic free calcium in isolated cardiac myocytes. J Mol Cell Cardiol 1991;23:617–625.
28. Yu Z, Quamme GA, McNeill JH. Depressed [Ca²⁺]_i responses to isoproterenol and cAMP in isolated cardiomyocytes from experimental diabetic rats. Am J Physiol 1994;266:H2334–H2342.
29. Noda N, Hayashi H, Miyata S, Suzuki S, Kobayashi A, Yamazaki N. Cytosolic Ca²⁺ concentration and pH of rat myocytes during metabolic inhibition. J Mol Cell Cardiol 1992;24:435–445.
30. Horackova M, Murphy MG. Effects of chronic diabetes mellitus on the electrical and contractile activities, ⁴⁵Ca²⁺ transport, fatty acid profiles and ultrastructure of isolated rat ventricular myocytes. Pflügers Arch 1988;411:564–572.
31. Sauviat MP, Feuvray D. Electrophysiological analysis of the sensitivity to calcium in ventricular muscle from alloxan diabetic rats. Basic Res Cardiol 1986;81:489–496.
32. Khandoudi N, Guo AC, Chesnais M, Feuvray D. Skinned cardiac fibres of diabetic rats: contractile activation and effects of 2,3 butandione monoxime (BDM) and caffeine. Cardiovasc Res 1993;27:447–452.
33. Yu Z, McNeill JH. Altered inotropic responses in diabetic cardiomyopathy and hypertensive-diabetic cardiomyopathy. J Pharmacol Exp Ther 1991;257:64–71.
34. Kapelko VI, Veksler VI, Popovich MI, Ventura-Clapier R. Energy-linked alterations in experimental cardiomyopathies. Am J Physiol 1991;261:39–44.
35. Veksler VI, Murat I, Ventura-Clapier R. Creatine kinase and mechanical and mitochondrial functions in hereditary and diabetic cardiomyopathies. Can J Physiol Pharmacol 1991;69:852–858.
36. Gunasekaran S, Young JA, Tenner TE, Jr. Pharmacological study of isoproterenol and diabetic cardiomyopathies in rat right ventricular strips. Pharmacology 1993;46:101–108.
37. Nobe S, Aomine M, Arita M, Ito S, Takaki R. Chronic diabetes mellitus prolongs action potential duration of rat ventricular muscles: circumstantial evidence for impaired Ca²⁺ channel. Cardiovasc Res 1990;24:381–389.
38. Yu Z, McNeill JH. Force–interval relationship and its response to ryanodine in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol 1991;69:1268–1276.
39. Bouchard RA, Bose D. Influence of experimental diabetes on sarcoplasmic reticulum function in rat ventricular muscle. Am J Physiol 1991;260:H341–H354.
40. Dillmann WH. Diabetes mellitus induces changes in cardiac myosin of the rat. Diabetes 1980;29:579–582.
41. Malhotra A, Penpargkul S, Fein FS, Sonnenblick EH, Scheuer J. The effect of streptozotocin-induced diabetes in rats on cardiac contractile proteins. Circ Res 1981;49:1243–1250.
42. Pierce GN, Dhalla NS. Mechanisms of the defect in myofibrillar function during diabetes. Am J Physiol 1985;248:E170–E175.
43. MacLean IM, Rajotte RV, Belcastro AN. Insulin and islet cell transplants: effects on diabetic rat cardiac myofibril ATPase. Am J Physiol 1987;252:E244–E247.
44. Belcastro AN, Gilchrist JS, Scrubb JA, Arthur G. Calcium-supported calpain degradation rates for cardiac myofibrils in diabetes. Mol Cell Biochem 1994;135:51–60.
45. Liu X, Takeda N, Dhalla NS. Troponin I phosphorylation in heart homogenate from diabetic rat. Biochim Biophys Acta 1996;1316:78–84.
46. Liu X, Takeda N, Dhalla NS. Myosin light chain phosphorylation in diabetic cardiomyopathy in rats. Metabolism 1997; in press.
47. Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol 1983;244:E528–E535.
48. Lopaschuk GD, Tahiliani AG, Vadlamudi RVSV, Katz S, McNeill JH. Cardiac sarcoplasmic reticulum function in insulin or carnitine-treated diabetic rats. Am J Physiol 1983;245:H969–H976.
49. Zarain-Herzberg A, Yano K, Elimban V, Dhalla NS. Cardiac sarcoplasmic reticular Ca(2+)-ATPase expression in streptozotocin-induced diabetic rat heart. Biochem Biophys Res Commun 1994;203:113–120.
50. Black SC, Katz S, McNeill JH. Cardiac performance and plasma lipids of omega-3 fatty acid-treated streptozotocin-induced diabetic rats. Diabetes 1989;38:969–974.
51. Rupp H, Elimban V, Dhalla NS. Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat heart by lipid-lowering interventions. Mol Cell Biochem 1994;132:69–80.
52. Levine SN, Sonnier GB, Abreo K. Effects of diabetes mellitus and aluminum toxicity on myocardial calcium transport. Toxicology 1990;65:137–148.
53. Fein FS, Aronson RS, Nordin C, Miller-Green B, Sonnenblick EH. Altered myocardial response to ouabain in diabetic rats: mechanics and electrophysiology. J Mol Cell Cardiol 1983;15:769–784.
54. Magyar J, Rusznak Z, Szentesi P, Szucs G, Kovacs L. Action potentials and potassium currents in rat ventricular muscle during experimental diabetes. J Mol Cell Cardiol 1992;24:841–853.
55. Jourdon P, Feuvray D. Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. J Physiol 1993;470:411–429.
56. Wang DW, Kiyosue T, Shigematsu S, Arita M. Abnormalities of K⁺ and Ca²⁺ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol 1995;269:H1288–H1296.
57. Lee SL, Ostadalova I, Kolar F, Dhalla NS. Alterations in Ca(2+)-channels during the development of diabetic cardiomyopathy. Mol Cell Biochem 1992;109:173–179.
58. Makino N, Dhalla KS, Elimban V, Dhalla NS. Sarcolemmal Ca²⁺ transport in streptozotocin-induced diabetic cardiomyopathy in rats. Am J Physiol 1987;253:E202–E207.
59. Heyliger CE, Prakash A, McNeill JH. Alterations in cardiac sarcolemmal Ca²⁺ pump activity during diabetes mellitus. Am J Physiol 1987;252:H540–H544.
60. Pierce GN, Ramjiawan B, Dhalla NS, Ferrari R. Na⁺–H⁺ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats. Am J Physiol 1990;258:H255–H261.
61. Pierce GN, Dhalla NS. Sarcolemmal Na⁺–K⁺ ATPase activity in diabetic rat heart. Am J Physiol 1983;245:C241–C247.
62. Lagadic-Gossmann D, Chesnais JM, Feuvray D. Intracellular pH regulation in papillary muscle cells from streptozotocin diabetic rats: an ion-sensitive microelectrode study. Pflügers Arch 1988;412:613–617.
63. Pierce GN, Kutryk MJB, Dhalla NS. Alterations in Ca²⁺ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes. Proc Natl Acad Sci USA 1983;80:5412–5416.
64. Pierce GN, Czubryt MP. The contribution of ionic imbalance to ischemia/reperfusion-induced injury. J Mol Cell Cardiol 1995;27:53–63.
65. Burton KP, Morris AP, Massey KD, Buja LM, Hagler HK. Free radicals alter ionic calcium levels and membrane phospholipids in cultured rat ventricular myocytes. J Mol Cell Cardiol 1990;22:1035–1047.
66. Tosaki A, Engelman DT, Engelman RM, Das DK. The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts. Cardiovasc Res 1996;31:526–536.
67. Russell JC, Koeslag DG, Dolphin PJ, Amy RM. Prevention of myocardial lesions in JCR:LA-corpulent rats by nifedipine. Arteriosclerosis 1990;10:658–664.
68. Russell JC, Dolphin PJ, Graham SE, Amy RM. Cardioprotective and hypolipidemic effects of nisoldipine in the JCR:LA-cp rat. Submitted.
69. Pijl AJ, Hendriks MG, Kam KL, Pfaffendorf M, van Zwieten PA. Antiischemic effects of nifedipine in isolated working heart preparations of healthy, diabetic, and hypertensive rats. J Cardiovasc Pharmacol 1994;23:379–386.
70. Heijnis JB, Mathy M-J, van Zwieten PA. Effects of nifedipine on global myocardial ischemic injury in hearts from diabetic and age-matched control rats. J Cardiovasc Pharmacol 1991;18:542–547.
71. Afzal N, Ganguly PK, Dhalla KS, Pierce GN, Dhalla NS. Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 1988;37:936–942.
72. Pierce GN, Dhalla NS. Heart mitochondrial function in chronic experimental diabetes in rats. Can J Cardiol 1985;1:48–54.
73. Tani M, Neely JR. Hearts from diabetic rats are more resistant to in vitro ischemia: possible role of altered Ca²⁺ metabolism. Circ Res 1988;62:931–940.
74. Khandoudi N, Bernard M, Cozzone P, Feuvray D. Intracellular pH and role of Na⁺/H⁺ exchange during ischaemia and reperfusion of normal and diabetic rat hearts. Cardiovasc Res 1990;24:873–878.
75. Suzuki O, Matsubara T, Kanashiro M, et al. Are diabetic hearts more resistant to ischemia/reperfusion injury? Jpn Circ J 1993;57:328–334.
76. Liu Y, Thornton JD, Cohen MV, Downey JM, Schaffer SW. Streptozotocin-induced non-insulin-dependent diabetes protects the heart from infarction. Circulation 1993;88:1273–1278.
77. Gamble J, Lopaschuk GD. Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats. Biochim Biophys Acta 1994;1225:191–199.
78. Feuvray D, Idell-Wenger JA, Neely JR. Effects of ischemia on rat myocardial function and metabolism in diabetes. Circ Res 1979;44:322–329.
79. Karmazyn M. Amiloride enhances postischemic ventricular recovery: Possible role of Na–H exchange. Am J Physiol 1988;255:H608–H615.
80. Meng HP, Pierce GN. Protective effects of 5-(N,N-dimethyl)amiloride on ischemia-reperfusion injury in hearts. Am J Physiol 1990;258:H1615–H619.
81. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 1991;68:1250–1258.
82. Tani M. Mechanisms of Ca²⁺ overload in reperfused ischemic myocardium. Annu Rev Physiol 1990;52:543–549.
83. Meng H, Pierce GN. Involvement of sodium in the protective effect of 5-(N,N-dimethyl)-amiloride on ischemia-reperfusion injury in isolated rat ventricular wall. J Pharmacol Exp Ther 1991;256:1094–1100.
84. Meng H, Maddaford TG, Pierce GN. The effect of amiloride and several selected analogues on post-ischemic recovery of cardiac contractile function. Am J Physiol 1993;264:H1831–H1835.
85. Lagadic-Gossmann D, Feuvray D. Intracellular sodium activity in papillary muscle from diabetic rat hearts. Exp Physiol 1991;76:147–149.
86. Khandoudi N, Bernard M, Cozzone P, Feuvray D. Mechanisms of intracellular pH regulation during postischemic reperfusion of diabetic rat hearts. Diabetes 1995;44:196–202.
87. Takeda N, Dixon IMC, Hata T, Elimban V, Shah KR, Dhalla NS. Sequence of alterations in subcellular organelles during the development of heart dysfunction in diabetes. Diabetes Res Clin Pract 1996;30:S113–S122.
88. Lagadic-Gossmann D, Buckler KJ, Le Prigent K, Feuvray D. Altered Ca²⁺ handling in ventricular myocytes isolated from diabetic rats. Am J Physiol 1996;270:H1529–1537.
89. Tahiliani AG, McNeill JH. Prevention of diabetes induced myocardial dysfunction in rats by methylpalmoxirate and triiodothyronine treatment. Can J Physiol Pharmacol 1985;63:925–931.
90. Rodrigues B, McGrath GM, McNeill JH. Cardiac function in spontaneously diabetic BB rats treated with low and high dose insulin. Can J Physiol Pharmacol 1989;67:629–636.
91. Dillmann WH. Diabetes-induced changes in specific proteins and mRNAs in the rat heart. In: Nagano M, Dhalla NS, eds. The Diabetic Heart. New York: Raven Press, 1991;263–270.
92. Pierce GN, Slotin T, Fliegel L, Gilchrist JSC, Maddaford TG. Expression and activity of the sodium–hydrogen exchanger in cardiac sarcolemma in health and disease. In: Fliegel L, ed. The Na⁺/H⁺ Exchanger. Austin, TX: RG Landes Publishing Co. 1996;217–228.
93. Fields LE, Daugherty A, Bergmann SR. Effect of fatty acid on performance and lipid content of hearts from diabetic rabbits. Am J Physiol 1986;250:H1079–H1085.
94. Rodrigues B, Goyal RK, McNeill JH. Effects of hydralazine on streptozotocin-induced diabetic rats: Prevention of hyperlipidemia and improvement in cardiac function. J Pharmacol Exp Ther 1986;237:292–299.
95. Rodrigues B, Xiang H, McNeill JH. Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats. Diabetes 1988;37:1358–1364.
96. Tada H, Oida K, Kutsumi Y, Shimada Y, Nakai T, Miyabo S. Effects of probucol on impaired cardiac performance and lipid metabolism in streptozotocin-induced diabetic rats. J Cardiovasc Pharmacol 1992;20:179–186.
97. Pierce GN, Ganguly PK, Dzurba A, Dhalla NS. Modification of the function of cardiac subcellular organelles by insulin. Adv Myocardiol 1985;6:113–125.
98. Gupta MP, Makino N, Khatter JC, Dhalla NS. Stimulation of Na⁺–Ca²⁺ exchange in heart sarcolemma by insulin. Life Sci 1986;39:1077–1083.
99. Pretto E, Schaible T, Scheuer J, Safar P, Stezoski SW. Insulin worsens ischemia-induced myocardial contracture in the isolated rat heart. Crit Care Med 1986;14:555–559.

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				L. Zhang, M. B. Cannell, A. R.J. Phillips, G. J.S. Cooper, and M.-L. Ward Altered Calcium Homeostasis Does Not Explain the Contractile Deficit of Diabetic Cardiomyopathy Diabetes, August 1, 2008; 57(8): 2158 - 2166. [Abstract] [Full Text] [PDF]

				S. Kobayashi, K. Mao, H. Zheng, X. Wang, C. Patterson, T. D. O'Connell, and Q. Liang Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury J. Biol. Chem., July 27, 2007; 282(30): 21945 - 21952. [Abstract] [Full Text] [PDF]

				R. J. Clark, P. M. McDonough, E. Swanson, S. U. Trost, M. Suzuki, M. Fukuda, and W. H. Dillmann Diabetes and the Accompanying Hyperglycemia Impairs Cardiomyocyte Calcium Cycling through Increased Nuclear O-GlcNAcylation J. Biol. Chem., November 7, 2003; 278(45): 44230 - 44237. [Abstract] [Full Text] [PDF]

				M. M. El-Omar, R. Lord, N. J. Draper, and A. M. Shah Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy Eur J Heart Fail, June 1, 2003; 5(3): 229 - 239. [Abstract] [Full Text] [PDF]

				S. U. Trost, D. D. Belke, W. F. Bluhm, M. Meyer, E. Swanson, and W. H. Dillmann Overexpression of the Sarcoplasmic Reticulum Ca2+-ATPase Improves Myocardial Contractility in Diabetic Cardiomyopathy Diabetes, April 1, 2002; 51(4): 1166 - 1171. [Abstract] [Full Text] [PDF]

				K. Dutta, D. A. Podolin, M. B. Davidson, and A. J. Davidoff Cardiomyocyte Dysfunction in Sucrose-Fed Rats Is Associated With Insulin Resistance Diabetes, May 1, 2001; 50(5): 1186 - 1192. [Abstract] [Full Text]

				G. Kotsanas, L. M. Delbridge, and I. R Wendt Stimulus interval-dependent differences in Ca2+ transients and contractile responses of diabetic rat cardiomyocytes Cardiovasc Res, June 1, 2000; 46(3): 450 - 462. [Abstract] [Full Text] [PDF]

				N. S Dhalla, X. Liu, V. Panagia, and N. Takeda Subcellular remodeling and heart dysfunction in chronic diabetes Cardiovasc Res, November 1, 1998; 40(2): 239 - 247. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Request Permissions Disclaimer Google Scholar Articles by Pierce, G. N Articles by Russell, J. C Search for Related Content PubMed PubMed Citation Articles by Pierce, G. N Articles by Russell, J. C Social Bookmarking          What's this?

Online ISSN 1755-3245 - Print ISSN 0008-6363

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics