• Users Online: 481
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 12  |  Issue : 3  |  Page : 111-118

Contraction and intracellular calcium transport in epicardial and endocardial ventricular myocytes from streptozotocin-induced diabetic rat


1 Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, UAE
2 School of Forensic and Applied Sciences, University of Central Lancashire, Preston, England, UK
3 Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi, UAE

Date of Submission13-May-2018
Date of Acceptance16-May-2018
Date of Web Publication23-Aug-2019

Correspondence Address:
Frank Christopher Howarth
Department of Physiology, College of Medicine and Health Sciences, UAE University, P.O. Box 17666, Al Ain
UAE
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HMJ.HMJ_32_18

Rights and Permissions
  Abstract 


Introduction: Diabetes mellitus (DM) is a global health problem. According to the International Diabetes Federation, 424.9 million people suffered from DM in 2017 and this number is expected to rise to 628.6 million by 2045. Although diabetes can affect every organ in the body, cardiovascular disease is a major cause of death and disability in people with diabetes. Diabetic patients frequently suffer from systolic and diastolic dysfunction. Within the ventricles, the electromechanical properties of cardiac myocytes vary transmurally. Aims and Objectives: The aim of this study was to investigate contraction and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) myocytes from the left ventricle in the streptozotocin (STZ) – induced diabetic rat heart. Materials and Methods: Experiments were performed 5-6 months after STZ treatment. Ventricular myocytes were isolated by enzymic and mechanical dispersal techniques from EPI and ENDO regions of the left ventricle. Contraction and free intracellular Ca2+ concentration [Ca2+]i were measured by video edge detection and fluorescence photometry techniques, respectively. Results: Myocyte length and calculated surface area were smaller in EPI-STZ compared to EPI-CON. Time to peak (TPK) shortening was prolonged in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON myocytes. Time to half (THALF) relaxation of shortening was prolonged in EPI-STZ compared to EPI-CON. TPK Ca2+ transient was prolonged in EPI-STZ compared to EPI-CON, ENDO-STZ compared to ENDO-CON, ENDO-STZ compared to EPI-STZ and in ENDO-CON compared to EPI-CON myocytes. THALF decay of the Ca2+ transient was prolonged in ENDO-STZ compared to ENDO-CON. Fractional release of Ca2+ was increased in ENDO-STZ compared to ENDO-CON and in ENDO-STZ compared to EPI-STZ. Recovery of the Ca2+ transient was prolonged in ENDO-STZ compared to ENDO-CON. Conclusion: In conclusion the kinetics of contraction and Ca2+ transient and fractional release of Ca2+ from the sarcoplasmic reticulum are altered to different extents in EPI and ENDO myocytes from STZ-induced diabetic rat.

Keywords: Epicardial and endocardial myocytes, intracellular Ca2+, myocyte contraction, rat heart ventricle, streptozotocin-induced diabetes


How to cite this article:
Howarth FC, A. Smail MM, Qureshi MA, Shmygol A, Singh J, Al Kury L. Contraction and intracellular calcium transport in epicardial and endocardial ventricular myocytes from streptozotocin-induced diabetic rat. Hamdan Med J 2019;12:111-8

How to cite this URL:
Howarth FC, A. Smail MM, Qureshi MA, Shmygol A, Singh J, Al Kury L. Contraction and intracellular calcium transport in epicardial and endocardial ventricular myocytes from streptozotocin-induced diabetic rat. Hamdan Med J [serial online] 2019 [cited 2019 Sep 18];12:111-8. Available from: http://www.hamdanjournal.org/text.asp?2019/12/3/111/237848




  Introduction Top


Diabetes mellitus (DM) is a global health problem. According to the International Diabetes Federation, 424.9 million people suffered from DM in 2017 and this number is expected to rise to 628.6 million by 2045 (http://www.diabetesatlas.org/resources/2017-atlas.html). Although DM can affect every organ in the body, cardiovascular disease is a major cause of death and disability in people with diabetes.[1],[2],[3] Diabetic patients frequently suffer from systolic and diastolic dysfunction.[4],[5],[6] The streptozotocin (STZ)-induced diabetic rat is a widely used experimental model of DM. STZ causes damage to the pancreatic β-cells, which in turn leads to a reduction in insulin synthesis and release and a consequent rise in blood glucose.[7],[8] Abnormalities in a variety of haemodynamic indices including stroke volume, ejection fraction, cardiac output, rate of pressure development and relaxation have been widely demonstrated in the STZ-induced diabetic heart.[9],[10],[11],[12] At the level of the individual ventricular myocyte, many studies have demonstrated prolonged time course of contraction and relaxation[13],[14] and either unaltered or reduced amplitude of shortening.[15],[16] These alterations in contraction are attributed, at least in part, to disturbances in Ca2+ transport.[9],[10],[14],[17] Within the ventricles, the electromechanical properties of cardiac myocytes vary transmurally and this may be related to the gradients of stress and strain experienced in vivo across the ventricular walls. Electrophysiological heterogeneity across the ventricular wall is a result of differential transmural expression of various ion channel proteins that underlie the different action potential waveforms observed in epicardial (EPI) and endocardial (ENDO) regions.[18],[19],[20] To date, many of the single-cell studies have been performed in ventricular myocytes obtained from whole ventricle. Very little is known about the regional effects of STZ-induced diabetes across the ventricles. The aim of the current study was to investigate the effects of DM after 5–6 months of STZ-treatment on contraction and Ca2+ transport in EPI and ENDO myocytes from the left ventricle of rat heart compared to healthy controls.


  Methods Top


Experimental model

Experiments were performed in the STZ-induced diabetic rat, a well-characterised animal model of DM.[7],[8] Diabetes was induced in young adult (220–250 g) male Wistar rats with a single intraperitoneal injection of STZ (60 mg/kg body weight) in citrate buffer. Age-matched control rats received an injection of citrate buffer alone. Body weight, heart weight and non-fasting blood glucose (OneTouch Ultra 2, LifeScan) were measured immediately before experiments. Experiments were performed in EPI and ENDO myocytes, 5–6 months after STZ treatment. Ethical approval for this project was obtained from the UAE University Animal Research Ethics Committee and experiments were performed in accordance with institutional guidelines.

Isolation of ventricular myocytes

Ventricular myocytes were isolated by enzymatic and mechanical dispersal techniques according to previously described techniques.[21] After rats were euthanised with a guillotine hearts were rapidly removed and mounted on a Langendorff perfusion system. Hearts were perfused with cell isolation solution at a flow rate of 8 ml.g heart–1 min–1 at a temperature of 36–37°C. The cell isolation solution contained in mmol/l: 130.0 NaCl, 5.4 KCl, 1.4 MgCl2, 0.75 CaCl2, 0.4 NaH2 PO4, 5.0 HEPES, 10.0 glucose, 20.0 taurine and 10.0 creatine (pH adjusted to 7.3 with NaOH). When contraction of the heart had stabilised, perfusion was switched for 4 min to Ca2+-free cell isolation solution containing 0.1 mmol/l EGTA, and then for 6 min to cell isolation solution containing 0.05 mmol/l Ca2+, 0.60 mg/ml Type 1 collagenase (Worthington Biochemical Corp, Lakewood, NJ, USA) and 0.075 mg/ml Type XIV protease (Sigma, Taufkirchen, Germany). After enzyme treatment, the heart was removed from the perfusion system and the left ventricle was carefully dissected according to previously described techniques.[21] Using fine scissors, thin sections were dissected from the outermost layer of the left ventricle (EPI) and innermost layer of the left ventricle (ENDO). The sections were carefully minced and gently shaken in collagenase-containing isolation solution supplemented with 1% BSA. Cells were filtered from this solution at 4-min intervals and resuspended in cell isolation solution containing 0.75 mmol/l Ca2+.

Ventricular myocyte shortening

Ventricular myocyte shortening was measured according to previously described techniques.[21] Cells were superfused (3–5 ml/min) with normal Tyrode containing the following in mmol/l: 140.0 NaCl, 5.0 KCl, 1.0 MgCl2, 10.0 glucose, 5.0 HEPES and 1.8 CaCl2(pH 7.4). Unloaded EPI and ENDO myocyte shortening were recorded using a video edge detection system (VED-114, Crystal Biotech, Northborough, MA, USA). Resting cell length, time to peak (TPK) shortening, time to half (THALF) relaxation and amplitude of shortening (expressed as a % of resting cell length) were measured in electrically stimulated (1 Hz) myocytes maintained at 35°C–36°C. Data were acquired and analysed with Signal Averager software v 6.37 (Cambridge Electronic Design, Cambridge, UK).

Intracellular Ca2+

Intracellular (Ca2+) was measured in Fura-2/AM-loaded myocytes according to previously described techniques.[21] Myocytes were alternately illuminated by 340 nm and 380 nm light using a monochromator (Cairn Research, Faversham, UK) which changed the excitation light every 2 ms. The resulting fluorescence, emitted at 510 nm, was recorded by a photomultiplier tube and the ratio of the emitted fluorescence at the two excitation wavelengths (340/380 ratio) provided an index of intracellular Ca2+ concentration. Resting Fura-2 ratio, TPK Ca2+ transient, THALF decay of the Ca2+ transient and the amplitude of the Ca2+ transient were measured in electrically stimulated (1 Hz) myocytes maintained at 35–36°C. Data were acquired and analysed with Signal Averager software v 6.37 (Cambridge Electronic Design, Cambridge, UK).

Measurement of sarcoplasmic reticulum Ca2+ transport

Sarcoplasmic reticulum (SR) Ca2+ was assessed using previously described techniques.[21] Fura-2/AM-loaded myocytes were stimulated electrically (1 Hz) and maintained at 35–36°C. When the Ca2+ transients had reached a steady state, electrical stimulation was paused for 5 s. Caffeine (20 mM) was then applied for 10 s using a rapid solution switching device.[22] Electrical stimulation was then restarted and the Ca2+ transients were allowed to recover to steady state. Fractional release of SR Ca2+ was calculated by comparing the amplitude of the electrically-evoked steady state Ca2+ transients with that of the caffeine-evoked Ca2+ transient. Ca2+ refilling of the SR was assessed by measuring the rate of recovery of electrically-evoked Ca2+ transients following application of caffeine.

Assessment of myofilament sensitivity to Ca2+

In some cells shortening and Fura-2 ratio were recorded simultaneously as previously described.[23] Myofilament sensitivity to Ca2+ was assessed from phase-plane diagrams of Fura-2 ratio versus cell length by measuring the gradient of the Fura-2-cell length trajectory during late relaxation of the twitch contraction. The position of the trajectory reflects the relative myofilament response to Ca2+ and hence can be used as a measure of myofilament sensitivity to Ca2+.[24],[25]

Statistics

The results were expressed as the mean ± standard error of mean of “n” observations. Statistical comparisons were performed using the Independent samples t-test or one-way ANOVA followed by Bonferroni-corrected t-tests for multiple comparisons, as appropriate. P < 0.05 was considered statistically significant.


  Results Top


General characteristics

Body weight and heart weight were reduced, while heart weight/body weight and non-fasting blood glucose were increased in STZ-induced diabetic rats compared to age-matched controls [Table 1].
Table 1: General characteristics of streptozotocin-induced diabetic rats compared to controls

Click here to view


Ventricular myocyte shortening

Cell width was not significantly (P > 0.05) altered in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON [Figure 1]a. Cell length was significantly (P < 0.05) shorter [Figure 1]b and calculated surface area [Figure 1]c was significantly (P < 0.05) smaller in EPI-STZ compared to EPI-CON (n = 20–53 cells from 6 hearts). Typical recordings of myocyte shortening in ENDO-CON and ENDO-STZ myocytes are shown in [Figure 2]a. TPK shortening was significantly prolonged in EPI-STZ (102.4 ± 4.7 ms) compared to EPI-CON (77.0 ± 1.8 ms) and in ENDO-STZ (100.2 ± 4.1 ms) compared to ENDO-CON (82.2 ± 2.7 ms) myocytes (n = 33–52 cells from 13 hearts) [Figure 2]b. THALF relaxation of shortening was significantly prolonged in EPI-STZ (67.0 ± 6.4 ms) compared to EPI-CON (46.5 ± 2.2 ms) and was not significantly altered in ENDO-STZ (56.6 ± 4.4 ms) compared to ENDO-CON (48.4 ± 2.8 ms) myocytes (n = 33–52 cells from 13 hearts) [Figure 2]c. Amplitude of shortening was not significantly altered in EPI-STZ compared to EPI-CON or in ENDO-STZ compared to ENDO-CON myocytes [n = 33–52 cells from 13 hearts; [Figure 2]d.
Figure 1: Cell width (a), cell length (b) and calculated cell surface area (c) in epicardial and endocardial left ventricular myocytes from streptozotocin and control rats. Data are mean ± standard error of mean, n = 20–53 cells from 6 hearts

Click here to view
Figure 2: Typical recordings of shortening in ENDO-CON and ENDO-STZ myocytes (a), time to peak shortening (b), time to half relaxation of shortening (c) and amplitude of shortening (d) in epicardial and endocardial left ventricular myocytes from streptozotocin and control rats. Data are mean ± standard error of mean, n = 33–52 cells from 13 hearts

Click here to view


Intracellular Ca2+ transients

Typical recordings of Ca2+ transients in ENDO-CON and ENDO-STZ myocytes are shown in [Figure 3]a. Resting Fura-2 ratio was not significantly altered in EPI-STZ compared to EPI-CON or in ENDO-STZ compared to ENDO-CON myocytes (n = 53–59 cells from 11 to 12 hearts) [Figure 3]b. TPK Ca2+ transient was significantly prolonged in EPI-STZ (62.6 ± 2.0 ms) compared to EPI-CON (53.0 ± 0.8 ms) and in ENDO-STZ (68.8 ± 1.9 ms) compared to ENDO-CON (59.8 ± 1.4 ms); myocytes TPK Ca2+ transient was also significantly prolonged in ENDO-STZ compared to EPI-STZ and in ENDO-CON compared to EPI-CON myocytes (n = 53–59 cells from 11 to 12 hearts) [Figure 3]c. THALF decay of the Ca2+ transient was not significantly altered in EPI-STZ (210.2 ± 9.1 ms) compared to EPI-CON (190.0 ± 9.6 ms) and was significantly prolonged in ENDO-STZ (210.4 ± 7.0 ms) compared to ENDO-CON (165.3 ± 6.3 ms) myocytes (n = 53–59 cells from 11 to 12 hearts) [Figure 3]d. Amplitude of the Ca2+ transient was not significantly altered in EPI-STZ compared to EPI-CON or in ENDO-STZ compared to ENDO-CON myocytes [n = 53–59 cells from 11 to 12 hearts; [Figure 3]e.
Figure 3: Typical recordings of Ca2+ transients in ENDO-CON and ENDO-STZ myocytes (a), resting Fura-2 ratio (b), time to peak Ca2+ transient (c), time to half decay of the Ca2+ transient (d) and amplitude of the Ca2+ transient (e) in epicardial and endocardial left ventricular myocytes from streptozotocin and control rats. Data are mean ± standard error of mean, n = 53–59 cells from 11 to 12 hearts

Click here to view


Sarcoplasmic reticulum Ca2+ transport

A typical recording of electrically-evoked Ca2+ transients followed, after a brief pause, by a caffeine-evoked Ca2+ transient, followed by recovery of Ca2+ transients during electrical stimulation in an ENDO-CON myocyte is shown in [Figure 4]a. Amplitude of the electrically-evoked Ca2+ transient was Significantly larger in ENDO-STZ compared to EPI-CON [Figure 4]b, amplitude of the caffeine-evoked Ca2+ transient [Figure 4]c and area under the curve of the caffeine-evoked Ca2+ transient [Figure 4]d were not significantly altered in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON myocytes (n = 16–22 cells from 4 to 6 hearts). Fractional release of Ca2+ was not significantly altered in EPI-STZ (0.72 ± 0.04) compared to EPI-CON (0.69 ± 0.03) and was increased in ENDO-STZ (0.88 ± 0.02) compared to ENDO-CON (0.63 ± 0.07) myocytes. Fractional release was also significantly increased in ENDO-STZ compared to EPI-STZ myocytes (n = 16–22 cells from 4 to 6 hearts) [Figure 4]e. Amplitude of Ca2+ transient data presented in [Figure 3]e and [Figure 4]b were acquired in different sets of experiments. It was interesting to note that in [Figure 3]e the amplitude of Ca2+ transient was unaltered in EPI-STZ and ENDO-STZ compared to respective controls however, in [Figure 4]b the amplitude of the Ca2+ transient was significantly (P < 0.05) increased in ENDO-STZ compared to ENDO-CON myocytes. These results show that in this model of DM there may be variability in results between sets of experiments. The rate of recovery of the electrically-evoked Ca2+ transient, following application of caffeine, was not significantly altered in EPI-STZ compared to EPI-CON but was increased in ENDO-STZ compared to ENDO-CON myocytes [n = 16–22 cells from 4 to 6 hearts; [Figure 4]f.
Figure 4: Typical recording of electrically-evoked Ca2+ transients and a caffeine-evoked Ca2+ transient in an ENDO-CON myocyte (a), amplitude of the electrically-evoked Ca2+ transient (b), amplitude of caffeine-evoked Ca2+ transient (c), area under the curve of the caffeine-evoked Ca2+ transient (d), fractional release of Ca2+ (e) and recovery of the Ca2+ transient after caffeine application and resumption of electrical stimulation (f). Data are mean ± standard error of mean, n = 16–22 cells from 4 to 6 hearts. ES = Electrical stimulation

Click here to view


Myofilament sensitivity to Ca2+

A typical simultaneous recording of shortening and Ca2+ transient and of Fura-2 ratio plotted against cell length are shown in [Figure 5]a. Myofilament sensitivity to Ca2+ was not significantly altered in EPI-STZ compared to EPI-CON or in ENDO-STZ compared to ENDO-CON [Figure 5]b.
Figure 5: Typical simultaneous recording of shortening and Ca2+ in an ENDO-CON myocyte (left panel) and typical phase plane diagram of Fura-2 ratio unit versus cell length (right panel) in an ENDO-CON myocyte. The line and arrow indicate where measurements were made (a), Graph showing mean gradient of the Fura-2-cell length trajectory during late relaxation of the twitch contraction during the period 500–800 ms (b). Data are mean ± standard error of mean, n = 26–29 cells from 5 hearts

Click here to view



  Discussion Top


The main findings of this study were as follows: (1) Cell length was shorter in EPI-STZ compared to EPI-CON; (2) TPK shortening was prolonged in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON; (3) THALF relaxation of shortening was prolonged in EPI-STZ compared to EPI-CON; (4) TPK Ca2+ transient was prolonged in EPI-STZ compared to EPI-CON, ENDO-STZ compared to ENDO-CON, ENDO-STZ compared to EPI-STZ and in ENDO-CON compared to EPI-CON; (5) THALF decay of the Ca2+ transient was prolonged in ENDO-STZ compared to ENDO-CON; (6) Fractional release of Ca2+ was increased in ENDO-STZ compared to ENDO-CON and in ENDO-STZ compared to EPI-STZ and (7) Ca2+ transient recovery was prolonged in ENDO-STZ compared to ENDO-CON.

The results show that blood glucose was 5-fold higher in STZ-induced diabetic rats compared to controls. STZ causes damage to β-cells which in turn leads to a reduction in synthesis and release of insulin and consequent elevation of blood glucose.[7],[8] Consistent with many previous studies STZ rats had reduced body weight and reduced heart weight, yet their heart weight/body weight ratio was larger compared to controls suggesting cardiac hypertrophy.[21],[26],[27] After 3 months of STZ treatment, a previous study has shown that EPI and ENDO myocyte lengths were unaltered.[21] However, in the current study, after 5–6 months of STZ treatment, the lengths of EPI and ENDO myocytes were smaller compared to respective controls.

TPK shortening was prolonged, and to similar extents, in EPI-STZ and ENDO-STZ compared to respective controls. THALF relaxation of shortening was prolonged only in EPI-STZ compared to EPI-CON. Amplitude of shortening was not altered in EPI and ENDO myocytes from STZ rat compared to controls. Previous studies have also reported prolonged TPK in myocytes isolated from whole ventricle and EPI and ENDO myocytes after 3 months of STZ treatment.[14],[21],[28],[29] Interestingly, THALF relaxation was only significantly prolonged in EPI-STZ compared to EPI-CON myocytes suggesting regional differences in the effects of DM on the kinetics of contraction. A previous study reported prolonged THALF relaxation in ENDO-STZ compared to ENDO-CON after 3 months of STZ treatment suggesting that the effects on dynamics of contraction alter with duration of DM.[21] Although the kinetics of contraction were altered the amplitude of contraction was not altered in EPI and ENDO myocytes from diabetic rat compared to respective controls and this was also previously the case after 3 months of STZ treatment.[21]

TPK Ca2+ transient was prolonged in EPI-STZ compared to EPI-CON and in ENDO-STZ compared to ENDO-CON. Previous studies in myocytes from whole ventricle have also demonstrated prolonged TPK Ca2+ transient in STZ-induced diabetic rat.[26],[29],[30],[31] It has also been previously reported that after 3 months of STZ treatment TPK Ca2+ transient was only prolonged in ENDO-STZ and not in EPI-STZ myocytes compared to respective controls.[21] It was interesting to note that TPK Ca2+ transient was also prolonged in ENDO-STZ compared to EPI-STZ and in ENDO-CON compared to EPI-CON suggesting regional differences in kinetics of the Ca2+ transient within control and diabetic hearts. THALF decay of the Ca2+ transient was only prolonged in ENDO-STZ compared to ENDO-CON myocytes. Previous studies have demonstrated prolonged THALF Ca2+ transient in myocytes from whole ventricle and ENDO-STZ compared to ENDO-CON myocytes after 3 months of STZ treatment.[21],[28],[32] Although the kinetics of the Ca2+ transient were altered the amplitude of contraction was not altered in EPI and ENDO myocytes from diabetic rat compared to respective controls and this was also previously the case after 3 months of STZ treatment.[21]

Fractional release of Ca2+ was increased in ENDO-STZ compared to ENDO-CON and in ENDO-STZ compared to EPI-STZ. The fractional release of Ca2+ provides a measure of the amount of Ca2+ that is released during electrical stimulation compared to the amount that is releasable during application of caffeine. The results suggest that the fractional release of Ca2+ is larger in ENDO-STZ and is not altered in EPI-STZ compared to respective controls. Previously, it has been reported that after 3 months of STZ treatment, fractional release was reduced in EPI-STZ and not altered in ENDO-STZ compared to respective controls.[21] These results provide further evidence of changes in Ca2+ handling with the duration of DM. The amplitude of the caffeine-evoked Ca2+ transient and area under the curve of the caffeine-evoked Ca2+ transient were not altered in EPI and ENDO myocytes from diabetic heart compared to respective controls. Suggesting that the changed fractional release is more likely to be associated with the generation of the electrically-evoked Ca2+ transient.

Ca2+ transient recovery was prolonged in ENDO-STZ compared to ENDO-CON. During caffeine application, there was a rapid rise in intracellular (Ca2+) as Ca2+ was released from the SR. This was followed, under the continued presence of caffeine, by a fall in Ca2+ to resting levels, as Ca2+ was extruded from the cell, primarily through the Na+/Ca2+ exchanger. When caffeine was stopped and electrical stimulation was restarted, the L-Type Ca2+ channels were activated allowing Ca2+ to re-enter the cell and refill the SR. Over several beats, the amplitude of the Ca2+ transient was restored. Regional defects in L-Type Ca2+ current, Na+/Ca2+ exchange current or SR Ca2+ ATPase activity may underlie the prolonged recovery of the Ca2+ transient in ENDO-STZ myocytes.[33],[34],[35],[36] It has been previously reported that there were no alterations in Ca2+ transient recovery in EPI and ENDO myocytes from STZ compared to respective controls after 3 months of STZ treatment.[21]

Myofilament sensitivity to Ca2+ was unaltered in EPI and ENDO myocytes from STZ compared to respective controls. Previous studies have also reported no alterations in myofilament sensitivity to Ca2+ in myocytes from whole ventricle of STZ-induced diabetic rat.[37] These data suggest that myofilament sensitivity is unaltered in the STZ-induced diabetic rat.


  Conclusion Top


The kinetics of contraction and Ca2+ transient and fractional release of Ca2+ from the SR are altered to different extents in EPI and ENDO myocytes from STZ-induced diabetic rat.

Acknowledgement

The work was supported by grants from the College of Medicine and Health Sciences, United Arab Emirates University, Al Ain; Sheikh Hamdan Bin Rashid Al Maktoum Award, Dubai; Zayed University, Abu Dhabi and funding from the Al Ain Equestrian, Shooting and Golf Club.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Julien J. Cardiac complications in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:123-30.  Back to cited text no. 1
    
2.
Giménez M, López JJ, Castell C, Conget I. Hypoglycaemia and cardiovascular disease in type 1 diabetes. Results from the Catalan National Public Health Registry on insulin pump therapy. Diabetes Res Clin Pract 2012;96:e23-5.  Back to cited text no. 2
    
3.
Eeg-Olofsson K, Cederholm J, Nilsson PM, Zethelius B, Svensson AM, Gudbjörnsdóttir S, et al. Glycemic control and cardiovascular disease in 7,454 patients with type 1 diabetes: An observational study from the Swedish National Diabetes Register (NDR). Diabetes Care 2010;33:1640-6.  Back to cited text no. 3
    
4.
Jensen MT, Sogaard P, Andersen HU, Gustafsson I, Bech J, Hansen TF, et al. Early myocardial impairment in type 1 diabetes patients without known heart disease assessed with tissue doppler echocardiography: The Thousand & 1 study. Diab Vasc Dis Res 2016;13:260-7.  Back to cited text no. 4
    
5.
Brunvand L, Fugelseth D, Stensaeth KH, Dahl-Jørgensen K, Margeirsdottir HD. Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study. BMC Cardiovasc Disord 2016;16:103.  Back to cited text no. 5
    
6.
Walker AM, Patel PA, Rajwani A, Groves D, Denby C, Kearney L, et al. Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction. Diab Vasc Dis Res 2016;13:331-40.  Back to cited text no. 6
    
7.
Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood) 2012;237:481-90.  Back to cited text no. 7
    
8.
Cheţa D. Animal models of type I (insulin-dependent) diabetes mellitus. J Pediatr Endocrinol Metab 1998;11:11-9.  Back to cited text no. 8
    
9.
Shao CH, Wehrens XH, Wyatt TA, Parbhu S, Rozanski GJ, Patel KP, et al. Exercise training during diabetes attenuates cardiac ryanodine receptor dysregulation. J Appl Physiol (1985) 2009;106:1280-92.  Back to cited text no. 9
    
10.
Shao CH, Rozanski GJ, Patel KP, Bidasee KR. Dyssynchronous (non-uniform) Ca2+release in myocytes from streptozotocin-induced diabetic rats. J Mol Cell Cardiol 2007;42:234-46.  Back to cited text no. 10
    
11.
Cheng YS, Dai DZ, Dai Y, Zhu DD, Liu BC. Exogenous hydrogen sulphide ameliorates diabetic cardiomyopathy in rats by reversing disordered calcium-handling system in sarcoplasmic reticulum. J Pharm Pharmacol 2016;68:379-88.  Back to cited text no. 11
    
12.
Afzal N, Ganguly PK, Dhalla KS, Pierce GN, Singal PK, Dhalla NS, et al. Beneficial effects of verapamil in diabetic cardiomyopathy. Diabetes 1988;37:936-42.  Back to cited text no. 12
    
13.
Howarth FC, Adem A, Adeghate EA, Al Ali NA, Al Bastaki AM, Sorour FR, et al. Distribution of atrial natriuretic peptide and its effects on contraction and intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rat. Peptides 2005;26:691-700.  Back to cited text no. 13
    
14.
Rithalia A, Qureshi MA, Howarth FC, Harrison SM. Effects of halothane on contraction and intracellular calcium in ventricular myocytes from streptozotocin-induced diabetic rats. Br J Anaesth 2004;92:246-53.  Back to cited text no. 14
    
15.
Wold LE, Relling DP, Colligan PB, Scott GI, Hintz KK, Ren BH, et al. Characterization of contractile function in diabetic hypertensive cardiomyopathy in adult rat ventricular myocytes. J Mol Cell Cardiol 2001;33:1719-26.  Back to cited text no. 15
    
16.
Moore CJ, Shao CH, Nagai R, Kutty S, Singh J, Bidasee KR, et al. Malondialdehyde and 4-hydroxynonenal adducts are not formed on cardiac ryanodine receptor (RyR2) and sarco (endo) plasmic reticulum Ca2+-ATPase (SERCA2) in diabetes. Mol Cell Biochem 2013;376:121-35.  Back to cited text no. 16
    
17.
Lacombe VA, Viatchenko-Karpinski S, Terentyev D, Sridhar A, Emani S, Bonagura JD, et al. Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol 2007;293:R1787-97.  Back to cited text no. 17
    
18.
Campbell SG, Flaim SN, Leem CH, McCulloch AD. Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model. Philos Trans A Math Phys Eng Sci 2008;366:3361-80.  Back to cited text no. 18
    
19.
Campbell SG, Howard E, Aguado-Sierra J, Coppola BA, Omens JH, Mulligan LJ, et al. Effect of transmurally heterogeneous myocyte excitation-contraction coupling on canine left ventricular electromechanics. Exp Physiol 2009;94:541-52.  Back to cited text no. 19
    
20.
Haynes P, Nava KE, Lawson BA, Chung CS, Mitov MI, Campbell SG, et al. Transmural heterogeneity of cellular level power output is reduced in human heart failure. J Mol Cell Cardiol 2014;72:1-8.  Back to cited text no. 20
    
21.
Smail MM, Qureshi MA, Shmygol A, Oz M, Singh J, Sydorenko V, et al. Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle. Physiol Rep 2016;4. pii: e13034.  Back to cited text no. 21
    
22.
Levi AJ, Hancox JC, Howarth FC, Croker J, Vinnicombe J. A method for making rapid changes of superfusate whilst maintaining temperature at 37 degrees C. Pflugers Arch 1996;432:930-7.  Back to cited text no. 22
    
23.
Salem KA, Sydorenko V, Qureshi M, Oz M, Howarth FC. Effects of pioglitazone on ventricular myocyte shortening and Ca(2+) transport in the Goto-Kakizaki type 2 diabetic rat. Physiol Res 2018;67:57-68.  Back to cited text no. 23
    
24.
Spurgeon HA, Stern MD, Baartz G, Raffaeli S, Hansford RG, Talo A, et al. Simultaneous measurement of Ca2+, contraction, and potential in cardiac myocytes. Am J Physiol 1990;258:H574-86.  Back to cited text no. 24
    
25.
Spurgeon HA, duBell WH, Stern MD, Sollott SJ, Ziman BD, Silverman HS, et al. Cytosolic calcium and myofilaments in single rat cardiac myocytes achieve a dynamic equilibrium during twitch relaxation. J Physiol 1992;447:83-102.  Back to cited text no. 25
    
26.
Howarth FC, Almugaddum FA, Qureshi MA, Ljubisavljevic M. The effects of heavy long-term exercise on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rat. J Diabetes Complications 2010;24:278-85.  Back to cited text no. 26
    
27.
da Silva MF, Natali AJ, da Silva E, Gomes GJ, Teodoro BG, Cunha DN, et al. Attenuation of Ca2+ homeostasis, oxidative stress, and mitochondrial dysfunctions in diabetic rat heart: Insulin therapy or aerobic exercise? J Appl Physiol (1985) 2015;119:148-56.  Back to cited text no. 27
    
28.
Ren J, Walsh MF, Hamaty M, Sowers JR, Brown RA. Altered inotropic response to IGF-I in diabetic rat heart: Influence of intracellular Ca2+ and NO. Am J Physiol 1998;275:H823-30.  Back to cited text no. 28
    
29.
Howarth FC, Almugaddum FA, Qureshi MA, Ljubisavljevic M. Effects of varying intensity exercise on shortening and intracellular calcium in ventricular myocytes from streptozotocin (STZ)-induced diabetic rats. Mol Cell Biochem 2008;317:161-7.  Back to cited text no. 29
    
30.
Okatan EN, Tuncay E, Turan B. Cardioprotective effect of selenium via modulation of cardiac ryanodine receptor calcium release channels in diabetic rat cardiomyocytes through thioredoxin system. J Nutr Biochem 2013;24:2110-8.  Back to cited text no. 30
    
31.
Yaras N, Ugur M, Ozdemir S, Gurdal H, Purali N, Lacampagne A, et al. Effects of diabetes on ryanodine receptor ca release channel (RyR2) and Ca2+ homeostasis in rat heart. Diabetes 2005;54:3082-8.  Back to cited text no. 31
    
32.
Tian C, Shao CH, Moore CJ, Kutty S, Walseth T, DeSouza C, et al. Gain of function of cardiac ryanodine receptor in a rat model of type 1 diabetes. Cardiovasc Res 2011;91:300-9.  Back to cited text no. 32
    
33.
Chattou S, Diacono J, Feuvray D. Decrease in sodium-calcium exchange and calcium currents in diabetic rat ventricular myocytes. Acta Physiol Scand 1999;166:137-44.  Back to cited text no. 33
    
34.
Bracken N, Howarth FC, Singh J. Effects of streptozotocin-induced diabetes on contraction and calcium transport in rat ventricular cardiomyocytes. Ann N Y Acad Sci 2006;1084:208-22.  Back to cited text no. 34
    
35.
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:H1288-96.  Back to cited text no. 35
    
36.
Hattori Y, Matsuda N, Kimura J, Ishitani T, Tamada A, Gando S, et al. Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: Implication in Ca2+overload. J Physiol 2000;527(Pt 1):85-94.  Back to cited text no. 36
    
37.
Hamouda NN, Sydorenko V, Qureshi MA, Alkaabi JM, Oz M, Howarth FC, et al. Dapagliflozin reduces the amplitude of shortening and Ca(2+) transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem 2015;400:57-68.  Back to cited text no. 37
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed68    
    Printed5    
    Emailed0    
    PDF Downloaded13    
    Comments [Add]    

Recommend this journal