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Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.

ABSTRACT: Ranolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran.To elucidate the mechanism(s) whereby Ran alters cardiac action potentials (APs) and cytosolic Ca(2+)transients and suppresses EADs and TdP in LQT2.The known effects of Ran were included in simulations (Shannon and Mahajan models) of rabbit ventricular APs and Ca(2+)transients in control and LQT2 models and compared with experimental optical mapping data from Langendorff rabbit hearts treated with E4031 (0.5 ?M) to block the rapid delayed rectifying K(+)current. Direct effects of Ran on cardiac ryanodine receptors (RyR2) were investigated in single channels and changes in Ca(2+)-dependent high-affinity ryanodine binding.Ran (10 ?M) alone prolonged action potential durations (206 ± 4.6 to 240 ± 7.8 ms; P <0.05); E4031 prolonged action potential durations (204 ± 6 to 546 ± 35 ms; P <0.05) and elicited EADs and TdP that were suppressed by Ran (10 ?M; n = 7 of 7 hearts). Simulations (Shannon but not Mahajan model) closely reproduced experimental data except for EAD suppression by Ran. Ran reduced open probability (P(o)) of RyR2 (half maximal inhibitory concentration = 10 ± 3 ?M; n = 7) in bilayers and shifted half maximal effective concentration for Ca(2+)-dependent ryanodine binding from 0.42 ± 0.02 to 0.64 ± 0.02 ?M with 30 ?M Ran.Ran reduces P(o) of RyR2, desensitizes Ca(2+)-dependent RyR2 activation, and inhibits Ca(i) oscillations, which represents a novel mechanism for its suppression of EADs and TdP.

SUBMITTER: Parikh A

PROVIDER: S-EPMC3335957 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.

Parikh Ashish A Mantravadi Rajkumar R Kozhevnikov Dmitry D Roche Michael A MA Ye Yanping Y Owen Laura J LJ Puglisi Jose Luis JL Abramson Jonathan J JJ Salama Guy G

Heart rhythm 20120111 6

<h4>Background</h4>Ranolazine (Ran) is known to inhibit multiple targets, including the late Na(+)current, the rapid delayed rectifying K(+)current, the L-type Ca(2+)current, and fatty acid metabolism. Functionally, Ran suppresses early afterdepolarization (EADs) and torsades de pointes (TdP) in drug-induced long QT type 2 (LQT2) presumably by decreasing intracellular [Na(+)](i) and Ca(2+)overload. However, simulations of EADs in LQT2 failed to predict their suppression by Ran.<h4>Objective</h4> ...[more]

PMID: 22245792

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Project description:Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-β estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Dataset Information

Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.

Publications

Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.

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