Dantrolene suppresses spontaneous Ca²⁺release without altering excitation-contraction coupling in cardiomyocytes of aged mice

Abstract

Cardiac dysfunction in the aged heart reflects abnormalities in cardiomyocyte Ca(2+) homeostasis including altered Ca(2+) cycling through the sarcoplasmic reticulum (SR). The ryanodine receptor antagonist dantrolene exerts antiarrhythmic effects by preventing spontaneous diastolic Ca(2+) release from the SR. We tested the hypothesis that dantrolene prevents spontaneous Ca(2+) release without altering excitation-contraction coupling in aged myocardium. Left ventricular cardiomyocytes isolated from young (3 to 4 mo) and aged (24-26 mo) C57BL/6 mice were loaded with the Ca(2+) indicator fluo-4. Amplitudes of action potential-induced Ca(2+) transients at 1-Hz pacing were similar between young and aged mice, yet cell shortening was impaired in aged mice. Isoproterenol (1 μM) increased Ca(2+) transient amplitude and cell shortening to identical levels in young and aged; dantrolene (1 μM) had no effect on Ca(2+) transients or cell shortening during pacing. Under Ca(2+) overload conditions induced with 10 mM extracellular Ca(2+) concentration, spontaneous Ca(2+) waves were of diminished amplitude and associated with lower SR Ca(2+) content in aged versus young mice. Despite no effect in young mice, dantrolene increased SR Ca(2+) content and Ca(2+) wave amplitude in aged mice. In the presence of isoproterenol following rest from 1-Hz pacing, Ca(2+) spark frequency was elevated in aged mice, yet the time to spontaneous Ca(2+) wave was similar between young and aged mice; dantrolene decreased Ca(2+) spark frequency and prolonged the time to Ca(2+) wave onset in aged mice with no effect in young mice. Thus dantrolene attenuates diastolic Ca(2+) release in the aged murine heart that may prove useful in preventing cardiac dysfunction.

Role of S100A1 in hypoxia-induced inflammatory response in cardiomyocytes via TLR4/ROS/NF-κB pathway

“…Cardiac dysfunction in the aged heart reflects abnormalities in myocardial ischaemia‐induced myocardial dysfunction [21]. The myocardial hypoxia‐induced oxidant strees and inflammatory responses, leading to heart injury [22].…”

Cardiomyocyte Ca 2+ homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction

“…As with HFpEF patients, these conditions associate with chronic inflammation and oxidative stress. Consistent with an extramyocardial origin of HFpEF, the amplitude of cardiomyocyte Ca 2+ transients in many HFpEF-related models is normal [15–18] or even enhanced [19–21], suggesting an adaptive phase where Ca 2+ flux shifts toward cardiomyocyte Ca 2+ accumulation [22]. Indeed, excessive Ca 2+ entry though Ca V1.2 [19] and non-selective cation channels of the transient receptor potential (TRP) family [23–25] has been observed with hypertrophic remodeling.…”

“…Indeed, excessive Ca 2+ entry though Ca V1.2 [19] and non-selective cation channels of the transient receptor potential (TRP) family [23–25] has been observed with hypertrophic remodeling. SR Ca 2+ release through RyR 2 [15,16,21,26] and IP 3 R 2 [20] is also increased in HFpEF-related models which further enhances Ca 2+ cycling and contraction. In addition to effects on ECC, augmented Ca 2+ entry through TRPC channels [24,27,28] or release via IP 3 R 2 [29] are established upstream regulators of hypertrophic remodeling processes.…”

Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model

“…Previous studies have shown that spontaneous Ca 2+ release events of aged cardiomyocytes are delayed in response to dantrolene treatment however this effect is not observed in cardiomyocytes derived from young mice [ 24 ]. Since 1 μM dantrolene supplementation improved functional recovery in young hearts, we tested whether dantrolene-mediated cardiac functional recovery could be further improved after prolonged cold storage of older hearts.…”

“…It has been proposed that dantrolene can preferentially access the RyR2 binding site when the interdomain interactions are disrupted under conditions of cellular stress [ 6 ] such as with ageing. Indeed, dantrolene corrected for calcium-induced dysfunction in aged cardiomyocytes more so than in young cardiomyocytes [ 24 ] suggesting that dantrolene-mediated cardioprotection may be more prominent in hearts from older donors. In our study the cardioprotective benefit of 1 μM dantrolene-supplementation in 3-month hearts was not statistically significant for 12-month hearts.…”