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Selected Publication:
Bracic, T.
Cellular effects of the soluble guanylate cyclase stimulator (sGC) BAY 41-8543 in a model of heart failure with preserved ejection fraction (HFPEF)
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2016. pp. 75
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- Authors Med Uni Graz:
- Advisor:
- Heinzel Frank
- Primessnig Uwe
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- Abstract:
- Background: The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing yearly with most of common therapeutic strategies for HF being ineffective. The NO-sGC-cGMP pathway is an important regulator of intracellular processes in cardiomyocytes and has a negative effect on contractility, accelerates relaxation and improves the stiffness of cardiomyocytes. Its activity is reduced in HFpEF, therefore it may present a possible therapeutic target. We used the sGC stimulator BAY 41-8543 to test its cellular effects in a rat model of HFpEF. Methods: Young male Wistar rats (250 – 275 grams) were subjected to either a subtotal nephrectomy (NXT) or sham operation (SOP). After 8 weeks, the animals started receiving 0,3mg/kg of sGC twice per day orally. After 16 weeks of treatment, the animals were sacrificed and the left ventricular cardiomyocytes were enzymatically isolated. For calcium measurements the fluorescent dye Fura-2 AM and a ratiometric setup with an inverted microscope and a CCD camera, which was also able to record cellular shortening under stimulation, was utilized. The cells were electrically stimulated and perfused with 1mM Ca2+ tyrode solution. For the measurements of the SR storage a 20 mM caffeine solution was used. Recordings of contraction and calcium transients were analyzed for amplitude, time to peek (TTP) and early and late relaxation (RT50, RT90). Furthermore, SR content (F/F0) and decay of the caffeine transient (TAU) were studied. Results: Gathered data from 20 animals was used. In the SOP vs. NXT group, cell shortening amplitude and TTP demonstrated no difference, whereas early and late relaxation time was significantly prolonged (p < 0.05). Amplitude and TTP of the Ca2+-transients also showed no changes, while the RT50 and RT90 were again prolonged (p < 0.05). SR Ca2+ content was decreased and TAU prolonged. Treatment with BAY 41-8543 significantly enhanced cell shortening amplitude (p < 0.05) and showed a tendency to improve RT50 (p = 0.07). Amplitude of Ca2+-transients was enhanced (p < 0.05) and a trend to improve RT50 (p = 0.08) was observed. Furthermore, SR Content was significantly increased (p < 0.05). Conclusion: Treatment with BAY 41-8543 enhanced the cell shortening amplitude, improved the amplitude of the calcium transients and demonstrated a tendency towards accelerating early relaxation. Furthermore, the therapy increased the SR Ca2+ content.