Abstract
This study aimed to explore the potential contribution of myofibrils to contractile dysfunction in Ca2+-paradox hearts. Isolated rat hearts were perfused with Krebs–Henseleit solution (Control), followed by Ca2+-depletion, and then Ca2+-repletion after Ca2+-depletion (Ca2+-paradox) by Langendorff method. During heart perfusion left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of pressure development (+ dP/dt), and pressure decay (-dP/dt) were registered. Control LVDP (127.4 ± 6.1 mmHg) was reduced during Ca2+-depletion (9.8 ± 1.3 mmHg) and Ca2+-paradox (12.9 ± 1.3 mmHg) with similar decline in +dP/dt and –dP/dt. LVEDP was increased in both Ca2+-depletion and Ca2+-paradox. Compared to Control, myofibrillar Ca2+-stimulated ATPase activity was decreased in the Ca2+-depletion group (12.08 ± 0.57 vs. 8.13 ± 0.19 µmol Pi/mg protein/h), besides unvarying Mg2+ ATPase activity, while upon Ca2+-paradox myofibrillar Ca2+-stimulated ATPase activity was decreased (12.08 ± 0.57 vs. 8.40 ± 0.22 µmol Pi/mg protein/h), but Mg2+ ATPase activity was increased (3.20 ± 0.25 vs. 7.21 ± 0.36 µmol Pi/mg protein/h). In force measurements of isolated cardiomyocytes at saturating [Ca2+], Ca2+-depleted cells had lower rate constant of force redevelopment (ktr,max, 3.85 ± 0.21) and unchanged active tension, while those in Ca2+-paradox produced lower active tension (12.12 ± 3.19 kN/m2) and ktr,max (3.21 ± 23) than cells of Control group (25.07 ± 3.51 and 4.61 ± 22 kN/m2, respectively). In biochemical assays, α-myosin heavy chain and cardiac troponin T presented progressive degradation during Ca2+-depletion and Ca2+-paradox. Our results suggest that contractile impairment in Ca2+-paradox partially resides in deranged sarcomeric function and compromised myofibrillar ATPase activity as a result of myofilament protein degradation, such as α-myosin heavy chain and cardiac troponin T. Impaired relaxation seen in Ca2+-paradoxical hearts is apparently not related to titin, rather explained by the altered myofibrillar ATPase activity.
Highlights
When a physiologically perfused isolated heart is perfused for a short period of time with a C a2+ free, otherwise normal Krebs–Henseleit buffer, and with buffer ensuring again physiological [Ca2+], the heart rapidly deteriorates
Our results suggest that contractile impairment in Ca2+-paradox partially resides in deranged sarcomeric function and compromised myofibrillar ATPase activity as a result of myofilament protein degradation, such as α-myosin heavy chain and cardiac troponin T
Since cell-to-cell detachment is a necessary step in this phenomenon, isolated cardiomyocytes are thought to avert C a2+-paradox [12, 13]
Summary
When a physiologically perfused isolated heart is perfused for a short period of time with a C a2+ free, otherwise normal Krebs–Henseleit buffer, and with buffer ensuring again physiological [Ca2+], the heart rapidly deteriorates. Ca2+-repletion results in excessive Ca2+ entry with reverse mode of Na+/Ca2+ exchanger and transient receptor potential channels [14], as well as through non-specific transmembrane influx [9], sarcolemmal disruption [15] with insufficient sarcolemmal Ca2+-activated and Mg2+ ATPase unable to extrude Ca2+ [16], injured microsomal fraction attended with depressed Ca2+-activated and Mg2+ ATPase activity, and Ca2+ binding of the sarcoplasmic reticulum [17], collectively provoking intracellular Ca2+-overload, leading to extensive perturbations of intracellular Ca2+ handling It has not been elucidated yet whether sarcomere disruption and myofilament damage contribute to the contractile failure in Ca2+-paradox. Despite Ca2+-paradox has not been a hot topic lately, recent scientific efforts apparently still have been able to provide new insights into the mechanism of Ca2+-overload-induced changes
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