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JSM Diabetology and Management

Effect of Streptozotocin-Induced Type 1 Diabetes Mellitus on Contraction and Calcium Transport in the Rat Heart

Review Article | Open Access Volume 2 | Issue 1 |

  • 1. Department of Physiology, UAE University, UAE
  • 2. Department of Health Sciences, Zayed University, UAE
  • 3. Department of Cellular Membranology, Bogomoletz Institute of Physiology, Ukraine
  • 4. Department of Basic Medical Sciences, Qatar University, Qatar
  • 5. School of Forensic & Applied Sciences, University of Central Lancashire, UK
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Corresponding Authors
Frank Christopher Howarth, Department of Physiology, College of Medicine & Health Sciences, P.O. Box 17666, Al Ain, UAE University, UAE,
Abstract

Diabetes mellitus (DM) is a major global health disorder currently affecting 450 million people. Diabetic cardiomyopathy (DC) is a disorder of cardiac muscle that is independent of coronary artery disease and that may lead to heart failure in diabetic patients. The precise mechanism(s) of diabetic cardiomyopathy are still not fully understood. Therefore, it is of paramount importance to develop experimental models of DM to study the time course and cellular, subcellular and molecular mechanisms of diabetic cardiomyopathy. With this in mind, scientists initially discovered that the antibiotic, streptozotocin (STZ) could be used to rapidly to induce diabetes mellitus in animal models. STZ destroys pancreatic beta cells, leading to hypoinsulinemia and hyperglycaemia. If left untreated hyperglycaemia may lead to DC and eventually heart failure. Initially in DM, the cardiac myocytes become apoptotic, disorganised and the number of myocytes are significantly reduced. The heart responds by enlarging itself (hypertrophy) which is accompanied by fibrosis leading to a physiological remodelling process. Within the myocytes, the process of excitation-contraction coupling (ECC) is deranged. This is due to an inability of the heart cells to regulate Ca2+ which is the initiator and regulator of cardiac muscle contraction. As a result, the heart takes longer to contract and to relax leading to DC, progressive heart failure and eventually sudden cardiac death. The aim of this review was to evaluate our current understanding of contractile dysfunction and disturbances in Ca2+ transport in the STZ-induced diabetic rat heart.

Keywords


•    Streptozotocin
•    Diabetes mellitus
•    Rat
•    Cardiomyopathy
•    Heart
•    Ventricle
•    Calcium signaling
•    Contraction

Citation

Howarth FC, AlKury L, Smail M, Qureshi MA, Sydorenko V, et al. (2017) Effect of Streptozotocin-Induced Type 1 Diabetes Mellitus on Contraction and Calcium Transport in the Rat Heart. JSM Diabetol Manag 2(1): 1004

ABBREVIATIONS

DM: Diabetes Mellitus; DC: Diabetic Cardiomyiopathy; STZ: Streptozotocin; ECC: Excitation-Contraction Coupling; SR: Sarcoplasmic Reticulum; SERCA2: Sarcoplasmic Reticulum Ca2+ ATPase Pump; TPK: Time to Peak; THALF: Time to Half; EPI: Epicardial; ENDO: Endocardial; DNA: Deoxyribonucleic Acid; mRNA: Messenger Ribonucleic Acid; RYR: Ryanodine Receptor

INTRODUCTION

The STZ-induced diabetic rat is a widely used experimental model of DM. STZ selectively enters pancreatic beta cells via the GLUT2 glucose transporter where it causes damage to the genetic machinery and ultimately leads to beta cell death [1]. The general characteristics of the STZ-induced diabetic rat include hypoinsulinemia, hyperglycemia, dyslipidemia, polyuria, reduced body weight gain, polydipsia and polyphagia [2]. Contractile dysfunction, which is frequently observed in the diabetic heart, may include disturbances in heart rate, stroke volume, cardiac output, ejection fraction and rates of pressure development and relaxation rate [3-7].

Experiments performed in ventricular myocytes isolated from diabetic heart have variously displayed either unaltered or reduced amplitude of shortening, and prolonged time course of contraction and relaxation [8-11]. Intracellular free Ca2+ [Ca2+]i transport systems are essential to the initiation and regulation of cardiac myocyte contraction and relaxation. During the process of ECC, the arrival of an action potential at a ventricular myocyte causes membrane depolarization leading to the opening of voltage-gated L-type Ca2+ channels and a small influx of Ca2+. This small entry of Ca2+ triggers a much larger release of Ca2+ from the sarcoplasmic reticulum (SR). There follows a transient rise in intracellular Ca2+ (Ca2+ transient) which binds to the troponin C and initiates and regulates the process of myocyte contraction. Relaxation of contraction begins when Ca2+ is pumped back into the SR via the SR Ca2+ ATPase pump (SERCA2) and effluxed from the cell, primarily via the Na+ /Ca2+ exchanger [12-14]. Experiments performed in cardiac myocytes from diabetic heart have variously displayed disturbances in Ca2+ transient, time course of Ca2+ transient, L-type Ca2+ current, SR Ca2+ content, uptake and release and Na+ /Ca2+ exchange current[5,15-18]. The aim of this review was to evaluate our current understanding of contractile dysfunction and disturbances in Ca2+ transport in the STZ-induced diabetic rat heart.

Diabetogenic Action of Streptozotocin

The general chemical structure of STZ is shown in Figure 1.

Figure 1 Diagram showing the chemical structure of streptozotocin.

Figure 1 Diagram showing the chemical structure of streptozotocin.

STZ is an antimicrobial agent which has also been used as a chemotherapeutic alkylating agent [19,20]. STZ is typically administered dissolved in a citrate buffer by either intraperitoneal or intravenousinjection. Once in the blood circulation, STZ travels to the pancreas where it selectively accumulates in pancreatic beta cells via the low-affinity GLUT2 glucose transporter in the plasma membrane. It should be noted that STZ is also able to damage other organs that express GLUT2 including the kidney and the liver [21,22]. It is generally believed that the toxicity of STZ is dependent upon the DNA alkylating activity of its methylnitrosourea moiety and methylation of the DNA molecule. Transfer of the methyl group from STZ to the DNA molecule causes damage and fragmentation of the DNA. Beta cell toxicity might also arise from the action of reactive oxygen species [1,23]. Whatever the mechanism(s) of action, the consequences of STZ treatment are damage to the beta islet cells of the pancreas and a reduction in the ability of these cells to produce insulin (Figure 2, 3)

 Figure 2 A schematic diagram showing the toxic effects of streptozotocin in  beta cells. Adapted from Lenzen, 2008(1).

Figure 2 A schematic diagram showing the toxic effects of streptozotocin in beta cells. Adapted from Lenzen, 2008(1).

Figure 3 Diagram showing the proposed actions of STZ-induced diabetes on  Ca2+ transport systems in the ventricular  myocyte.  -=No effect, ?=Reduced  activity, ?=Increased activity.

Figure 3 Diagram showing the proposed actions of STZ-induced diabetes on Ca2+ transport systems in the ventricular myocyte. -=No effect, ↓=Reduced activity, ↑=Increased activity.

The nature of the pathophysiological effects of STZ depends to a large extent on the dose and duration of treatment.

Blood Chemistry in the Streptozotocin-Induced Diabetic Rat

The general characteristics of the STZ-induced diabetic rat include hypoinsulinemia, hyperglycemia, polyuria, decreased body weight gain, polydipsia and polyphagia [2]. Insulin levels fall dramatically in diabetic rats compared to controls (Table 1).

Tables

Table 1: Blood insulin levels in the streptozotocin-induced diabetic rat

Dose of STZ

(mg/kg body weight)

Treatment time

Insulin level

(Control vs. STZ)

Reference

55 iv

6 w

43.3 vs. 31.3 µU/ml

[44]

65 iv

15, 27 d

31.2 vs. 12.4 15 d, 13.1 27 d µU/ml

[7]

55 ip

7 w

1.08 vs. 0.29 ng/ml

[5]

45-50 ip

7-8 w

1.98 vs. 0.27 ng/ml

[4]

65 iv

8 w

157 vs. 45 pmol/L

[64]

45 ip

8 w

1.2 vs. 0.3 ng/ml

[6]

45

8 w

1.12 vs. 0.3 ng/ml

[37]

60 ip

8-12 w

20.63 vs. 4.80 ng/ml

[2

Due to the falling concentrations of insulin, target organs like the liver and muscle are unable to clear glucose from the blood circulation and blood glucose rises. Following a 45-60 mg/kg body weight injection of STZ in adult rats the blood glucose levels typically rise to an average of 400 mg/dl in STZ treated rats compared to 100 mg/dl in controls (Table 2).

Table 2: Blood glucose levels in the streptozotocin-induced diabetic rat.

Dose STZ (mg/kg body weight)

Treatment time

Glucose level (Control vs. STZ)

Reference

60  ip

3d, 30 d

70 vs. 265, 77 vs. 309 mg/dl

[40]

100 iv

4-6 d

96 vs. 329 mg/dl

[50]

65 ip

5-7 d

270 vs. 529 mg/dL

[51]

60 ip

1 w

128.6 vs. 479.0 mg/dL

[49]

65 iv

7 d

126 vs. 509 mg/dL

[52]

65 iv

7 d

6.9 vs. 27 mmol/L

[27]

65 iv

15 d,27 d

130 vs. 388 15 d, 130 vs. 435 27 d mg/dL

[7]

40 ip

28 d

3.40 vs.28.78 mmol/l

[36]

40 iv

3-4 w

10.3 vs. 40.4 mM

[61]

40 ip

4 w

3.40 vs. 28.78 mmol/L

[36]

50 ip

4-5 w

10.08 vs. 48.05 mmol/L

[56]

60 iv

4-6 w

163.2 vs. 511.3 mg/dL

[60]

50 iv

4-7 w

217 vs. 529 mg/dL

[55]

60 ip

4-10 w

92.4 vs. 407.5 mg/dL

[16]

60 ip

4 w,24 w

76 vs. 292, 66 vs. 252 mg/dl

[3]

50 ip

5 w

101 vs. 458 mg/dL

[57]

50 ip

5 w

105 vs. 421 mg/dL

[17]

55 iv

6 w

6.2 vs. 19.1 mmol/L

[44]

55 iv

7 w

94 vs. 333 mg/dL

[26]

55 ip

7 w

4.9 vs. 21.2 mmol/L

[5]

45-50 ip

7-8 w

7.2 vs. 22.8 mmol/L

[4]

60 ip

8 w

104.06 vs. 469.64 mg/dl

[65]

60 ip

8 w

98.00 vs. 440.38 mg/dl

[66]

45

8 w

5.2 vs. 22.6 mmol

[37]

60 ip

8 w

70.1 vs. 307.2 mg/dl

[48]

65 iv

8 w

180 vs. 546 mg/dl

[64]

55

8 w

105 vs. 344 mg/dl

[50]

45

8 w

5.2 vs. 22.6 mmol/L

[37]

55 iv

8 w

110 vs. 348 mg/dL

[45]

50 ip

8 w

116.6 vs. 386.8 mg/dL

[41]

45 iv

8 w

6.2 vs. 20.8 mmol/L

[6]

60 iv

8 w

4.7 vs. 30.8 mmol/L

[30]

65 iv

8 w

155 vs. 473 md/dL

[35]

60 ip

8w

70.1 vs. 307.2 mg/dL

[48]

60 ip

8-12 w

69.4 vs. 322.5 mg/dl

[43]

60 ip

8-12 w

92.4 vs. 407/5 mg/dl

[29]

60 ip

8-12 w

71.83 vs. 308.23 mg/dl

[47]

60 ip

8-12 w

78.3 vs. 366.7 mg/dL

[28]

60 ip

8-12 w

70.0 vs. 331.5 mg/dL

[46]

60 ip

8-12 w

71.83 vs. 308.23 mg/dL

[47]

60 ip

8-12 w

92.4 vs. 407.5 mg/dL

[29]

60 ip

8-12 w

68.0 vs. 347.4 mg/dL

[10]

60 ip

8-12 w

69.4 vs. 322.5 mg/dL

[43]

60 ip

9 w

70.50 vs. 260.17 mg/dL

[59]

60 ip

9 w

90.21 vs. 529.21 mg/dL

[38]

60 ip

12 w

7.57 vs. 19.47 mmol/L

[39]

60 ip

12 w

90.5 vs. 455.0 mg/dL

[11]

60 ip

13-24 w

110 vs. 554 mg/dl

[49]

Urine glucose is also elevated in diabetic rats [24] compared to controls. Persistently elevated levels of glucose in the blood of diabetic rats causes glycosylation of hemoglobin and glycosylated hemoglobin is a widely used diagnostic criterion for DM (Table 3)

Table 3: Glycosylated hemoglobin in the streptozotocin-induced diabetic rat.

Dose STZ (mg/kg body weight)

Treatment time

Glucose level (Control vs. STZ)

Reference

45-50 ip

7-8 w

3.9 vs. 8.3 %

[4]

55 ip

7 w

4.1 vs. 8.4 %

[5]

45 iv

8 w

3.3 vs. 8.3 %

[6]

45

8 w

4.3 vs. 8.9 %

[37]

 Glycosylated hemoglobin can rise to an average of 8.5% in diabetic rats compared to 4.0 % in controls (Table 3). Alterations in lipid profile including increased cholesterol [7], increased free fatty acids [7], increased atrial and brain natriuretic peptides[10,25], reduced insulin-like growth factor-1 and triiodothyronine [7,26], increased creatine [27], and increased blood osmolarity also occur in diabetic animals compared to controls [28,29].

Body and Heart Weight in the Streptozotocin-Induced Diabetic Rat

Body weight gain is typically reduced in diabetic rats compared to controls (Table 4).

Table 4: Body weight in the streptozotocin-induced diabetic rat.

Dose STZ (mg/kg body weight)

Treatment time

Body weight

(Control vs. STZ)

Reference

100 iv

4-6 d

237 vs. 190 g

[50]

65 ip

5-7 d

370 vs. 269 g

[8]

65 ip

5-7 d

370 vs. 269 g

[51]

60 ip

7 d

282.1 vs. 237.2 g

[49]

65 iv

7 d

334.4 vs. 285.5 g

[27]

65 iv

7 d

351 vs. 279 g

[52]

40 ip

28 d

265 vs. 202 g

[36]

60 ip

30 d

314 vs. 238 g

[40]

50 ip

4-5 w

256.32 vs. 186.12 g

[56]

60 iv

4-6 w

420 vs. 239 g

[60]

50 iv

4-7 w

425 vs. 233 g

[55]

60 ip

4-10 w

385.4 vs. 233.8 g

[16]

60 ip

4, 24 w

305 vs. 248, 410 vs. 308 g

[3]

50 ip

5 w

240.2 vs. 196.8 g

[17]

50 ip

5 w

249.2 vs. 197.8 g

[57]

55 iv

6 w

448 vs. 335 g

[44]

55 iv

7 w

434 vs. 293 g

[26]

55 ip

7 w

366.6 vs. 270.6 g

[5]

45-50 ip

7-8 w

416.5 vs. 329.8 g

[4]

60 ip

8 w

352.25 vs. 267.57 g

[65]

60 ip

8 w

351.05 vs. 259.05 g

[66]

45

8 w

393.0 vs. 289.1 g

[37]

60 ip

8 w

312.0 vs. 229.1 g

[48]

65 iv

8 w

467 vs. 258 g

[64]

55 iv

8 w

380 vs. 285 g

[50]

55 iv

8 w

411 vs. 310 g

[45]

45 iv

8 w

422.5 vs. 312.8 g

[6]

60 iv

8 w

438 vs. 247 g

[30]

65 iv

8 w

462 vs.270 g

[35]

60 ip

8-12 w

304.3 vs. 221.1 g

[43]

60 ip

8-12 w

381.4 vs. 232.8 g

[29]

60 ip

8-12 w

326.83 vs. 226.23 g

[47]

60 ip

8-12 w

269.1 vs. 209.9 g

[46]

60 ip

8-12 w

300.6 vs. 224.0 g

[10]

60 ip

8-12 w

307.1 vs. 232.8 g

[28]

60 ip

9 w

351.20 vs. 198.80 g

[38]

60 ip

9 w

285.33 vs. 229.33 g

[59]

60 ip

12 w

589.83 vs. 256 g

[39]

60 ip

12 w

361.5 vs. 255.8 g

[11]

60 ip

13-24 w

426 vs. 266 g

[49]

Heart weight is typically reduced but may occasionally be unaltered in diabetic rats (Table 5).

Table 5: Heart weight in the streptozotocin-induced diabetic rat.

Dose STZ (mg/kg body weight)

Treatment time

Heart weight

(Control vs. STZ)

Reference

65 ip

5-7 d

1.10 vs. 0.92 g

[8]

65 ip

5-7 d

1.10 vs. 0.92 g

[51]

65 iv

7 d

1.10 vs. 0.90 g

[52]

50 iv

4-7 w

1.35 vs. 0.88 g

[55]

60 ip

4-10 w

1.1 vs. 1.0 g

[16]

50 ip

5 w

4.04 vs. 4.08 mg/g

[57]

55 iv

7 w

1.85 vs. 1.37 g

[26]

55 ip

7 w

1.2 vs. 1.0 g

[5]

45-50 ip

7-8 w

1.25 vs. 0.97 g NSD

[4]

60 ip

8 w

1.2 vs. 1.06 g

[65]

60 ip

8 w

1.18 vs. 1.05 g

[66]

55 iv

8 w

1.54 vs. 1.29 gNSD

[45]

45 iv

8 w

1.3 vs. 1.0 g

[6]

60 iv

8 w

1.60 vs. 1.24 g

[30]

65 iv

8 w

1.04 vs. 0.74 g

[35]

60 ip

8-12 w

1.17 vs. 1.01 g

[43]

60 ip

8-12 w

1.1 vs. 1.0 g

[29]

60 ip

8-12 w

1.25 vs. 0.99 g

[47]

60 ip

8-12 w

1.17 vs. 1.04 g

[46]

60 ip

8-12 w

1.25 vs. 1.02 g

[10]

60 ip

8-12 w

1.21 vs. 1.04 g

[28]

60 ip

9 w

1.86 vs. 1.00 g

[38]

60 ip

12 w

780 vs. 595.1 mg

[39]

60 ip

12 w

1.13 vs. 0.96 g

[11]

60 ip

13-24 w

1.33 vs. 1.05 g

[49]

NSD=No significant difference

Heart weight to body weight ratio is generally increased indicating a sign of hypertrophy but may also be unaltered in diabetic rats compared to controls (Table 6).

Table 6: Heart weight to body weight ratio in the streptozotocin-induced diabetic rat.

Dose STZ (mg/kg body weight)

Treatment time

Heart weight to body weight ratio (Control vs. STZ)

Reference

65 ip

    1. d

3.05 vs. 3.03 mg/g NSD

[8]

65 ip

5-7 d

3.03 vs. 3.05 mg/gNSD

[51]

65 iv

7 d

3.12 vs. 3.21 mg/g

[52]

50 iv

4-7 w

3.16 vs. 3.81 mg/g

[55]

55 iv

7 w

4.33 vs. 5.23 mg/gNSD

[26]

55 ip

7 w

3.3 vs. 3.7 mg/g

[5]

60 ip

8 w

3.42 vs. 4.00 mg/g

[65]

60 ip

8 w

3.38 vs. 4.11 mg.g

[66]

55 iv

8 w

3.74 vs. 4.16 mg/g

[45]

45 iv

8 w

3.1 vs. 2.9 mg/gNSD

[6]

60 iv

8 w

3.7 vs. 5.3 mg/g

[30]

65 iv

8 w

2.25 vs. 2.74 mg/g

[35]

60 ip

8-12 w

4.41 vs. 5.04 mg/g

[46]

60 ip

8-12 w

4.28 vs. 4.71 mg/gNSD

[10]

60 ip

9 w

5.43 vs. 5.07 mg/gNSD

[38]

60 ip

12 w

3.13 vs. 3.78 mg/g

[11]

60 ip

13-24 w

3.14 vs. 3.97 mg/g

[49]

NSD=No significant difference

Other studies have reported unaltered heart weight to tibial length [30], reduced left ventricle weight [31,32] and increased left ventricle to body weight ratio [33] in diabetic rats compared to controls. These data provide evidence of cardiac hypertrophy in the STZ-induced diabetic rat.

Hemodynamic Function In vivo and in the Isolated Perfused Heart of the Streptozotocin-Induced Diabetic Rat

Measures of hemodynamic function are shown in Table 7. Echocardiographic and other techniques have generally reported reduced heart rate [3-6,32,34,35,35-38] but sometimes unaltered heart rate [7,39] in diabetic rats compared to controls (Table 7)

Table 7: In vivoventricular function in the streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

HR

60 ip

10 d

348 vs. 255 bpm

[40]

 

65 iv

24, 27 d

412 vs. 376 bpm, 412 vs. 362 bpm

[7]

 

40 ip

28 d

388.63 vs. 339.50 bpm NSD

[36]

 

60 ip

4, 22 w

347 vs. 268,316 vs. 266 bpm

[3]

 

55 ip

7 w

416.5 vs. 304.8 bpm

[5]

 

45-50 ip

7-8 w

401.5 vs. 320.8 bpm

[4]

 

60 iv

8 w

390 vs. 311 bpm

[30]

 

45 iv

8 w

370.2 vs. 283.9 bpm

[6]

 

50  ip

8 w

318.24 vs. 243.80 bpm

[32]

 

45

8 w

382 vs. 291 bpm

[37]

 

65 iv

8 w

357 vs. 283 bpm

[35]

 

60 ip

9 w

346 vs. 267 bpm

[38]

 

55 iv

12 w

346 vs. 264 bpm

[9]

 

60 ip

12 w

420 vs. 388 bpm NSD

[39]

CO

55 ip

7 w

127.0 vs. 94.5 ml/min

[5]

 

45-50 ip

7-8 w

128.4 vs. 93.0 ml/min

[4]

 

45 iv

8 w

118.7 vs. 82.3 ml/min

[6]

SV

55 ip

7 w

0.31 vs. 0.31 ml NSD

[5]

 

45-50 ip

7-8 w

0.32 vs. 0.29 ml

[4]

 

45 iv

8 w

0.32 vs. 0.29 ml NSD

[6]

EF

55 ip

7 w

84.1 vs. 76.5%

[5]

 

45-50 ip

7-8 w

84.06 vs. 71.8%

[4]

 

50 ip

8 w

NSD

[41]

 

45 iv

8 w

83.5 vs. 72.5%

[6]

 

50 ip

8 w

84.4 vs. 67.8%

[32]

 

45

8 w

85 vs. 70%

[37]

 

60 ip

9 w

77.33 vs. 64.80%

[38]

 

60 ip

12 w

76.1 vs. 67.7%

[39]

FS

55 ip

7 w

61.7 vs. 51.9%

[5]

 

45-50 ip

7-8 w

60.6 vs. 52.9%

[4]

 

45 iv

8 w

60.9 vs. 49.3%

[6]

 

50 ip

8 w

55.7 vs. 39.6%

[32]

 

45

8 w

61 vs. 51%

[37]

 

60 ip

9 w

41.0 vs. 30.8%

[38]

 

60 ip

12 w

45.4 vs. 37.6%

[39]

LVSP

65 iv

21, 24, 27 d

150 vs.136 mmHg 21 d,150 vs. 131 mmHg 24 d,150 vs. 122 mmHg 27 d

[7]

 

40 ip

28 d

136.87 vs. 106.32 mmHg

[36]

 

55 ip

7 w

Reduced

[5]

 

45

8 w

130 vs. 104 mmHg

[37]

 

65 iv

8 w

151 vs. 123 mmHg

[35]

LVDP

65 iv

21, 24, 27 d

2.3 vs. 8.6 mmHg 21 d,9.6 mmHg 24 d,9.8 mmHg 27 d

[7]

 

65 ip

21 d

Increased

[42]

 

40 ip

28 d

2.38 vs. 6.30 mmHg

[36]

 

60 ip

8 w

Increased

[33]

 

45

8 w

0.6 vs. 4.8 mmHg

[37]

 

65 iv

8 w

3 vs. 19 mmHg

[35]

 

60 ip

12 w

Increased

[39]

LVPD (+dP/dt)

65 iv

21, 24, 27 d

Reduced

[7]

 

40 ip

28 d

5.71 vs. 3.12 mmHg/ms

[36]

 

60 ip

8 w

Reduced

[33]

 

60 ip

8 w

Reduced

[31]

 

5 ip

8 w

Reduced

[5]

 

45

8 w

9753 vs. 5176 mmHg/sec

[37]

 

65 iv

8 w

6137 vs. 4332 mmHg/sec

[35]

 

60 ip

12 w

Reduced

[39]

LVPR (-dP/dt)

65 iv

21, 24, 27 d

Reduced

[7]

 

40 ip

28 d

-4.91 vs. -2.66 mmHg/ms

[36]

 

55 ip

7 w

Reduced

[5]

 

60 ip

8 w

Reduced

[33]

 

60 ip

8 w

Reduced

[31]

 

45 ip

8 w

9088 vs. 4723 mmHg/sec

[37]

 

65 iv

8 w

5415 vs. 3610 mmHg/sec

[35]

 

60 ip

12 w

Reduced

[39]

LVRT

60 ip

8 w

Longer

[31]

LVEDD

55 ip

7 w

6.28 vs. 6.91

[5]

 

45-50 ip

7-8 w

6.58 vs. 6.70 mm NSD

[4]

 

45 iv

8 w

2.6 vs. 3.6 mm

[6]

 

60 ip

12 w

11.67 vs. 7.5 mm

[39]

 

55 iv

12 w

6.73 vs. 6.86 mm NSD

[9]

LVESD

55 ip

7 w

2.66 vs. 3.35

[5]

 

45-50 ip

7-8 w

2.67 vs. 3.234 mm NSD

[4]

 

60 ip

12 w

5.84 vs. 4.1 mm

[39]

 

55 iv

12 w

2.52 vs. 2.86 mm NSD

[9]

IVRT

50 ip

8 w

Increased

[32]

 

55 iv

12 w

Longer

[9]

IVCT

60 ip

8 w

Longer

[31]

BP

55 iv

8 w

110 vs. 105 mmHg NSD

[45]

HR=Heart rate, CO=Cardiac output, SV=Stroke volume, EF=Ejection fraction, FS=Fractional shortening, LVSP=Left ventricular systolic pressure, LVDP=Left ventricular diastolic pressure, LVPR=Left ventricular rate of pressure relaxation, LVRT=Left ventricle relaxation time, LVEDD=Left ventricular end-diastolic dimension, LVESD=Left ventricular end-systolic dimension, IVRT=Isovolumic relaxation time, IVCT=Isovolumic contraction time, BP=Blood pressure.NSD=No significant difference

. Associated with the changes in heart rate electrophysiological measurements of QRS, QT, PQ and PR intervals are generally prolonged [4,5,35,40] and sometimes unaltered [3,35,40] in diabetic rats compared to controls. Cardiac output may either be reduced or unaltered [4-6], stroke volume may be reduced or unaltered [4-6] and ejection fraction was generally reduced [5,6,32,37-39] but may also be unaltered [41] in diabetic rats compared to controls. Percentage fractional shortening was reduced [4-6,32,37-39] in diabetic rat. Left ventricular systolic pressure was reduced [33,35,36,39,42] and left ventricular diastolic pressure was increased [33,35-37,39,42] in diabetic rats compared to controls. Rates of pressure development and decline were lower [5,31,33,35-37,39] in diabetic rat. In the isolated perfused heart the spontaneous heart rate was lower [9,43], rates of pressure development and decline were lower [9] and the time to peak (TPK) and half relaxation (THALF) of pressure were prolonged [9] in diabetic rat heart. Collectively, these in vivo and in vitro experiments provide evidence of disturbances in hemodynamic function including heart rate, left ventricular systolic and diastolic pressure, rate of pressure development and decline, and cardiac output in the STZ-induced diabetic rat heart compared to controls.

Contraction in Ventricular Myocytes from Streptozotocin-Induced Diabetic Rat

The characteristics of ventricular myocyte contraction are shown in Table 8.

Table 8: Contraction in ventricular myocytes from streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

CV

60 ip

4-10 w

49.4 vs. 25.3%

[16]

 

55 iv

6 w

79.4 vs. 70.4%

[44]

 

45-50 ip

7-8 w

70 vs. 55%

[4]

 

60 ip

8-12 w

49 vs. 25%

[29]

 

55 iv

12 w

69 vs. 60 % NSD

[9]

RCL

100 iv

4-6 d

110 vs. 109 µm NSD

[50]

 

65 ip

5-7 d

129 vs. 108 µm

[8]

 

65 ip

5-7 d

127 vs. 113 µm

[51]

 

65 iv

7 d

95 vs. 103 µm

[52]

 

65 iv

7 d

128.9 vs. 113.9 µm LV

[27]

 

40 iv

3-4 w

126.4 vs. 121.7 µm NSD

[61]

 

55 ip

7 w

110.7 vs. 117.8 µm LV NSD

[5]

 

45-50 ip

7-8 w

112.30 vs. 112.83 µm NSD

[4]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

55 iv

8 w

111 vs. 110 µm NSD

[50]

 

55 iv

8 w

NSD

[45]

 

60 ip

8-12 w

NSD

[29]

 

60 ip

8-12 w

131.49 vs. 122.48 µm

[47]

 

60 ip

8-12 w

117 vs. 113 µm NSD

[46]

 

60 ip

8-12 w

131.49 vs. 122.48 µm

[47]

 

60 ip

8-12 w

117 vs. 123 µm NSD

[10]

 

60 ip

8-12 w

126 vs. 125 µm NSD

[43]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

12 w

124.5 vs. 124.4 µm EPI NSD, 119.9 vs 121.7 ENDO NSD LV

[11]

 

60 ip

13-24 w

138.80 vs. 136.93 µm NSD

[49]

 

60 ip

20 w

134.88 vs. 134.94 µm NSD

[48]

TPK Shortening

100 iv

4-6 d

0.1-2.0 Hz NSD

[50]

 

65 ip

5-7 days

117 vs. 131 ms

[8]

 

65 ip

5-7 days

119 vs. 181 ms

[51]

 

65 iv

7 days

103.3 vs. 97.3 ms NSD

[52]

 

55 iv

7 w

Prolonged

[26]

 

60 ip

8 w

NSD

[66]

 

55 iv

8 w

0.1-2.0 Hz Prolonged

[50]

 

55 iv

8 w

Prolonged

[45]

 

60 ip

8-12 w

305 vs. 360 ms

[10]

 

60 ip

8-12 w

105.5 vs. 137.2 ms

[67]

 

60 ip

8-12 w

94 vs. 113 ms

[46]

 

60 ip

8-12 w

103 vs. 135 ms

[47]

 

60 ip

8-12 w

99 vs. 136 ms

[29]

 

60 ip

8-12 w

73 vs. 100 ms

[43]

 

60 ip

8-12 w

Prolonged

[28]

 

55 iv

12 w

Prolonged

[9]

 

60 ip

12 w

83 vs. 107 ms EPI, 90 vs. 110 ms ENDO

[11]

 

60 ip

13-24 w

97.4 vs. 123.5 ms

[49]

 

60 ip

20 w

98.1 vs. 112.1 ms

[48]

THALF relaxation of shortening

100 iv

4-6 d

Prolonged

[50]

 

55 ip

7 w

285.9 vs. 445.8 ms NSD

[5]

 

45-50 ip

7-8 weeks

382.60 vs. 472.52 ms

[4]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

55 iv

8 w

Prolonged

[50]

 

60 ip

8-12 w

NSD

[10]

 

60 ip

8-12 w

46.5 vs. 48.6 ms NSD

[67]

 

60 ip

8-12 w

NSD

[29]

 

60 ip

8-12 w

NSD

[68]

 

60 ip

8-12 weeks

41 vs. 51 ms

[46]

 

60 ip

8-12 weeks

37 vs. 48 ms

[43]

 

60 ip

8-12 w

NSD

[28]

 

55 iv

12 w

Prolonged

[9]

 

60 ip

12 w

51 vs. 59 ms EPI NSD, 51 vs. 59 ms ENDO

[11]

 

60 ip

13-24 w

55.7 vs. 61.1 ms NSD

[49]

 

60 ip

20 w

54.7 vs. 53.8 ms NSD

[48]

Time to 90% relaxation of shortening

65 ip

5-7 d

143 vs. 160 ms

[8]

 

65 ip

5-7 days

141 vs. 184 ms

[51]

 

65 iv

7 days

104.9 vs 138.5 ms

[52]

Tau relaxation

55 iv

7 w

Prolonged

[26]

 

55 iv

8 w

Prolonged

[45]

 

55 iv

12 w

Prolonged

[9]

Velocity of shortening (+dL/dt)

100 iv

4-6 days

0.5-2.0 Hz Slowed

[50]

 

65 iv

7 d

58 vs 58 µm/s NSD

[52]

 

55 iv

7 w

Reduced

[26]

 

55 ip

7 w

132.2 vs. 75.0 µm/s

[5]

 

45-50 ip

7-8 w

159.44 vs. 74.91 µm/s

[4]

 

55 iv

8 w

0.1-2.0 Hz Slowed

[50]

 

55 iv

8 w

NSD

[45]

 

45

8 w

228.6 vs. 89.9 µm/s

[37]

 

55 iv

12 w

Lower

[9]

Velocity of relengthening    (-dL/dt)

100 iv

4-6 d

0.1-2.0 Hz Slowed

[50]

 

65 iv

7 d

-54 vs. -52 µm/s NSD

[52]

 

55 iv

7 w

Reduced

[26]

 

55 ip

7 w

117.9 vs. 60.9 µm/s

[5]

 

45-50 ip

7-8 w

111.56 vs. 65.21 µm/s

[4]

 

55 iv

8 w

0.1-2.0 Hz Slowed

[50]

 

55 iv

8 w

NSD

[45]

 

45

8 w

186.5 vs. 77.1 µm/s

[37]

 

55 iv

12 w

Lower

[9]

AMP of shortening

100 iv

4-6 d

0.1 – 2.0 Hz NSD

[50]

 

65 ip

5-7 d

7.5 vs. 8.1% NSD

[8]

 

65 ip

5-7 d

7.5 vs. 6.7% NSD

[51]

 

65 iv

7 d

5.69 vs. 5.51 %

[52]

 

65 iv

7 d

9.6 vs. 7.2 (0.5 Hz), 9.7 vs. 8.7 % (2 Hz) NSD

[27]

 

55 ip

7 w

11.4 vs. 8.4 µm

[5]

 

55 iv

7 w

Reduced

[26]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

45

8 w

14.3 vs. 9.6 %

[37]

 

55 iv

8 w

NSD

[45]

 

55 iv

8 w

0.1-2.0 Hz Reduced

[50]

 

60 ip

8-12 w

NSD

[43]

 

60 ip

8-12 w

9.3 vs. 9.6 % NSD

[10]

 

60 ip

8-12 w

NSD

[67]

 

60 ip

8-12 w

NSD

[29]

 

60 ip

8-12 w

NSD

[47]

 

60 ip

8-12 w

NSD

[46]

 

60 ip

8-12 weeks

9.3 vs. 9.6 % NSD

[10]

 

60 ip

8-12 w

NSD

[28]

 

55 iv

12 w

Lower

[9]

 

60 ip

12 w

6.0 vs. 6.1 %   EPI NSD, 6.3  vs. 6.2 %  ENDO NSD

[11]

 

60 ip

13-24 w

7.29 vs. 7.32 % NSD

[49]

 

60 ip

20 w

7.15 vs. 7.41 % NSD

[48]

CV=Cell viability, RCL=Resting cell length, TPK=Time to peak, THALF=Time to half, AMP=Amplitude.NSD=No significant difference

Generally, ventricular myocytes are isolated from heart using a combination of enzymatic and mechanical dispersal techniques [9,16]. The viability, calculated as the percentage of rod shaped compared to round shaped myocytes, was generally lower [4,16,29,44] in myocytes isolated from diabetic rats compared to controls. Resting cell length was generally unaltered [4,5,10,11,28,43,45-49], but sometimes reduced [27] in ventricular myocytes from diabetic rats compared to controls. Cell width was either unaltered [28] or reduced [27], cell thickness was unaltered [27], surface area was increased [10] and calculated cell volume may be unaltered [28] or reduced [27] in myocytes from diabetic rats compared to controls. A recent study reported unaltered length in epicardial (EPI) and endocardial (ENDO) ventricular myocytes from diabetic rat [11]. The time course of shortening was prolonged [4,5,8-11,26,28,29,43,45-51] and the time course for half relaxation was either prolonged [4,5,8,9,11,26,43,45,46,50- 52] or unaltered [10,28,29,47-49] in myocytes from diabetic rats compared to controls. A recent study reported prolonged TPK shortening in EPI and ENDO myocytes and prolonged THALF relaxation of shortening in ENDO but not in EPI left ventricular myocytes from STZ-induced diabetic rat [11]. Rate of development of shortening may be reduced [4,5,9,26,37] or unaltered [45,52] and the rate of decline of shortening may also be reduced [4,5,9,26,37] or unaltered [45,52] in myocytes from diabetic rats compared to controls. Amplitude of shortening may be reduced [4,5,9,26,27,37] or unaltered [8,10,11,28,29,43,45-49] in myocytes from diabetic rat. Increasing frequency of stimulation produces a negative staircase effect that was unaltered in myocytes from STZ- induced diabetic rat compared to control [26,45]. Spontaneous contractions (arrhythmic contractions) were increased in myocytes from diabetic rat [2]. Experiments in sarcomeres have reported reduced fractional shortening, decreased maximal rate of shortening and re-lengthening in diabetic rats compared to controls [31]. Collectively, these experiments provide evidence of disturbances in the time course of shortening, relaxation of shortening, and amplitude of shortening in ventricular myocytes from STZ-induced diabetic rats compared to age-matched healthy controls.

Excitation-Contraction Coupling in Ventricular Myocyte

The arrival of an action potential at a ventricular myocyte causes depolarization of the myocyte plasma membrane and opening of L-type Ca2+ channels. A small entry of Ca2+ through the Ca2+ channels triggers a large release of Ca2+ from the SR via the SR Ca2+ release channels (Ryanodine receptors). There is a transient rise in intracellular Ca2+ concentration, which binds to troponin C and triggers and regulates the process of myocyte contraction. The process of myocyte relaxation takes place when Ca2+ is pumped back into the SR via the SERCA pump and extruded from the myocyte, primarily via the Na+ /Ca2+ exchanger, and also to lesser extents via the plasma membrane Ca2+ ATPase [12-14]. Alterations in intracellular [Ca2+]i and the mechanisms that control intracellular [Ca2+]i including L-type Ca2+ current, SR Ca2+ transport and Na+ /Ca2+ exchange might partly underlie the disturbances reported in myocyte shortening.

Calcium Transport in Ventricular Myocytes from the Streptozotocin-Induced Diabetic Rat

The effects of STZ-induced diabetes on intracellular Ca2+ are shown in Table 9.

Table 9: Intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

Resting fluorescence ratio or calcium

100 iv

4-6 d

1.72 vs. 1.59 RU NSD

[50]

 

65 ip

5-7 d

1.04 vs. 0.98 RU NSD

[51]

 

65 ip

5-7 d

1.04 vs. 1.01 RU NSD

[8]

 

65 iv

7 d

1.00 vs. 0.90 RU

[52]

 

40 iv

3-4 w

Reduced

[15]

 

45 iv

4-6 w

0.306 vs. 0.327 RU NSD

[18]

 

50 ip

5 w

Increased

[17]

 

50 ip

5 w

0.41 vs. 0.49 RU

[57]

 

55 iv

6 w

79 vs. 79 nM NSD

[44]

 

55 ip

7 w

83.1 vs. 119.1 nM RU LV

[5]

 

55 iv

7 w

Reduced

[26]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

60 ip

8-12 w

1.13 vs. 1.08 RU

[47]

 

60 ip

8-12 w

2.10 vs. 2.31RU

[10]

 

60 ip

8-12 w

2.29 vs. 2.40 RU

[43]

 

60 ip

8-12 w

NSD

[28]

 

55 iv

12 w

44 vs. 48 nM

[9]

 

60 ip

12 w

0.71 vs. 0.69 EPI NSD, 0.73 vs. 0.73 ENDO NSD LV

[11]

 

60 ip

13-24 w

1.19 vs. 1.15 RU NSD

[49]

 

65 ip

14 w

Reduced

[54]

 

60 ip

20 w

1.13 vs. 1.17 RU NSD

[48]

Rate of Ca rise (+dP/dt)

55 ip

7 w

78.8 vs. 12.4 f.u/s LV

[5]

 

45-50 ip

7-8 w

39.4 vs. 9.8 f.au/s

[4]

 

45 iv

8 w

98.7 vs. 72.2 f.au/s

[6]

 

45

8 w

90.7 vs. 70.7 f.au/s

[37]

 

55 iv

12 w

Lower

[9]

Rate of Ca decline (-dP/dt)

55 ip

7 w

3.0 vs. 0.6 s-1 LV

[5]

 

45-50 ip

7-8 w

3.7 vs. 1.2 s-1

[4]

 

45

8 w

280.5 vs. 710.0 f.au/ms

[37]

 

55 iv

12 w

Lower

[9]

TPK Ca transient

50 ip

4-5 w

Longer

[56]

 

60 ip

4-8 w

NSD

[16]

 

50 ip

5 w

Prolonged

[17]

 

50 ip

5 w

180 vs. 260 ms

[57]

 

45-50 ip

7-8 w

65.0 vs. 200.2 ms

[4]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

60 ip

8-12 w

NSD

[43]

 

60 ip

8-12 w

NSD

[10]

 

60 ip

8-12 w

NSD

[67]

 

60 ip

8-12 w

NSD

[29]

 

60 ip

8-12 w

64.1 vs. 74.3 ms NSD

[47]

 

60 ip

8-12 w

Prolonged

[28]

 

60 ip

9 w

NSD

[38]

 

55 iv

12 w

Prolonged

[9]

 

60 ip

12 w

56.2 vs. 64.2 EPI ms NSD, 60.6 vs. 71.3 ms ENDO LV

[11]

 

60 ip

13-24 w

63.5 vs. 76.9 ms

[49]

 

60 ip

20 w

65.5 vs. 76.9 ms NSD

[48]

 

 

 

 

 

THALF decay Ca transient

65 ip

5-7 days

130 vs. 170 ms

[8]

 

40 iv

3-4 w

108 vs. 139 ms

[15]

 

50 ip

4-5 w

Longer

[56]

 

60 ip

4-8 w

91.8 vs. 166.5 ms

[16]

 

50 ip

5 w

Prolonged

[17]

 

50 ip

5 w

500 vs. 640 ms LV

[57]

 

50 ip

7 w

231.5 vs. 1076.1 ms LV

[5]

 

45-50 ip

7-8 w

193.2 vs. 742.6 ms

[4]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

45 iv

8 w

260.5 vs. 699.1 ms

[6]

 

60 ip

8-12 w

NSD

[43]

 

60 ip

8-12 w

104.8 vs. 148.4 ms

[67]

 

60 ip

8-12 w

Prolonged

[29]

 

60 ip

8-12 w

NSD

[47]

 

60 ip

8-12 w

215 vs. 267 ms

[10]

 

60 ip

8-12 w

Prolonged

[28]

 

60 ip

9 w

Prolonged

[38]

 

55 iv

12 w

Longer

[9]

 

60 ip

12 w

189.6 vs. 197.5 ms EPI NSD, 150.3 vs 189.1 ms ENDO LV

[11]

 

60 ip

13-24 w

118.4 vs. 160.3 ms

[49]

 

60 ip

20 w

115.4 vs. 159.9 ms

[48]

Tau Ca transient

100 iv

4-6 d

0.5 & 1.0 Hz Increased

[50]

 

40 iv

3-4 w

89.6 vs. 105.2 ms

[15]

 

55 iv

7 w

Elevated

[26]

 

50 ip

8 w

Longer

[32]

 

55 iv

12 w

Longer

[9]

Fluorescence decay time

65 ip

5-7 d

141 vs. 223 ms

[51]

 

65 iv

7 d

248 vs. 320 ms

[52]

 

65 ip

14 w

34 vs. 47 ms

[54]

AMP Ca transient

100 iv

4-6 d

2.00 vs. 1.77 RU

[50]

 

65 iv

7 d

0.5 Hz 4.78 vs. 4.03 FU

2.0 Hz 3.64 vs. 3.50 FU NSD

[27]

 

40 iv

3-4 w

Decreased

[15]

 

50 ip

4-5 w

Decreased

[56]

 

45 iv

4-6 w

0.377 vs. 0.399 RU NSD

[18]

 

60 ip

4-8 w

NSD

[16]

 

50 ip

5 w

Reduced

[17]

 

50 ip

5 w

0.35 vs. 0.23 AU

[57]

 

55 iv

7 w

Reduced

[26]

 

55 ip

7 w

3.0 vs. 1.1 f.u LV

[5]

 

45-50 ip

7-8 w

2.3 vs. 1.1 f.au

[4]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

50 ip

8 w

Decreased

[32]

 

50 ip

8 w

1.82 vs. 1.46 RU

[41]

 

45 iv

8 w

4.4 vs. 3.0 fu

[6]

 

45

8 w

6.1 vs. 3.8 f.au

[37]

 

60 ip

8-12 w

NSD

[43]

 

60 ip

8-12 w

NSD

[67]

 

60 ip

8-12 w

NSD

[29]

 

60 ip

8-12 w

NSD

[47]

 

60 ip

8-12 w

NSD

[46]

 

60 ip

8-12 w

0.29 vs. 0.39 RU

[10]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

9 w

Reduced

[38]

 

55 iv

12 w

Lower

[9]

 

60 ip

12 w

0.17 vs. 0.18 EPI NSD, 0.20 vs. 0.19 RU ENDO NSD LV

[11]

 

60 ip

13-24 w

0.42 vs. 0.43 RU NSD

[49]

 

65 ip

14 w

0.25 vs. 0.21 RU

[54]

 

60 ip

20 w

0.39 vs. 0.47 RU NSD

[48]

RU=Ratio Units, AU=Arbitrary Units, FU=Fluorescence Units, TPK=Time to peak, THALF=Time to half, AMP=Amplitude.NSD=No significant difference

Resting [Ca2+]i was generally unaltered [8,9,11,18,28,43,44,47-49,51,53] but sometimes reduced [15,26,44,52,52,54] in ventricular myocytes from diabetic rats compared to controls. A recent study reported unaltered resting Ca2+ in EPI and ENDO myocytes in EPI and ENDO left ventricular myocytes from STZ-induced diabetic rats compared to controls [11]. TPK Ca2+ transient was either prolonged [9,17,28,49,55,56] or unaltered [10,16,29,38,43,47,48] in myocytes from diabetic rats. THALF decay of the Ca2+ transient was generally prolonged [4-6,8-10,16,17,26,28,29,38,48-52,54-57] in myocytes from diabetic rats compared to controls. A recent study reported prolonged TPK Ca2+ transient and prolonged THALF decay of the Ca2+ transient in ENDO, but not in EPI left ventricular myocytes from STZ-induced diabetic rat [11]. Amplitude of the Ca2+ transient was either unaltered [11,16,18,28,29,43,46- 49,53,55] or lowered[4-6,9,15,17,26,27,31,32,37,38,54,56,57] in ventricular myocytes from diabetic rats. In addition, the rate of Ca2+transient development and decay were lower in ventricular myocytes from STZ-induced diabetic rats compared to controls [4-6,9,37]. Collectively, these experiments provide evidence of disturbances in the time course of development and decay of the Ca2+transient and the amplitude of the Ca2+ transient in ventricular myocytes from STZ-induced diabetic rats compared to controls.

Sarcoplasmic Reticulum Calcium in Ventricular Myocytes from the Streptozotocin-Induced Diabetic R

The effects of STZ-induced diabetes on SR Ca2+ transport are shown in Table 10.

Table 10: Sarcoplasmic reticulum calciumtransport in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

AMP caffeine-evoked Ca transient

40 3-4 w

 

3-4 w

210.1 vs. 140.8 nM Reduced

 

[15]

 

 

50ip

5 w

0.42 vs. 0.36 AU

[57]

 

50 ip

5 w

Reduced

[17]

 

55 6 w

6 w

303 vs. 208 nM. Reduced

[44]

 

60 ip

6-8 w

25.7 vs. 25.9 % NSD

[16]

 

55  ip

7 w

Reduced LV

[5]

 

45-50 ip

7-8 w

0.26 vs. 0.20 RU

[4]

 

60 ip

8 w

NSD

[66]

 

60 ip

8-12 w

NSD

[46]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

8 w

NSD

[65]

 

50 ip

8 w

Reduced

[32]

 

50 ip

8 w

Reduced

[41]

 

55 iv

12 w

Reduced

[9]

 

60 ip

12 w

EPI ENDO LV NSD

[11]

 

65

14 w

0.89 vs. 0.57 RU

[54]

Rate of rise of caffeine-evoked Ca transient

55

7 w

0.014 vs. 0.040 RU/s LV

[5]

 

45-50 ip

7-8 w

0.058 vs. 0.048 RU/s

[4]

 

55 iv

12 w

Decreased

[9]

TPK caffeine-evoked Ca transient

60 ip

6-8 w

250.3 vs.330.1 ms NSD

[16]

 

55 iv

12 w

Prolonged

[9]

Rate of decay of the caffeine-evoked Ca transient

55

 

6 w

38 vs. 14 nM/sec Decreased

 

[44]

 

 

60 ip

6-8 w

0.73 vs. 0.56 RU/s

[16]

 

60iv

8 w

NSD

[30]

 

60 ip

8-12 w

Decreased

[46]

 

55 iv

12 w

Decreased

[9]

THALF decline of the caffeine-evoked Ca transient

60

6-8 w

91.8 vs. 156.1 ms

[16]

 

55 ip

7 w

17.31 vs. 8.66 s LV

[5]

 

45-50 ip

7-8 w

6.70 vs. 11.29 s

[4]

 

60 ip

8-12 w

Prolonged

[29]

 

55 iv

12 w

0.52 vs. 1.00 s

[9]

Tau rate of decline of the caffeine-evoked Ca transient

45-50 ip

7-8 w

0.116 vs. 0.065 s-1

[4]

 

55 iv

12 w

0.54 vs. 1.18 s

[9]

Recovery rate of  electrically-evoked Ca transient after caffeine-evoked Ca transient

40 iv

3-4 w

2.26 vs. 3.15 s NSD

[15]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

NSD

[66]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

8-12 w

Increased

[46]

 

60 ip

12 w

ENDO EPI LV NSD

[11]

SR fractional Ca release

60 ip

6-8 w

89.7 vs. 83.5 NSD

[16]

 

60 ip

8 w

NSD

[65]

 

60 ip

8 w

Increased

[66]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

8-12 w

NSD

[46]

 

60 ip

8-12 w

NSD

[28]

 

60 ip

12 w

ENDO NSD EPI Decreased  LV

[69]

 

60

20 w

NSD

[48]

SR Ca uptake

65 iv

15-27 d

Reduced 21-27 d

[7]

 

55 iv

12 w

0.482 vs. 0.149 µM/s

[9]

SR Ca-stimulated ATPase

65 iv

15-27 d

Reduced 21-27 d

[7]

 

 

 

50 ip

8 w

Decreased

[41]

SR Ca ATPase mRNA

60 ip

8 w

Reduced

[33]

SR Ca ATPase protein (SERCA2)

55 iv

7 w

Reduced

[26]

 

55

7 w

LV NSD

[5]

 

60 ip

8 w

Reduced

[33]

 

50 ip

8 w

Reduced

[41]

 

50

8 w

Reduced

[32]

 

45

8 w

NSD

[37]

 

60 iv

8 w

Reduced

[30]

 

60 ip

12 w

Reduced

[39]

 

55 iv

12 w

Reduced

[9]

 

65 ip

14 w

Reduced

[54]

PLB/PLN protein

55 ip

7 w

NSD LV

[5]

 

55 iv

7 w

NSD

[26]

 

50 ip

8 w

NSD

[41]

 

45

8 w

NSD

[37]

 

60 ip

12 w

Increased

[39]

 

55 iv

12 w

Increased

[9]

PLB/PLN Ser 16/Thr 17 (Phos)

55 ip

7 w

NSD LV

[5]

 

50 ip

8 w

NSD

[41]

 

60 ip

12 w

Reduced

[39]

RyR mRNA

45-50 ip

7-8 w

NSD

[4]

RyR protein

50 ip

4-5 w

Reduced

[56]

 

50 ip

5 w

Reduced

[17]

 

55

7 w

LV NSD

[5]

 

45-50 ip

7-8 w

NSD

[4]

 

45

8 w

NSD

[6]

 

50

8 w

Reduced

[32]

 

45

8 w

NSD

[37]

 

55 iv

12 w

Reduced

[9]

 

65

14 w

Reduced

[54]

RyR2 phosphorylated

50 ip

4-5 w

Increased

[56]

 

50 ip

5 w

Reduced

[17]

 

55 ip

7 w

Increased LV

[5]

Phos RyR2/RyR2

50 ip

4-5 w

Decreased

[56]

Vmax Ca uptake into SR

55 iv

12 w

Decreased

[9]

TPK=Time to peak, THALF=Time to half, AMP=Amplitude.NSD=No significant difference

Rapid application of caffeine stimulates release of Ca2+ from the SR and provides a measure of releasable SR Ca2+ content [58]. Generally, caffeine-evoked Ca2+ transients were reduced [4,5,9,15,17,32,41,44,54,57] or sometimes unaltered [11,16,46] in ventricular myocytes from diabetic rats compared to controls. The rate of rise of the caffeine-evoked Ca2+ transient was slower [4,5,9] in diabetic rat. TPK caffeine-evoked Ca2+ transient was either prolonged [9] or unaltered [16], while the rate of decay of the caffeine-evoked Ca2+ transient was generally decreased [5,9,16,44,46] or sometimes unaltered [30] in diabetic rats compared to controls. In contrast, the THALF decay of the caffeine-evoked Ca2+ transient was prolonged [4,9,16,29] in ventricular myocytes from diabetic rats compared to controls. The recovery rate of electrically-evoked Ca2+ transients following application of caffeine was generally unaltered [11,15,28] or sometimes increased [46]. SR fractional Ca2+ release (electricallyevoked as a fraction of caffeine-evoked Ca2+ transient) was unaltered [16,28,46,48] in ventricular myocytes from diabetic rats compared to controls. Ca2+-stimulated ATPase activity was generally decreased [26,41], but sometimes unaltered [7], SR Ca2+ATPase mRNA was reduced [33] and SR Ca2+ ATPase protein was generally reduced [9,30,32,39,54] or unaltered [5,37] in diabetic rats compared to controls. Ryanodine receptor (RyR) mRNA was unaltered [4]and RyR protein was either reduced [9,17,32,39,54,56] or unaltered [4-6,37] in diabetic rats compared to controls. Moreover, RyR number of functional receptors was decreased [4] RyR activity was decreased [37] and RyR sensitivity to Ca2+ was increased [4,5] in diabetic rats compared to controls. In general, the RyR receptors, which conveyed less current, were more responsive to Ca2+, but instead had reduced threshold for Ca2+ activation and displayed gain of function [6]. In addition calsequestrin mRNA and calsequestrin total protein content were either reduced [33]or unaltered [9,59] in diabetic rats compared to controls.

Calcium Sparks in Ventricular Myocytes from the Streptozotocin-Induced Diabetic Rat

Calcium sparks represent SR Ca2+ release from clusters of ryanodine receptors. The peak amplitude of sparks was either unaltered [17,57], lower [4,5,41] or increased [39] in myocytes from diabetic rat compared to controls. In addition, the spark frequency was either increased [5,6,17,57], reduced [39,41] or unaltered [4], and the duration of sparks was also unaltered [4,5] or reduced [6] in diabetic rats compared to controls. The TPK amplitude of sparks was either prolonged [17,57] or unaltered [39] and the rate of Ca2+ rise was either shorter [4-6] or unaltered [41] in myocytes from diabetic hearts compared to controls. There was also evidence that the THALF decay of sparks were either prolonged [5,17,39,57], or unaltered [6] and SR Ca2+ load was reduced [39] in ventricular myocytes from diabetic rats compared to controls.

L-type Calcium Current and Sodium/Calcium Exchange Currents in Ventricular myocytes from the Streptozotocin-Induced Diabetic Rat

The effects of STZ-induced diabetes on L-type Ca2+ current and Na+/Ca2+ exchange are shown in Table 11 and 12.

Table 11: L-type Ca2+ current in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

Myocyte capacitance

40 iv

3-4 q

127.4 vs. 127.7 pF NSD

[61]

 

40 iv

3-4 w

123 vs. 106 pF NSD

[63]

 

45 iv

4-6 w

134.4 vs. 146.8 pF NSD

[18]

 

60 iv

4-6 w

196.1 vs. 175.7 pF NSD

[60]

 

50 ip

5 w

189.9 vs. 180.6 pF NSD

[57]

 

50 ip

5 w

189.9 vs 180.6 pF NSD

[17]

 

60 ip

8-12 w

NSD

[29]

 

55 iv

12 w

173.82 vs. 112.71 pF

[9]

L-type Ca2+ current density

40 iv

3-4 w

Reduced

[63]

 

40 iv

3-4 w

NSD

[61]

 

60iv

4-6 w

7.5 vs. 8.3 pA/pF NSD

[60]

 

60 ip

4-10 w

Reduced

[16]

 

50

5 w

NSD

[57]

 

45-50

7-8 w

12.0 vs. 11.8 pA/pF NSD

[4]

 

60 ip

8 w

11.27 vs. 7.36 pA/pF

[66]

 

50 iv

8 w

NSD LV

[2]

 

60 ip

8-12 w

Peak  current -0.465 vs. –0.304 nA

[67]

 

60 ip

12 w

Unaltered EPI ENDO LV

[11]

 

65

24-34 w

Reduced

[62]

EPI=Epicardial, ENDO=Endocardial.NSD=No significant differences

Table 12: Sodium/calcium exchange in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter

Dose STZ (mg/kg body weight)

Treatment time

Control vs. STZ

Reference

Na+/Ca2+ exchange current density

40 iv

3-4 w

0.49 vs. 0.33 pA/pF

[63]

 

45iv

4-6 w

3.50 vs. 1.94 pA/pF

[18]

 

50 ip

8 w

Reduced

[41]

Na+/Ca2+ current decay

40 iv

3-4 w

1.59 vs. 3.42  s

[63]

NCX1 protein

45 iv

4-6 w

100 vs. 69 %

[18]

 

60 iv

8 w

NSD

[30]

 

55 iv

12 w

Reduced

[9]

 

65

14 w

Reduced

[54]

 

60 ip

12 w

Reduced

[39]

Reversal potential

45 iv

4-6 w

-96 vs. -89 mV

[18]

NSD=No significant difference

CONCLUSION

Figure 3 summarizes some of the mechanisms of Ca2+ transport that are altered in STZ-induced diabetic rat heart. It is well known that STZ (45-65 mg/kg ip or iv), administered to adult rats, damages pancreatic beta cells and reduces the capacity of these cells to release insulin resulting in hyperglycemia and various other characteristics that are observed in DM. In vivo, and to a certain extent in the isolated perfused heart, contractile function, in terms of amplitude and kinetics of contraction, are frequently disturbed in the STZ-induced diabetic rat heart. These contractile disturbances are due to many factors including alterations in cellular Ca2+ homeostasis, disorganization of the structure of the myocytes, apoptosis, endothelial and mitochondrial dysfunctions, fibrosis and remodeling of the myocardium. In turn, these endogenous processes lead to hemodynamic dysfunction including reduced cardiac output, reduced stroke volume and ejection fraction, reduced percentage of fractional shortening, reduced systolic and increased diastolic pressure, and lower rate of pressure development and decline. In ventricular myocytes, the amplitude of shortening is frequently reduced and the time course of shortening and re-lengthening may be prolonged (delayed contraction) and this can be partly attributed to derangement in cellular Ca2+ transport. Alterations in cellular Ca2+transport,including disturbances in L-type Ca2+current(the primary trigger for SR Ca2+ release), Na+ /Ca2+ exchange current (the major pathway for Ca2+ efflux from the cell), SR Ca2+ content and SR Ca2+ uptake and release mechanism(s) all contribute to contractile dysfunction in the STZ-induced diabetic rat heart.

Table 9: Intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rat.

Parameter Dose STZ (mg/kg 
body weight)
Treatment time Control vs. STZ Reference
Resting fluorescence ratio 
or calcium
100 iv 4-6 d 1.72 vs. 1.59 RU NSD [50]
  65 ip 5-7 d 1.04 vs. 0.98 RU NSD [51]
  65 ip 5-7 d 1.04 vs. 1.01 RU NSD [8]
  65 iv 7 d 1.00 vs. 0.90 RU [52]
  40 iv 3-4 w Reduced [15]
  45 iv 4-6 w 0.306 vs. 0.327 RU NSD [18]
  50 ip 5 w Increased [17]
  50 ip 5 w 0.41 vs. 0.49 RU [44]
  55 iv 6 w 79 vs. 79 nM NSD [5]
  55 ip 7 w 83.1 vs. 119.1 nM RU LV [26]
  55 iv 7 w Reduced [65]
  60 ip 8 w NSD [66]
  60 ip 8 w NSD [47]
  60 ip 8-12 w 1.13 vs. 1.08 RU [10]
  60 ip 8-12 w 2.10 vs. 2.31RU [26]
  60 ip 8-12 w 2.29 vs. 2.40 RU [10]
  60 ip 8-12 w NSD [43]
  55 iv 12 w 44 vs. 48 nM [28]
  60 ip 12 w 0.71 vs. 0.69 EPI NSD, 0.73 vs. 0.73 ENDO NSD LV [9]
  60 ip 13-24 w 1.19 vs. 1.15 RU NSD [11]
  65 ip 14 w Reduced [49]
  60 ip 20 w 1.13 vs. 1.17 RU NSD [54]
Rate of Ca rise (+dP/dt) 55 ip 7 w 78.8 vs. 12.4 f.u/s LV [48]
  45-50 ip 8 w 39.4 vs. 9.8 f.au/s [5]
  45 iv 8 w 98.7 vs. 72.2 f.au/s [4]
  45 12 w 90.7 vs. 70.7 f.au/s [6]
  55 iv 7 w Lower [37]
Rate of Ca decline (-dP/dt) 55 ip 7-8 w 3.0 vs. 0.6 s-1 LV [9]
  45-50 ip 8 w 3.7 vs. 1.2 s-1 [5]
  45 12 w 280.5 vs. 710.0 f.au/ms [4]
  55 iv 4-5 w Lower [37]
TPK Ca transient 50 ip 4-8 w Longer [9]
  60 ip 5 w NSD [56]
  50 ip 5 w Prolonged [16]
  50 ip 7-8 w 180 vs. 260 ms [57]
  45-50 ip 8 w 65.0 vs. 200.2 ms [4]
  60 ip 8 w NSD [66]
  60 ip 8-12 w NSD [43]
  60 ip 8-12 w NSD [10]
  60 ip 8-12 w NSD [67]
  60 ip 8-12 w NSD [29]
  60 ip 8-12 w 64.1 vs. 74.3 ms NSD [47]
  60 ip 8-12 w Prolonged [28]
  60 ip 9 w NSD [38]
  55 iv 12 w Prolonged [9]
  60 ip 12 w 56.2 vs. 64.2 EPI ms NSD, 60.6 vs. 71.3 ms ENDO LV [11]
  60 ip 13-24 w 63.5 vs. 76.9 ms [49]
  60 ip 20 w 65.5 vs. 76.9 ms NSD [48]
THALF decay Ca transient 65 ip 5-7 days 130 vs. 170 ms [8]
  40 iv 3-4 w 108 vs. 139 ms [15]
  50 ip 4-5 w Longer [56]
  60 ip 4-8 w 91.8 vs. 166.5 ms [16]
  50 ip 5 w Prolonged [17]
  50 ip 5 w 500 vs. 640 ms LV [57]
  50 ip 7 w 231.5 vs. 1076.1 ms LV [5]
  45-50 ip 7-8 w 193.2 vs. 742.6 ms [4]
  60 ip 8 w NSD [65]
  60 ip 8 w NSD [66]
  45 iv 8 w 260.5 vs. 699.1 ms [6]
  60 ip 8-12 w NSD [43]
  60 ip 8-12 w 104.8 vs. 148.4 ms [67]
  60 ip 8-12 w Prolonged [20]
  60 ip 8-12 w NSD [47]
  60 ip 8-12 w 215 vs. 267 ms [10]
  60 ip 8-12 w Prolonged [28]
  60 ip 9 w Prolonged [38]
  55 iv 12 w Longer [9]
  60 ip 12 w 189.6 vs. 197.5 ms EPI NSD, 150.3 vs 189.1 ms 
ENDO LV
[11]
  60 ip 13-24 w 118.4 vs. 160.3 ms [49]
  60 ip 20 w 115.4 vs. 159.9 ms [48]
Tau Ca transient 100 iv 4-6 d 0.5 & 1.0 Hz Increased [50]
  40 iv 3-4 w 89.6 vs. 105.2 ms [15]
  55 iv 7 w Elevated [26]
  50 ip 8 w Longer [32]
  55 iv 12 w Longer [9]
Fluorescence decay time 65 ip 5-7 d 141 vs. 223 ms [51]
  65 iv 7 d 248 vs. 320 ms [52]
  65 ip 14 w 34 vs. 47 ms [54]
AMP Ca transient 100 iv 4-6 d 2.00 vs. 1.77 RU [50]
  65 iv 7 d 0.5 Hz 4.78 vs. 4.03 FU
2.0 Hz 3.64 vs. 3.50 FU NSD
[27]
  40 iv 3-4 w Decreased [15]
  50 ip 4-5 w Decreased [56]
  45 iv 4-6 w 0.377 vs. 0.399 RU NSD [18]
  60 ip 4-8 w NSD [16]
  50 ip 5 w Reduced [17]
  50 ip 5 w 0.35 vs. 0.23 AU [57]
  55 iv 7 w Reduced [26]
  55 ip 7 w 3.0 vs. 1.1 f.u LV [5]
  45-50 ip 7-8 w 2.3 vs. 1.1 f.au [4]
  60 ip 8 w NSD [65]
  60 ip 8 w NSD [66]
  50 ip 8 w Decreased [32]
  50 ip 8 w 1.82 vs. 1.46 RU [41]
  45 iv 8 w 4.4 vs. 3.0 fu [6]
  45 8 w 6.1 vs. 3.8 f.au [37]
  60 ip 8-12 w NSD [43]
  60 ip 8-12 w NSD [67]
  60 ip 8-12 w NSD [29]
  60 ip 8-12 w NSD [47]
  60 ip 8-12 w NSD [46]
  60 ip 8-12 w 0.29 vs. 0.39 RU [10]
  60 ip 8-12 w NSD [28]
  60 ip 9 w Reduced [38]
  55 iv 12 w Lower [9]
  60 ip 12 w 0.17 vs. 0.18 EPI NSD, 0.20 vs. 0.19 RU ENDO NSD LV [11]
  60 ip 13-24 w 0.42 vs. 0.43 RU NSD [49]
  65 ip 14 w 0.25 vs. 0.21 RU [54]
  60 ip 20 w 0.39 vs. 0.47 RU NSD [48]
RU=Ratio Units, AU=Arbitrary Units, FU=Fluorescence Units, TPK=Time to peak, THALF=Time to half, AMP=Amplitude.NSD=No significant difference

Table 10: Sarcoplasmic reticulum calciumtransport in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter Dose STZ (mg/kg body 
weight)
Treatment time Control vs. STZ Reference
AMP caffeine-evoked Ca 
transient
40 3-4 w 3-4 w 210.1 vs. 140.8 nM Reduced [15]
  50ip 5 w 0.42 vs. 0.36 AU [57]
  50ip 5 w Reduced [17]
  55 6 w 6 w 303 vs. 208 nM. Reduced [44]
  60 ip 6-8 w 25.7 vs. 25.9 % NSD [5]
  55 ip 7 w Reduced LV [4]
  45-50 ip 7-8 w 0.26 vs. 0.20 RU [66]
  60 ip 8 w NSD [46]
  60 ip 8-12 w NSD [28]
  60 ip 8-12 w NSD [65]
  60 ip 8 w NSD [32]
  50 ip 8 w Reduced [66]
  50 ip 8 w Reduced [46]
  55 iv 12 w Reduced [28]
  60 ip 12 w EPI ENDO LV NSD [65]
  65 14 w 0.89 vs. 0.57 RU [32]
Rate of rise of caffeine-evoked 
Ca transient
55 7 w 0.014 vs. 0.040 RU/s LV [41]
  45-50 ip 7-8 w 0.058 vs. 0.048 RU/s [9]
  55 iv 12 w Decreased [11]
TPK caffeine-evoked Ca transient 60 ip 6-8 w 250.3 vs.330.1 ms NSD [54]
  55 iv 12 w Prolonged [5]
Rate of decay of the caffeineevoked Ca transient 55 6 w 38 vs. 14 nM/sec Decreased [4]
  60 ip 6-8 w 0.73 vs. 0.56 RU/s [9]
  60iv 8 w NSD [16]
  60 ip 8-12 w Decreased [9]
  55 iv 12 w Decreased [44]
THALF decline of the caffeineevoked Ca transien 60 6-8 w 91.8 vs. 156.1 ms [16]
  55 ip 7 w 17.31 vs. 8.66 s LV [5]
  45-50 ip 7-8 w 6.70 vs. 11.29 s [4]
  60 ip 8-12 w Prolonged [29]
  55 iv 12 w 0.52 vs. 1.00 s [9]
Tau rate of decline of the caffeine-evoked Ca transient 45-50 ip 7-8 w 0.116 vs. 0.065 s-1 [4]
  55 iv 12 w 0.54 vs. 1.18 s [9]
Recovery rate of electricallyevoked Ca transient after caffeine-evoked Ca transient 40 iv 3-4 w 2.26 vs. 3.15 s NSD [15]
  60 ip 8 w NSD [65]
  60 ip 8 w NSD [66]
  60 ip 8-12 w NSD [28]
  60 ip 8-12 w Increased [46]
  60 ip 12 w ENDO EPI LV NSD [11]
  60 ip 6-8 w 89.7 vs. 83.5 NSD [16]
  60 ip 8 w NSD [65]
  60 ip 8 w Increased [66]
  60 ip 8-12 w NSD [28]
  60 ip 8-12 w NSD [46]
  60 ip 8-12 w NSD [28]
  60 ip 12 w ENDO NSD EPI Decreased LV [69]
  60 20 w NSD [48]
SR Ca uptake 65 iv 15-27 d Reduced 21-27 d [7]
  55 iv 12 w 0.482 vs. 0.149 µM/s [9]
SR Ca-stimulated ATPase 65 iv 15-27 d Reduced 21-27 d [7]
  50 ip 8 w Decreased [41]
SR Ca ATPase mRNA 60 ip 8 w Reduced [33]
SR Ca ATPase protein 
(SERCA2)
55 iv 7 w Reduced [26]
  55 7 w LV NSD [5]
  60 ip 8 w Reduced [33]
  50 ip 8 w Reduced [41]
  50 8 w Reduced [32]
  45 8 w NSD [37]
  60 iv 8 w Reduced [30]
  60 ip 12 w Reduced [39]
  55 iv 12 w Reduced [9]
  65 ip 14 w Reduced [54]
PLB/PLN protein 55 ip 7 w NSD LV [5]
  55 iv 7 w NSD [26]
  50 ip 8 w NSD [41]
  45 8 w NSD [37]
  60 ip 12 w Increased [39]
  55 iv 12 w Increased [9]
PLB/PLN Ser 16/Thr 17 
(Phos)
55 ip 7 w NSD LV [5]
  50 ip 8 w NSD [41]
  60 ip 12 w Reduced [39]
RyR mRNA 45-50 ip 7-8 w NSD [4]
RyR protein 50 ip 4-5 w Reduced [56]
  50 ip 5 w Reduced [17]
  55 7 w LV NSD [5]
  45-50 ip 7-8 w NSD [4]
  45 8 w NSD [6]
  50 8 w Reduced [32]
  45 8 w NSD [37]
  55 iv 12 w Reduced [9]
  65 14 w Reduced [54]
RyR2 phosphorylated 50 ip 4-5 w Increased [56]
  50 ip 5 w Reduced [17]
  55 ip 7 w Increased LV [5]
Phos RyR2/RyR2 50 ip 4-5 w Decreased [56]
Vmax Ca uptake into SR 55 iv 12 w Decreased [9]
TPK=Time to peak, THALF=Time to half, AMP=Amplitude.NSD=No significant difference

Table 11: L-type Ca2+ current in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter Dose STZ (mg/kg body 
weight)
Treatment time Control vs. STZ Reference
Myocyte capacitance 40 iv 3-4 q 127.4 vs. 127.7 pF NSD [61]
  40 iv 3-4 w 123 vs. 106 pF NSD [63]
  45 iv 4-6 w 134.4 vs. 146.8 pF NSD [18]
  60 iv 4-6 w 196.1 vs. 175.7 pF NSD [60]
  50 ip 5 w 189.9 vs. 180.6 pF NSD [57]
  50 ip 5 w 189.9 vs 180.6 pF NSD [17]
  60 ip 8-12 w NSD [29
  55 iv 12 w 173.82 vs. 112.71 pF [9]
L-type Ca2+ current density 40 iv 3-4 w Reduced [63]
  40 iv 3-4 w NSD [61]
  60iv 4-6 w 7.5 vs. 8.3 pA/pF NSD [60]
  60 ip 4-10 w Reduced [16]
  50 5 w NSD [57]
  45-50 7-8 w 12.0 vs. 11.8 pA/pF NSD [4]
  60 ip 8 w 11.27 vs. 7.36 pA/pF [66]
  50 iv 8 w NSD LV [2]
  60 ip 8-12 w Peak current -0.465 vs. –0.304 
nA
[67]
  60 ip 12 w Unaltered EPI ENDO LV [11]
  65 24-34 w Reduced [62]
EPI=Epicardial, ENDO=Endocardial.NSD=No significant difference

Table 12: Sodium/calcium exchange in ventricular myocytes from the streptozotocin-induced diabetic rat.

Parameter Dose STZ (mg/kg body 
weight)
Treatment time Control vs. STZ Reference
Na+/Ca2+ exchange current 
density
40 iv 3-4 w 0.49 vs. 0.33 pA/pF [63]
  45iv 4-6 w 3.50 vs. 1.94 pA/pF [18]
  50 ip 8 w Reduced [41]
Na+ /Ca2+ current decay 40 iv 3-4 w 1.59 vs. 3.42 s [63]
NCX1 protein 45 iv 4-6 w 100 vs. 69 % [18]
  60 iv 8 w NSD [30]
  55 iv 12 w Reduced [9]
  65 14 w Reduced [54]
  60 ip 12 w Reduced [39]
Reversal potential 45 iv 4-6 w -96 vs. -89 mV [18]
NSD=No significant difference

 

ACKNOWLEDGMENTS

Grants from the College of Medicine & Health Sciences, United Arab Emirates University, Al Ain; United Arab Emirates University, Al Ain; Sheikh Hamdan Bin Rashid Al Maktoum Award, Dubai; Zayed University, Abu Dhabi.

REFERENCES

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Received : 16 Sep 2017
Accepted : 28 Sep 2017
Published : 29 Sep 2017
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