Cellular mechanism of contractile dysfunction in diabetes-induced cardiomyopathy

Qureshi, Muhammad Anwar (2003) Cellular mechanism of contractile dysfunction in diabetes-induced cardiomyopathy. Masters thesis, University of Central Lancashire.

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This study investigated the cellular mechanism(s) that underlying contractile dysfunction in the streptozotocin-induced (type 1) diabetic cardiomyopathy compared to age-matched control heart. Human and animal studies have shown that diabetes mellitus can be associated with altered cardiac function that is independent of vascular complications. The effects of
increased extracellular (hyperosmotic) osmolarity on the contractility of ventricular myocytes in STZ-treated rat were also investigated compared to control. Diabetes was induced in male Wistar rats by a single i.p. injection of STZ (60mg kg', body weight) which, resulted in an experimental model of type I diabetes that was characterised by hyperglycaemia,
hypoinsulinaemia, hyperosmolarity, glucosuria and decreased in heart and body weights.
Total calcium and magnesium contents , but not sodium, were significantly (P<0.05) increased in the STZ-induced diabetic heart compared to age-matched controls. Contraction was measured in electrically stimulated single ventricular cardiomyocyte using a video-edge detector and results showed that the amplitude of contraction as a percentage of resting cell length (RCL) was significantly (P<0.01) increased in STZ-induced diabetic myocytes (6.8 ± 0.5 %, n30) as compared to age-matched control (4.1 ± 1.04 %, n=27) following 2 and 10 months of STZ-treatment. Moreover, afler 2 months of STZ-treatment the tpk contmaion was significantly (P<0.01) longer in diabetic myocytes (164.1 ± 7.4, n= 30) as compared to agematched controls myocytes (132.3 ± 5.9, n= 28). However, after 10 months of STZ-treatment tpk contmaion (134.2 ± 4.6, n=37) appeared to be normalize towards controls (133.1 ± 5.5, n=35). lit contrast, t12 relaxation was not significantly altered at 2 months of STZ-treatment (60.6 ± 4.1, n=30 Vs. 70.6 ± 5.6, n=28) compared to age-matched control, respectively, but became significantly shorter in STZ-diabetic (55.3 ± 2.7, n37, Vs. 85.1 ± 7.1, n=30) rat myocytes compared to age-matched control, respectively.
Superfusion of myocytes with HT (high osmolarity) caused alterations in both the amplitude and time course of shortening in myocytes from STZ-treated and age-matched control rats. Resting cell length was significantly decreased on exposure to HT and returned towards normal upon wash. Amplitude of shortening was significantly reduced in myocytes from STZ-treated and age-matched control rats after either 1 or 5 min HT. However, the differences in basal contractility and in the response to HT were not significantly altered by STZ treatment. Mean tpk shortening was significantly increased in myocytes from STZ-treated rats compared to controls in NT and was significantly increased in myocytes from STZtreated rats after either 1 or 5 min HT. Mean t'/, relaxation was significantly increased in myocytes from STZ-treated compared to age-matched control rats after either I or 5 min HT.
The magnitude of the increases in tpk contraction, and t,4 relaxation were not significantly different between STZ and control myocytes. The results show that changes in contraction upon exposure to HT were not altered by diabetes. Since contraction is ultimately dependent on cytosolic Ca 2 , it was relevant to measure free intracellular Ca 2 concentrations ([Ca2']) using the fluorescent dye fura-2. Intracellular Ca2 ([Ca2i) transients were measured in cells superfused with normal tyrode (NT, 300 mmol/kg) and then hyperosmotic (HT, 440 mmol/kg) at 35-36 0C. Shrinking significantly increased Ca 2 transient both in control and STZ-treated myocytes. Time to peak (tpk) Ca2 transient was (70.8 ms) in STZ-treated myocyte as compared to (44.6 ms) agematched control. Shrinking increased fractional SR Ca 2 release, assessed by the application
of caffeine. However, the effect of raised extracellular osmolarity on contractility and [Ca 2 ]1 were not altered by chronic hyperglycaemia found in STZ-treated rats.
This study also investigated morphological changes in the heart to determine whether progressive ultrastructure defects might underlying the contractile dysfunction observed in diabetic myocytes. The ultrastructure studies were performed in papillary or ventricular muscle from heart at 4 or 8 months of STZ-treatment compared to age-matched controls. The
electron microscopy results of cardiac muscle showed that the ultrastructure of cardiac muscle, especially associated with contraction, were not greatly altered after STZ-treatment. Sarcomere lengths were not significantly different in papillary or ventricular muscle at 4 or 8 months after STZ-treatment compared to age-matched control. Hence, our data support the
evidence that morphological defects in contractile myofilament and associated structures cannot explain contractile dysfunctions seen in ventricular myocytes from STZ-treated animals.
In conclusion the amplitude of contraction in diabetic myocytes was more pronounced compared to age-matched control. It is suggested that basal Ca 2 in the diabetic heart coupled with increases in Ca2+ influx through Na+/C 2a± -e xchanger, overcompensate for the reduction in trigger Ca2 through voltage sensitive Ca 2 channels, leading to an increase amplitude of contraction and increase myofilaments sensitivity in the diabetic heart. The significant reduction in the rate of C2 uptake into the SR and Ca 2 efflux through Na/Ca 2texchanger result in longer decays of Ca 2 transient during diastole in the diabetic heart.

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